Multiple Sclerosis References 2003; Authors: C
(50 References)
Caillier, S., L. F. Barcellos, et al. (2003). "Osteopontin polymorphisms and disease course in multiple sclerosis." Genes Immun 4(4): 312-5.
Osteopontin (OPN), also known as early T-cell activating gene (Eta-1), has been recently shown to be a critical factor in the progression of experimental autoimmune encephalomyelitis, and perhaps multiple sclerosis (MS). Here we investigated whether the 327T/C, 795C/T, 1128A/G or 1284A/C single-nucleotide polymorphisms in the OPN gene were correlated with susceptibility or any of the several clinical end points in a cohort of 821 MS patients. Overall, we observed no evidence of genetic association between the OPN polymorphisms and MS. Although not reaching statistical significance, a modest trend for association with disease course was detected in patients carrying at least one wild-type 1284A allele, suggesting an effect on disease course. Patients with this genotype were less likely to have a mild disease course and were at increased risk for a secondary-progressive clinical type.Genes and Immunity (2003) 4, 312-315. doi:10.1038/sj.gene.6363952
Cannella, B., S. Gaupp, et al. (2003). "Differential efficacy of a synthetic antagonist of VLA-4 during the course of chronic relapsing experimental autoimmune encephalomyelitis." J Neurosci Res 71(3): 407-16.
The integrin VLA-4 has been shown to play a key role in the entry of antigen-specific T cells into the CNS during autoimmune demyelination. Treatment of animals with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, with antibodies to VLA-4 is known to suppress acute disease. In the present study, a synthetic antagonist of VLA-4 (TBC 3486) was injected subcutaneously into mice adoptively sensitized for chronic relapsing EAE. TBC 3486 was administered daily for 14 days at early (before acute signs) and late time points (during chronic disease). Early treatment led to marked delay in disease onset and reduction in clinical severity and demyelination. After termination of treatment, clinical severity remained lower than in controls for more than 1 week. TBC 3486-treated animals showing no clinical signs (at the height of disease in controls) displayed moderate levels of inflammation but little damage to myelin. Late administration of TBC 3486 to animals with chronic EAE had no effect clinically. Immunocytochemistry and Western blotting of CNS tissue from acutely treated animals supported a moderate shift toward a Th2-type cytokine profile after treatment. Thus, TBC 3486 effectively delayed and reduced the acute (but not chronic) phase of EAE, and this amelioration correlated with changes in the inflammatory molecule profile.
Cao, M. D. and B. G. Xiao (2003). "Influence of gamma irradiation on phenotype and function of human dendritic cells in vitro." Zhongguo Shi Yan Xue Ye Xue Za Zhi 11(3): 282-6.
To determine whether gamma irradiation influences phenotype and function of human dendritic cells (DC) in vitro, dendritic cells were induced from the peripheral blood mononuclear cells of multiple sclerosis patients with RPMI 1640 medium containing recombinant human GM-CSF (rhGM-CSF, 800 U/ml) and recombinant human IL-4 (rhIL-4, 500 U/ml). Phenotypic changes were monitored by light microscopy. Lipopolysaccharide at a concentration of 5 micro g/ml was added into the cultures after 6 days of growth for DC complete maturation, and the cells were cultured for another 24 hours. The harvested DC on day 7 were divided equally into several parts. One part was used as non-irradiated DC (naive DC) while the other parts were irradiated by gamma ray at a dose of 25 Gy and 30 Gy respectively. Cell surface molecules were analyzed by flow cytometry. The capability of DC to stimulated autologous T cell proliferation were determined. The results showed that gamma irradiation reduced expression of CD86, CD80 and HLA-DR molecules on dendritic cells, especially CD86 molecules. Dendritic cells effectively stimulated autologous T cells proliferation while irradiated DC in all groups showed profound decrease of capability to promote T cells proliferation. It is concluded that gamma irradiation of dendritic cells not only influenced phenotype of DC but also altered their function as stimulator cells in mixed lymphocyte reaction.
Caon, C., M. Zvartau-Hind, et al. (2003). "Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis." Neurology 60(2): 323-5.
Intercaudate nucleus ratio (ICR) is a linear measure of brain atrophy that does not require software application and is independent of image acquisition techniques. The authors examined the relationship between ICR and disability in 190 patients with MS. The results show that ICR correlates with Expanded Disability Status Scale score (r = 0.67; p = 0.0001) and disease duration (r = 0.32; p < 0.01). Intercaudate ratio appears to be a reliable and reproducible linear measure of brain atrophy and correlates with disability and disease duration in MS.
Carreras, E., A. Saiz, et al. (2003). "CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients." Haematologica 88(3): 306-14.
BACKGROUND AND OBJECTIVES: Autologous stem cell transplantation (ASCT) is currently being evaluated as a therapy for patients with multiple sclerosis (MS). We report the results of a phase II trial to evaluate feasibility and toxicity of CD34+ selected ASCT (CD34+/ASCT) and treatment results at one year of follow-up. DESIGN AND METHODS: Patients with advanced secondary progressive (SP) or relapsing-remitting (RR) MS and confirmed worsening of the extended disability status scale (EDSS) in the previous year despite interferon or other immunotherapies were included. Peripheral blood stem cells were obtained by leukaphereses after mobilization with cyclophosphamide (Cy) and granulocyte colony-stimulating factor (G-CSF). CD34+ selection was performed by means of an Isolex 300 or CliniMACS device. BCNU, Cy and antithymocyte globulin (ATG) were administered as conditioning regimen. RESULTS: Fifteen patients (9 SPMS and 6 RRMS) with a median EDSS of 6.0 (4.5-6.5) and a median of 3 (1-7) relapses in the previous year were included. Mobilization was unsuccessful in one patient. During mobilization, one patient had a transient neurologic deterioration. The main complication during ASCT were engraftment syndrome, which developed in three patients, CMV reactivation in one, and neurologic deterioration in two patients coinciding with high-fever related to ATG. Hematologic recovery was fast and complete in all cases. At 12 months, the EDSS had improved in three patients, worsened in two and remained stable in nine. Despite withdrawal of all immunosuppressive therapy only two patients had relapses. Magnetic resonance imaging showed disappearance of enhanced T1 lesions but oligoclonal bands persisted in the cerebrospinal fluid of all evaluated cases. INTERPRETATION AND CONCLUSIONS: CD34+/ASCT using BCNU, Cy and ATG as conditioning regimen has an acceptable toxicity and clearly reduces the progression of MS. Further follow-up is necessary to establish the real impact of this procedure on the long-term evolution of the disease.
Casanova, B., M. C. Martinez-Bisbal, et al. (2003). "Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study." J Neurol 250(1): 22-8.
OBJECTIVE: Wallerian degeneration in normal appearing white matter in early relapsing-remitting multiple sclerosis (RRMS), and its correlation with the number of relapses and disease duration. Background Recent pathological studies have demonstrated Wallerian degeneration in normal appearing white matter (NAWM) in multiple sclerosis (MS), in established RRMS, and in chronic MS. However, the presence of Wallerian degeneration early in the disease and its correlation with relapse and with disease duration has not been studied. METHODS: We performed proton magnetic resonance spectroscopic imaging in 21 MS patients, and 4 healthy controls, age and gender matched, aged under 45 years, with a maximum of 4 years since first bout, and an EDSS score of less than 3.0. N-acetyl-aspartate (NAA) (an index of axonal integrity) was measured in the NAWM from the pons and the cerebellar peduncles. RESULTS: We observed that the NAA levels were abnormally low in the NAWM in the early RRMS patients (p = 0.04, Student's t-test). The decrease in the NAA concentration correlated with disease duration in the two areas studied (p = 0.03 for pons and p = 0.04 for cerebellar peduncle); and with the number of previous relapses (Pearson's correlation = -0.582, p < 0.002). CONCLUSION: Wallerian degeneration measured by the NAA concentration at pons and cerebellar peduncles is present early in the disease and correlates with the number of relapses and disease duration.
Castriota-Scanderbeg, A., F. Fasano, et al. (2003). "Coefficient D(av) is more sensitive than fractional anisotropy in monitoring progression of irreversible tissue damage in focal nonactive multiple sclerosis lesions." AJNR Am J Neuroradiol 24(4): 663-70.
BACKGROUND AND PURPOSE: Persistently hypointense lesions on T1-weighted MR images have been shown to correlate with the amount of axonal damage and clinical disability in multiple sclerosis (MS) patients. The purpose of this study was to investigate whether diffusion coefficient D(av) and fractional anisotropy (FA) are able to detect quantifiable differences among three groups of focal nonactive multiple sclerosis (MS) lesions that appear qualitatively different on T1-weighted images. METHODS: Conventional and diffusion tensor MR images of the brain were obtained in 18 patients with relapsing remitting (n = 10) or secondary progressive (n=8) MS and in 18 healthy volunteers. Focal nonactive MS lesions were classified as T1 isointense, T1 mildly hypointense, and T1 severely hypointense on unenhanced T1-weighted images. Differences among groups were assessed with one-way analysis of variance using the T1 lesion appearance as the grouping factor and either FA or coefficient D(av) as the dependent measure. RESULTS: FA was lowest and coefficient D(av) was highest in T1 severely hypointense lesions, and then, in ascending and descending order, respectively, T1 mildly hypointense lesions and T1 isointense lesions. A significant difference in the values of FA was detected only between T1 isointense lesions and T1 severely hypointense lesions (P <.01), whereas no difference was found between T1 mildly hypointense lesions and either one of these two groups. A significant difference was found in the values of coefficient D(av) among all investigated lesion groups. Coefficient D(av) was found to correlate inversely with the T1-weighted contrast ratio (r=-0.58, P <.0001), whereas FA and deltaFA (percentage of FA variation in the lesion, a relative FA measure that minimizes the effect of FA spatial dependence) were not. CONCLUSION: Coefficient D(av) is more sensitive than FA to variations in the degree of T1 hypointensity and, thus, in the amount of the permanent brain tissue damage in patients with MS.
Cattaneo, C., C. Almici, et al. (2003). "A case of acute promyelocytic leukaemia following mitoxantrone treatment of multiple sclerosis." Leukemia 17(5): 985-6.
Cazzato, G. and M. Zorzon (2003). "[Clinical surveillance of patients with multiple sclerosis]." Recenti Prog Med 94(4): 173-6.
Clinical management of people with multiple sclerosis (MS) is based not only on the control of side-effects of disease-modifying drugs but also on the recognition and treatment of disease exacerbations, on the evaluation of disease progression and on the management of the wide range of MS symptoms. A multidisciplinary approach is essential to achieve the best results and improve the quality of life of MS patients.
Cazzullo, C. L., D. Trabattoni, et al. (2003). "Research on psychoimmunology." World J Biol Psychiatry 4(3): 119-23.
Several lines of evidence suggest a role for the immune system in the multifactorial pathogenesis of schizophrenia and other psychiatric and neurodegenerative disease. Later, the role of immune mediators like cytokines became a source of main interest related to the process on inflammation in the CSM. In this article we report the results of our research on cytokines in a different groups of psychiatric patients following their clinical symptomatology and the course of diseases. In particular, we observed a prevalent type 1 cytokine profile in acute multiple sclerosis patients, while IL-10 production predominated in stable multiple sclerosis individuals. The modifications of cytokine profiles observed in schizophrenic patients suggests that clinical improvement is associated with a reduction in the inflammatory-like situation present in those not currently under treatment. Our data on Alzheimer's disease (AD) support the role of the inflammatory process in the pathogenesis of AD and reinforce the hypothesis that the neurodegenerative processes in the AD patients are associated with an abnormal antigen-specific immune response. The activation of immune system mechanisms observed in obsessive compulsive disorders could be due to the combination of endogenous (hormonal alterations associated to the modifications in the hypothalamic-pituitary-adrenal axis) and exogenous (viral or bacterial infections) factors.
Cermelli, C., R. Berti, et al. (2003). "High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection." J Infect Dis 187(9): 1377-87.
The frequency of human herpesvirus 6 (HHV-6) DNA was assessed in autopsy material from multiple sclerosis (MS) plaques and normal-appearing white matter (NAWM) from brains of persons with MS, healthy brains, and brains of persons with other neurologic diseases. Specific areas from formalin-fixed, paraffin-embedded brain tissue samples were isolated by laser microscope. DNA was extracted from laser microdissected brain material, and HHV-6 genomic sequences were amplified by nested polymerase chain reaction. We analyzed 44 NAWM samples and 64 MS plaques from 13 patients with MS, 46 samples from 13 patients with non-MS neurologic disorders, and 41 samples from 12 healthy control brains. Of the 44 NAWM samples, 7 (15.9%) were positive for HHV-6 DNA sequences, versus 37 (57.8%) of 64 MS plaques (P<.0005). HHV-6 DNA was detected in 10 (21.7%) of 46 samples from patients with non-MS neurologic disorders and in 11 (26.8%) of 41 samples from patients without known neurologic disease. Although the frequency of HHV-6 DNA did not differ significantly by sample type, HHV-6 DNA was significantly more common in MS plaques, suggesting that HHV-6 may play a role in MS pathogenesis.
Cetta, F. (2003). "[Gastro-enteropathic neuroendocrine tumors in diverse hereditary multiple tumor syndromes of multiple endocrine neoplasms (MEN)]." G Chir 24(1-2): 5-10.
Chadwick, D. and R. Gray (2003). "Shared scheme for assessing drugs for multiple sclerosis: dealing with uncertainties about cost effectiveness of treatments is difficult problem." Bmj 326(7400): 1212-3.
Chancellor, A. M., M. Addidle, et al. (2003). "Multiple sclerosis is more prevalent in northern New Zealand than previously reported." Intern Med J 33(3): 79-83.
BACKGROUND: There have been no studies of multiple sclerosis (MS) prevalence from New Zealand (NZ) in the past two decades, and only one in a northern NZ district. Our impression was that the local prevalence of MS was higher than previously published data would suggest. There is limited access to new treatments for MS in NZ. AIMS: The present paper aims to: (i). measure the prevalence of definite and probable MS in the Bay of Plenty (BOP), a North Island province, (ii). compare this with previous NZ studies, (iii). study the profile of disability in this population-based group and (iv). determine the proportion of MS patients who receive government funding for modern drug treatment (beta-interferons). METHODS: Patients were identified from a geographically and demographically defined area of the North Island of NZ, using multiple sources of case ascertainment and modern diagnostic criteria. All clinical records were reviewed and data were supported by a telephone interview. All patients' eligibility for -government-funded treatment with beta-interferon was considered. RESULTS: Eighty-six patients were identified as residents in BOP, NZ, on 15 January 2001. Excluding 'possible' cases, this represented a prevalence of 50/105 (95% confidence interval 40-62/105). Half of the population-based cohort had a disability defined as 'moderate to severe' (i.e. aids needed to walk, unable to take more than a few steps, or worse). Eleven patients (13%) had a primarily progressive form of MS. Eleven patients (13%) had the relapsing--remitting form of the disease and qualified for -government-funded treatment with beta-interferon. CONCLUSION: The prevalence of MS in the defined region was twice as high as that reported from an adjacent area, the Waikato, 20 years previous. Our data will help to update NZ prevalence statistics and are of direct relevance to current funding issues for modern treatments which, in NZ, are presently limited to a proportion of patients with relapsing- remitting disease.
Chang, C. H., D. L. Nyenhuis, et al. (2003). "Psychometric evaluation of the Chicago Multiscale Depression Inventory in multiple sclerosis patients." Mult Scler 9(2): 160-70.
OBJECTIVE: The Chicago Multiscale Depression Inventory (CMDI), a comprehensive self-report measure of depression, has proven useful in the assessment of patients with chronic medical conditions. The objective of this study was to determine the validity of the CMDI in multiple sclerosis (MS) patients and explore the nature of depressive symptoms reported by people with MS. METHOD: Using a combined classical and modern psychometric approach, the factor structure of responses in MS patients was compared with that of a normative sample to confirm meaningful subtypes of depression in MS (mood, depressive cognition, and vegetative symptoms). Patient groups also were compared by disease severity to evaluate differences in depression associated with differences in disease severity. RESULTS: The results supported the factor structures of the measure, which was internally consistent, reliable, and factorially valid. Some items function differently in MS patients when compared with depressed patients and normals, offering a further opportunity to understand the unique clinical aspects of depression in people with MS compared with those without a concurrent physical illness. CONCLUSIONS: Use of the CMDI to assess separate dimensions of depression may help to clarify the complex interrelationships among aspects of depression and health-related behavior.
Chapenko, S., A. Millers, et al. (2003). "Correlation between HHV-6 reactivation and multiple sclerosis disease activity." J Med Virol 69(1): 111-7.
This study examined the association between HHV-6 infection and multiple sclerosis (MS) and the relationship between HHV-6 reactivation and disease activity. The frequency of HHV-6 genomic sequences in peripheral blood mononuclear cells (PBMCs), the incidence of plasma viremia (nPCR), the transcription of viral mRNA in PBMCs (RT-PCR), the presence of antiviral IgM and IgG class antibodies in the plasma (IFA) of 16 relapsing/remitting and secondary progressive MS patients were studied in comparison with clinical manifestations of the disease, magnetic resonance imaging (MRI) of brain, and serum interleukin (IL)-12 concentrations (ELISA). The prevalence of HHV-6 infection was significantly higher in patients with MS (16/26) than in patients with other neurological diseases (6/21) and in blood donors (43/150). HHV-6 reactivation was found during periods of disease activity with Gadolinium-enhancing lesions on MRI in both relapsing/remitting and secondary progressive MS (10/13; 76.9%). In patients with active MS disease, serum concentrations of IL-12 were significantly higher in those patients with active HHV-6 infection than in patients with latent infection. The data confirm an association between HHV-6 infection and MS and show a correlation between HHV-6 reactivation and disease activity in relapsing/remitting and secondary progressive MS. The risk of an exacerbation of MS was significantly higher (P < 0.005) in patients with active HHV-6 infection than in patients with latent infection. A clear correlation between HHV-6 reactivation and serum IL-12 concentrations during disease activity has been demonstrated. The results suggest that HHV-6 reactivation is implicated in exacerbation of MS, possibly through modulation of IL-12 synthesis.
Chaudhuri, A. and P. O. Behan (2003). "Shared scheme for assessing drugs for multiple sclerosis: why are eyes tightly shut to considering causes other than autoimmunity?" Bmj 326(7400): 1213.
Chaudhuri, A. and P. O. Behan (2003). "Natalizumab for relapsing multiple sclerosis." N Engl J Med 348(16): 1598-9; author reply 1598-9.
Chaudhuri, A. and P. O. Behan (2003). "Mitoxantrone trial in multiple sclerosis." Lancet 361(9363): 1133-4; author reply 1134.
Cheema, J. I., L. E. Grissom, et al. (2003). "Radiographic characteristics of lower-extremity bowing in children." Radiographics 23(4): 871-80.
Lower-extremity bowing is common in infants and children and can result from a variety of conditions. At radiography, developmental bowing shows varus angulation centered at the knee, "metaphyseal beaking," thickening of the medial tibial cortices, and tilted ankle joints. Tibia vara (Blount disease) demonstrates genu varum and depression of the proximal tibia medially. Congenital bowing manifests as posteromedial bowing with cortical thickening along the concavity of the curvature and, in some cases, diaphyseal broadening. In rickets, radiographic changes occur primarily at sites of rapid growth and are predominantly metaphyseal, with widening of the zone of provisional calcification. Achondroplasia is characterized by shortening and thickening of the long bones with metaphyseal flaring and cupping. In neurofibromatosis, there may be anterolateral bowing of the tibia, and there is often focal narrowing and intramedullary sclerosis or cystic change at the apex of the angulation. The tibia is typically involved at the junction of the middle and distal thirds. Osteogenesis imperfecta demonstrates bowing from softening due to osteoporosis and multiple fractures and typically involves the entire skeleton. In camptomelic dysplasia, lower-extremity bowing is associated with a short trunk, short limbs, and deficiencies in pelvic bone development. Recognition of these pathologic conditions is important for differentiating those that will resolve spontaneously from those that require surgery or other treatment.
Cheknev, S. B. (2003). "[Endogenous biological retranslation in current clinical and biological studies]." Vestn Ross Akad Med Nauk(4): 28-34.
The paper generalizes the results of research implemented within the framework of the methodological concept of the Endogenous Biological Retranslation (EBR) for the purpose of finding new data about the immune pathogenesis of multiple sclerosis (MS), whose mechanisms are related with violations of the EBR processes in the body. A possibility is considered to use the priming of interferon (INF) production, as an EBR variant, for evaluating the functioning of the INF system. The thus obtained materials prove convincingly that the experimental approaches, based on priming the blood cells to the IFN production, can be clinically used in the diagnosis and therapy of MS. A new effective combined IFN-therapy scheme for the disease in question was demonstrated. A set of criteria, which makes it possible to prescribe the INF preparations for MS patients with regard for an evaluated response degree of patients' blood cells to them and with regard for a prognosticated efficacy of an assumed treatment is offered. Possibilities of an individualized comprehensive therapy for MS by using the offered experimental approaches are discussed.
Chiaravalloti, N. D., H. Demaree, et al. (2003). "Can the repetition effect maximize learning in multiple sclerosis?" Clin Rehabil 17(1): 58-68.
OBJECTIVE: The 'repetition effect' stipulates that recall ability improves as the number of learning trials that a person receives increases. While the repetition effect has been supported through many empirical investigations in healthy individuals, it has not yet been applied to clinical populations. The present study tested the hypothesis that an increased number of learning trials improves recall ability in persons with a neurological disorder, namely multiple sclerosis (MS). DESIGN: Prospective between-group design with 30-minute, 90-minute and one-week assessments. SETTING: Private, nonprofit, research facility. SUBJECTS: Sixty-four MS subjects; 20 healthy control subjects (HC). INTERVENTIONS: Subjects were given a modified Selective Reminding Test (SRT), a list of 10 words to remember in a selective reminding format. To control for the amount of information initially learned, the learning trials were repeated until the subject recalled all 10 words on two consecutive trials. MAIN OUTCOME MEASURES: SRT word recall and recognition was tested 30 minutes, 90 minutes and one week subsequent to initial acquisition. RESULTS: Interestingly, the antithesis of our hypothesis was found. That is, persons with MS who required more learning trials to reach the perfect learning criterion performed significantly worse on the recall trials. However, this was not the case in a sample of healthy individuals undergoing the same protocol. CONCLUSIONS: These results indicate that individuals with MS may not benefit from repetition in isolation, but rather require the use of more intensive cognitive rehabilitation strategies (i.e., increased organization) to help improve their depth of encoding of new information.
Chilcott, J., C. McCabe, et al. (2003). "Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis." Bmj 326(7388): 522; discussion 522.
OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.
Chitnis, T. and S. J. Khoury (2003). "20. Immunologic neuromuscular disorders." J Allergy Clin Immunol 111(2 Suppl): S659-68.
Immune-mediated disorders of each of the structural subdivisions of the nervous and neuromuscular system have been described. Despite the immune privilege of the central nervous system, and to a lesser extent the peripheral nervous system, immune dysregulation is not uncommon. Environmental, genetic, and immunologic factors have been postulated to be involved in the development of these disorders. Major immune-mediated neurologic diseases of the central nervous system include multiple sclerosis and acute disseminated encephalomyelitis. Immune-mediated diseases of the peripheral nervous system include myasthenia gravis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and inclusion body myositis. Some of these disorders, such as myasthenia gravis and certain forms of acute inflammatory demyelinating polyneuropathy, are clearly autoimmune in nature, whereas the immune system plays an important role in pathogenesis in others. Understanding the immune mechanisms of disease and uncovering potential therapeutic targets are essential for the design of new treatments. The epidemiology, pathogenesis, diagnostic criteria, and current therapeutic approaches to the major neuroimmunologic diseases are reviewed.
Choyke, P. L., G. M. Glenn, et al. (2003). "Hereditary renal cancers." Radiology 226(1): 33-46.
Hereditary renal cancer syndromes can lead to multiple bilateral kidney tumors that occur at a younger age than do nonhereditary renal cancers. Imaging plays an important role in the diagnosis and management of these syndromes. During the past decade, several new hereditary renal syndromes have been discovered but are not yet widely known. Whereas previously, the list of hereditary renal cancers in adults included von Hippel-Lindau disease and a rare form of chromosomal translocation, the list now includes the following syndromes: tuberous sclerosis, hereditary papillary renal cancer, Birt-Hogg-Dube syndrome, hereditary leiomyoma renal cell carcinoma, familial renal oncocytoma, hereditary nonpolyposis colon cancer, and medullary carcinoma of the kidney. In addition, a number of newly described but poorly understood syndromes are under investigation. Even at this early stage, it is clear that elucidation of the underlying genetic mutations that cause hereditary renal cancer syndromes will have profound implications for understanding the origins of nonhereditary renal tumors. These studies will likely culminate in a better understanding of the causes of renal cancer, its prevention, and, ultimately, its cure.
Christensen, T., P. D. Sorensen, et al. (2003). "Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients." Mult Scler 9(1): 6-15.
The human endogenous retrovirus HERV-H is associated with multiple sclerosis (MS). Previously performed reverse transcriptase-polymerase chain reactions (RT-PCR) on virion-RNA demonstrated sequence variants of the HERV-H family located in the particulate fraction of MS patient plasma samples and not in controls. In this study a significantly elevated level of antibodies towards peptides derived from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (CSF) from MS patients is demonstrated. Further, Wistar rats immunized with purified virions develop a specific serologic response, indicating that some virion proteins are encoded by HERV-H-related sequences. Also shown is that in RNA from blood cells, a HERV-H protease-env splice variant can be found together with an env splice variant in about 40% of MS patients but only in 10% of controls. The results substantiate the association between activated HERV-H and MS, but a causal relationship is yet to be demonstrated. HERV-H could represent a causal factor either by eliciting an autoimmune response or through the pathogenic potential of the retrovirus itself.
Christensen, T. and A. Moller-Larsen (2003). "[Human endogenous retroviruses and disease?]." Ugeskr Laeger 165(6): 556-61.
Endogenous retroviruses represent sequences descended from ancient virus infections integrated in the host genome. They participate in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. It has been suggested in recent years that human endogenous retroviruses may play a role in certain types of cancer and autoimmune diseases. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases like systemic lupus erythematosus, Sjogren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple sclerosis is specifically associated with expression of human endogenous retroviruses as virions. It is not yet known if the human endogenous retroviruses also represent causal factors, but several pathogenic mechanisms are possible.
Chutorian, A. M. (2003). "[Acute loss of vision in children]." Rev Neurol 36(1): 264-71.
The differential diagnosis of acute loss of vision in children includes acute loss of vision due to retinal or optic nerve disease, and cortical blindness. The retinal disorders which may be mis diagnosed as optic neuritis include Leber neuroretinitis, Leber hereditary optic neuropathy, and Stargardt macular dystrophy. Retinal changes which evolve in neuroretinitis, and the pseudopapilledema in Leber heredity optic neuropathy are helpful in differentiating these disorders from optic neuritis. Stargardt macular dystrophy, a disorder associated with a variety of mutations, may be mis diagnosed as psychogenic visual loss due to the early normal appearance of the retina, and the loss of vision over a period of weeks. The differentiation of optic neuritis from anterior ischemic optic neuropathy (AION), depends upon the initial appearance of the optic disc (in AION either hyperemia due to reperfusion, or swelling and pallor if total infarction has occurred). The authors have described children with abrupt loss of vision during renal dialysis, whose risk factors for AION included systemic hypotension and intra ocular hypertension. Children with vigorous treatment of accelerated hypertension, and children with migraine and pro thrombotic disorders have also incurred AION. Thus, AION should be suspected when acute loss of vision occurs in association with certain ocular and systemic risk factors. In children capable of cooperating for visual field examination, the typical change in AION is an altitudinal defect, while optic neuritis it is a central scotoma. The association of optic neuritis with multiple sclerosis, DeVic disease, and with acute demyelinating1 encephalomyelitis require special consideration in regard to treatment and prognosis. Acute loss of vision due to cerebral cortical insults involves a large differential diagnosis which includes vascular, metabolic and infective disease; as well as disorders causing transitory blindness such as seizures and migraine
Ciccarelli, O., D. J. Werring, et al. (2003). "A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging--evidence of Wallerian degeneration." J Neurol 250(3): 287-92.
Diffusion tensor imaging (DTI) investigates brain tissue microstructure in vivo. In multiple sclerosis (MS) Wallerian degeneration of axons traversing focal lesions is a potential mechanism of damage in normal-appearing white matter. In vivo evidence for this hypothesis is limited. The present study investigated the relationship between DTI-derived indices in the normal-appearing corpus callosum (CC) and the lesion loads (LLs) in connected cerebral regions. DTI was performed in 39 MS patients and in 21 age-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in the genu, body and splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = -0.56 and r = 0.54, p < 0.0001). The LL of individual cerebral lobes correlated with both FA and MD in the corresponding callosal regions, with the body showing the strongest correlations with frontal and parietal LL (p < 0.0001). The strong correlations between DTI indices in the CC and the extent of lesions in connected brain regions support the hypothesis that Wallerian degeneration of axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS.
Cid, C., J. C. Alvarez-Cermeno, et al. (2003). "Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients." J Neuroimmunol 136(1-2): 119-24.
Neuronal apoptosis has recently been implicated in multiple sclerosis (MS). Apoptotic cell death of neurons is induced in cultures exposed to cerebrospinal fluid (CSF) from MS patients. Since caspases are essential in the regulation of apoptosis, direct evidence was sought linking caspases to CSF-induced neuronal death. Caspase activity was measured in cell extracts from MS CSF-treated cultured neurons by the cleavage of caspase-1 and caspase-3 substrates. Caspase-3 activity, but not caspase-1, was induced in neuronal cultures in response to MS CSF treatment. This caspase-3 activity was inhibited in vitro by Ac-YVAD-cmk and Ac-DEVD-cmk caspase inhibitors. Treatment of MS CSF-incubated neuronal cells with these caspase inhibitors completely preserved neuronal survival and largely attenuated DNA fragmentation detected in situ. These findings show that neuronal cells are rescued from MS CSF-induced death by caspase inhibitors and suggest ways to treat MS.
Cimini, A., A. Bernardo, et al. (2003). "TNFalpha downregulates PPARdelta expression in oligodendrocyte progenitor cells: implications for demyelinating diseases." Glia 41(1): 3-14.
TNFalpha has been implicated in several demyelinating disorders, including multiple sclerosis (MS) and X-adrenoleukodystrophy (X-ALD). TNFalpha abundance is greatly increased in the areas surrounding damaged regions of the central nervous system of patients with MS and X-ALD, but its role in the observed demyelination remains to be elucidated. A class of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), has been implicated in several physiological and pathological processes. In particular, PPARdelta has been shown to promote oligodendrocyte (OL) survival and differentiation and PPARgamma has been implicated in inflammation. In the present study, we investigate on the effects of TNFalpha on OLs during differentiation in vitro. The results obtained show that TNFalpha treatment impairs PPARdelta expression with concomitant decrease of lignocerolyl-CoA synthase and very-long-chain fatty acid beta-oxidation as well as plasmalogen biosynthesis. We propose a hypothetical model possibly explaining the perturbation effects of proinflammatory cytokines on myelin synthesis, maturation, and turnover.
Cipriani, B., L. Chen, et al. (2003). "Upregulation of group 1 CD1 antigen presenting molecules in guinea pigs with experimental autoimmune encephalomyelitis: an immunohistochemical study." Brain Pathol 13(1): 1-9.
In humans, group 1 CD1 glycoproteins present foreign and self lipid and glycolipid antigens to T-cells. Homologues of these molecules are not found in mice or rats but are present in guinea pigs (GPs). We examined CD1 and MHC class II expression in the central nervous system (CNS) of GPs sensitized for experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In normal GPs and the uninflamed CNS, low-level MHC class II (MHC II) immunoreactivity occurred on vascular elements, meningeal macrophages and parenchymal microglial cells, whereas immunoreactivity for CD1 was absent. In the inflamed CNS, the majority of infiltrating cells were MHC II+ and microglia showed increased expression. CD1 immunoreactivity was detected on astrocytes and subsets of inflammatory cells Including B cells and macrophages. Minimal CD1 and MHC II co-expression was noted on inflammatory cells or glia. We conclude that group 1 CD1 molecules are strongly upregulated in the inflamed CNS on subsets of cells distinct from the majority of MHC II bearing cells. The expression of CD1 proteins in such lesions broadens the potential repertoire of antigens recognized at these sites and highlights the value of the GP as a model for studies of the relevance of CD1 molecules in host defense and autoimmune diseases.
Clanet, M., E. Cassol, et al. (2003). "Clinical-MRI correlations in the secondary progressive phase of MS: lessons from the treatment trials." J Neurol Sci 206(2): 139-44.
Conventional MRI techniques are sensitive to detect MS lesions and their change overtime. In relapsing-remitting MS correlations with clinical measures are weak suggesting a pathological heterogeneity of these lesions. There are less data available in secondary progressive phase of the disease. The best source for clinical MRI correlations analysis is the placebo arm of the published interferon beta trials. This review presents the main clinical-MRI findings from these trials then focuses on recent promising observations obtained with non conventional MRI techniques in SP MS patients.
Clement, P., C. Conessa, et al. (2003). "[Susac syndrome or microangiopathy of the cochlea, brain and retina]." Ann Otolaryngol Chir Cervicofac 120(1): 49-53.
OBJECTIVES: Susac syndrome, also called SICRET syndrome (small infarction of cochlear, retinal, and encephalic tissue) is a rare condition difficult to diagnose. Sudden deafness may be the inaugural sign. MATERIAL AND METHODS: A female patient developed subacute encephalopathy, bilateral sensorineural hearing loss, and ischemic retinopathy. The patient was given cyclophosphamid and methylprednisolone for six months, followed by prednisone for eight months. RESULTS: Signs of encephalopathy had totally regressed by month 14 and retinal arteries were free of obstruction. Deafness remained unchanged. CONCLUSION: Diagnosis of this microangiopathy involving the inner ear, the brain, and the retina is suggested by the clinical triad and established on the basis of tonal audiometry, fundus examination, fluorescein angiography, examination of the cerebrospinal fluid, magnetic resonance imaging. Multiple sclerosis is the main differential diagnosis. The pathogenesis remains unknown. We observed transient-evoked otoacoustic emissions. There is no consensus concerning treatment. Many advocate combining corticosteroids and immunosuppressors. Otolaryngologists should be aware that an ophthalmological examination is required for patients with central or visual disorders associated with hearing loss.
Clowse, M. E. and F. M. Wigley (2003). "Digital necrosis related to carboplatin and gemcitabine therapy in systemic sclerosis." J Rheumatol 30(6): 1341-3.
We present a woman with scleroderma who developed multiple ischemic digits after chemotherapy for lung cancer. The ischemia started during treatment with carboplatin and gemcitabine and required amputation of the affected digits. A review of the literature shows that thrombotic episodes coinciding with chemotherapy are not uncommon, though venous thrombosis occurs more frequently than arterial. Scleroderma patients are at particular risk for digital infarction because of their underlying vascular disease and associated Raynaud's phenomenon. This case illustrates the risk of severe digital ischemia and digital loss in patients with scleroderma during chemotherapy with carboplatin and gemcitabine.
Cohen, Y., A. Polliack, et al. (2003). "Treatment of refractory autoimmune diseases with ablative immunotherapy using monoclonal antibodies and/or high dose chemotherapy with hematopoietic stem cell support." Curr Pharm Des 9(3): 279-88.
Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.
Colman, D., C. Lubetzki, et al. (2003). "Multiple paths towards repair in multiple sclerosis." Trends Neurosci 26(2): 59-61.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, affecting approximately 1/1000 individuals in the Western world. Available treatments limit CNS inflammation and strategies to repair damage in the CNS offer the potential of recovery of both tissue and function. With further fundamental knowledge developing, this area is ripe for 'translation' to clinical application.
Columba-Cabezas, S., B. Serafini, et al. (2003). "Lymphoid chemokines CCL19 and CCL21 are expressed in the central nervous system during experimental autoimmune encephalomyelitis: implications for the maintenance of chronic neuroinflammation." Brain Pathol 13(1): 38-51.
The simultaneous presence of dendritic, T- and B-cells in the central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, suggests that interactions among these cell types might be instrumental in the local induction and maintenance of autoimmune reactions. In this study, we explored the possibility that such aberrant leukocyte recruitment in the CNS could be sustained by "lymphoid" chemokines which orchestrate dendritic cell and lymphocyte homing to lymphoid organs. Transcripts for CCL19 and CCL21 and their common receptor CCR7 were induced in the CNS of mice undergoing relapsing-remitting and chronic-relapsing EAE. While CCL21 immunoreactivity was confined to the endothelium of some inflamed blood vessels, CCL19 was expressed by many infiltrating leukocytes and some astrocytes and microglia in the CNS parenchyma. CCR7+ cells accumulated in inflammatory lesions during EAE progression, when abundant infiltration of the CNS by mature dendritic cells, B-cells and cells expressing naive T-cell markers also occurred. These findings suggest that CCL19 and CCL21 produced in the EAE-affected CNS may be critical for the homing of antigen presenting cells and lymphocytes, resulting in continuous local antigenic stimulation and maintenance of chronic neuroinflammation.
Confavreux, C., S. Vukusic, et al. (2003). "Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process." Brain 126(Pt 4): 770-82.
Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan-Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing-remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.
Cooper, G. S. and B. C. Stroehla (2003). "The epidemiology of autoimmune diseases." Autoimmun Rev 2(3): 119-25.
Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly-diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100000 person-years. Prevalence rates range from less than 5 per 100000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100000 (Grave disease, rheumatoid arthritis, thyroiditis). At least 85% of thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjogren disease patients are female. Although most diseases can occur at any age, some diseases primarily occur in childhood and adolescence (e.g. type 1 diabetes), in the mid-adult years (e.g. myasthenia gravis, multiple sclerosis), or among older adults (e.g. rheumatoid arthritis, primary systemic vasculitis). Ethnic and geographic differences in incidence of specific autoimmune diseases have been documented, but specific groups may be at higher risk for some diseases and lower risk for other diseases. The incidence of type 1 diabetes increased but the rates of rheumatoid arthritis declined over the past 40 years. Thus although there are commonalities, there are also important demographic differences between diseases. Disease-specific research, as well as studies that focus on potentially related diseases, needs to be conducted.
Corboy, J. R., D. S. Goodin, et al. (2003). "Disease-modifying Therapies for Multiple Sclerosis." Curr Treat Options Neurol 5(1): 35-54.
Multiple sclerosis (MS) is likely an autoimmune disorder, although this remains unproven. Immunotherapeutic treatments have been shown to be helpful, especially in relapsing forms of the illness, but the treatments are incomplete, and many patients continue to worsen over time, even with standard therapy. Immunotherapies presently available appear to have their greatest effect when used early in the course of the illness. In relapsing-remitting multiple sclerosis (RRMS), there is overwhelming Class I data from large clinical trials that supports the use of interferon-beta-1a (IFNbeta-1a), interferon-beta-1b (IFNbeta-1b), and glatiramer acetate. Comparative data are limited, and results published in different trials support the idea that treatment outcomes with the various drugs are more similar than different. Decisions about treatment choice should be tailored to the needs of the individual patient. With the exception of a small number of patients with benign MS, all RRMS patients should be treated with one of the interferons or glatiramer acetate. There are Class I data consistent with the idea that higher dose or more frequent administration of interferon-beta (IFNbeta) is associated with better clinical outcome and reduced progression of changes on brain MRI scans. The duration of this effect is not clear, and higher dose with more frequent administration is associated with higher cost, more side effects, and greater production of interferon antibodies. Interferon antibodies possibly reduce efficacy of IFNbeta in RRMS and secondary progressive multiple sclerosis (SPMS). Clinically isolated syndromes (CIS) of demyelination in the central nervous system can be reliably diagnosed, and the risk of further episodes of demyelination is consistent with the diagnosis of RRMS stratified by use of brain MRI scans. Patients at high risk of developing RRMS after CIS achieve significant benefit after treatment with IFNbeta-1a, and initiation of therapy after CIS should be given strong consideration. There are no similar data for IFNbeta-1b or glatiramer acetate, but logic would dictate a similar response with these agents. In SPMS, there are Class I data that treatment with IFNbeta-1a or IFNbeta-1b has a significant effect on progression of brain MRI lesions, but clinical outcomes are less clearly affected. It is justifiable to treat SPMS patients with IFNbeta. Mitoxantrone may be effective in slowing progression of SPMS, and its risks are moderate. It should be used in patients with SPMS, but potential long-term risks must be discussed with the patient in detail. Results of treatment of SPMS in advanced cases (Extended Disability Status Score greater than 6.5, or restricted to wheelchair) is mostly unknown. These patients are at high risk of developing infections, especially if they use indwelling catheters, and the use of agents that induce immunosuppression may be risky. There are no effective therapies for primary progressive multiple sclerosis (PPMS). Although PPMS patients are frequently treated with one or more therapeutic agents, there is no medical justification for this now.
Correale, J. and M. de los Milagros Bassani Molinas (2003). "Time course of T-cell responses to MOG and MBP in patients with clinically isolated syndromes." J Neuroimmunol 136(1-2): 162-71.
CD4(+) T-cell lines (TCLs) from patients with clinically isolated syndromes (CIS) were selected with purified human myelin basic protein (MBP) and recombinant human myelin oligodendrocyte glycoprotein (rhMOG), at onset of neurological symptoms and when patients developed clinically definite multiple sclerosis (CDMS). The epitope specificity of each TCL was mapped with overlapping synthetic peptides. TCLs were assessed for their ability to secrete IFN-gamma, IL-4, and IL-6. Diverse patterns of epitope recognition were observed: (a) recognition of a broad spectrum of MBP peptide epitopes with evidence of shifts over time; (b) an initial T-cell response focused to a restricted segment of the MBP molecule (83-102) that broadened over the course of disease; and (c) persistence of a focused anti-MOG T-cell response. CIS patients who failed to develop CDMS maintained a focused epitope response against two to six MBP epitopes. Most MBP peptide-specific TCLs secreted considerable amounts of IFN-gamma and low amounts of IL-4 and IL-6, whereas anti rhMOG(Igd) peptide-specific TCLs secreted preferentially IL-4 and IL-6. These data raise important issues for the pathogenesis and treatment of multiple sclerosis (MS).
Costello, K. and C. Harris (2003). "Differential diagnosis and management of fatigue in multiple sclerosis: considerations for the nurse." J Neurosci Nurs 35(3): 139-48.
Fatigue is one of the most disabling aspects of multiple sclerosis (MS), affecting an estimated 70%-90% of patients. Yet, despite its prevalence, it is also one of the most difficult MS symptoms to accurately diagnose and effectively treat. This is because of numerous factors, including the subjective and nonspecific nature of fatigue; its variable manifestations; its similarity to psychological, motor, cognitive, respiratory, and non-MS-related disturbances and conditions; and a lack of understanding of its precise etiology. In contrast to fatigue experienced by people without MS, MS fatigue is characterized by its persistence and sensitivity to core and ambient temperatures. Differential diagnosis of MS fatigue is largely dependent on delineating chronic versus acute onset and determining whether fatigue is a symptom in and of itself (primary MS fatigue) or an aspect of an MS-related or non-MS-related etiology (secondary MS fatigue). Once the presence of fatigue is established, a through medical history, physical examination, and fatigue assessments can guide effective management, which includes education, self-care strategies, and pharmacological treatment. As patient advocates and gatekeepers, MS nurses are in an optimal position to establish and evaluate fatigue as a symptom in and of itself and effectively guide this process.
Craner, M. J., A. C. Lo, et al. (2003). "Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination." Brain 126(Pt 7): 1552-61.
Myelinated fibres are characterized by the aggregation of Nav1.6 sodium channels within the axon membrane at nodes of Ranvier, where their presence supports saltatory conduction. In this study, we used immunocytochemical methods to study the organization of sodium channels along axons in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. We studied axons within the optic nerve, a CNS tract commonly affected in multiple sclerosis, and their cell bodies of origin (retinal ganglion cells), using subtype-specific antibodies generated against sodium channel subtypes Nav1.1, Nav1.2, Nav1.3 and Nav1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Nav1.6 to Nav1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Nav1.6-positive nodes (84.5% Nav1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Nav1.2-positive nodes (11.8% Nav1.2 immunopositive nodes in control versus 74.9% in EAE). Moreover, we observed a significant increase in the number of linear (presumably demyelinated) axonal profiles demonstrating extended diffuse immunostaining for Nav1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Nav1.6 and increased Nav1.2 protein, together with increased levels of Nav1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Nav1.6 and increased expression of Nav1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Nav1.2 channels support conduction of action potentials along axons.
Craner, M. J., A. C. Lo, et al. (2003). "Annexin II/p11 is up-regulated in Purkinje cells in EAE and MS." Neuroreport 14(4): 555-8.
The sensory neuron specific sodium channel Na(v)1.8 is normally detectable at only very low levels within cerebellar Purkinje cells. Annexin II light chain (p11) binds to the amino terminus of Na(v)1.8 and facilitates its functional expression within the cell membrane. We previously demonstrated that expression of Na(v)1.8 is up-regulated in cerebellar Purkinje cells in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). In this study we demonstrate that expression of p11 is significantly up-regulated in Purkinje cells in EAE (71 +/- 9.0% vs 21.3 +/- 4.9% in controls) and in MS(65.5 +/- 1.6% vs 21.8 +/- 6.2% in controls). We also demonstrate a high degree of co-expression of p11 and Na(v)1.8 (84.8 +/- 8.9%). Together with earlier results which show that experimental expression of Na(v)1.8 within Purkinje cells perturbs the temporal pattern of impulse generation in these cells, our results extend the evidence for an acquired channelopathy which interferes with cerebellar function in MS.
Croxford, J. L. and S. D. Miller (2003). "Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212." J Clin Invest 111(8): 1231-40.
Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.
Croxford, J. L. (2003). "Therapeutic potential of cannabinoids in CNS disease." CNS Drugs 17(3): 179-202.
The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
Cushman, K. E., M. Maqbool, et al. (2003). "Variation of podophyllotoxin in leaves of Eastern Red Cedar (Juniperus virginiana)." Planta Med 69(5): 477-8.
Leaves of Eastern red cedar (Juniperus virginiana L. Cupressaceae) have been reported to contain podophyllotoxin, a pharmaceutical compound used to manufacture drugs for treatment of cancer, rheumatoid arthritis, genital warts, psoriasis, and multiple sclerosis. Podophyllotoxin content of leaves of immature, mature male, and mature female plants (approximately 1.45 mg x g -1) was significantly higher than that of leaves of juvenile plants (0.60 mg x g -1). Sampling date also affected podophyllotoxin content. Leaves harvested in January and April exhibited higher podophyllotoxin contents (1.56 and 1.45 mg x g -1, respectively) than leaves harvested in February and June (1.06 and 1.08 mg x g -1, respectively). There was no obvious pattern or trend in the data due to sampling date. There was no significant interaction between plant type and sampling date. These results indicate that foliage of mature Eastern red cedar, a waste product of the lumber industry, could be a low-yielding, but relatively stable, source of podophyllotoxin.
Cwiklinska, H., M. P. Mycko, et al. (2003). "Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains." Int Immunol 15(2): 241-9.
Heat shock proteins (hsp) are known to facilitate the generation of specific immune responses by chaperoning proteins and peptides involved in T cell activation. Hsp have been shown to be strikingly elevated in multiple sclerosis (MS) lesions. The unique chaperonin properties of hsp70 have allowed identification of immunogenic proteins bound to it by the ex vivo demonstration of hsp associations with proteins implicated in the immune response. We have investigated the association of hsp70 with myelin basic protein (MBP), myelin proteolipid protein (PLP) and myelin oligodendrocyte protein (MOG) in MS and control brain tissue. In co-immunoprecipitation experiments, in all samples of MS brains examined (n = 3), but not control brain tissue (n = 3), direct association of MBP with hsp70, but not with hsp90, was found. In some MS brain samples, association between PLP and hsp70 was also seen. In similar co-immunoprecipitation experiments on brain tissue obtained from mice with experimental autoimmune encephalomyelitis (n = 5) induced by immunization with PLP peptide, specific association of hsp70 with PLP and MBP was found. Using surface plasmon resonance we demonstrated specific binding of hsp70 with MBP in vitro. Analysis of the amounts of MBP bound to hsp70 yielded a molecular ratio of MBP binding to hsp70 at 6.5:1. MBP complexed with hsp70 was taken up at significantly higher rates by antigen-presenting cells than MBP alone and enhanced MBP-specific immune responses. These results indicate that hsp70 specifically associates with MBP in MS brain tissue. This association might be relevant to the enhanced immune recognition of MBP in MS.
Cymet, T. C. (2003). "A practical approach to fibromyalgia." J Natl Med Assoc 95(4): 278-85.
Fibromyalgia is the name given to a collection of symptoms with no clear physiologic cause, The constellation of symptoms are clearly recognizable as a distinct pathologic entity. The diagnosis is made through clinical observations made by the examiner. Differential diagnosis must include other somatic syndromes as well as disease entities like hepatitis, hypothyroidism, diabetes mellitus, electrolyte imbalance, multiple sclerosis, and cancer. Diagnostic criteria are given as guidelines for the diagnosis, not as absolute requirements. Treatment of this condition remains individualized and relies heavily on having a therapeutic relationship with a provider. Treatment of this syndrome needs to be looked at as an ongoing process. Goal oriented treatment aimed at maintaining specific functions can be directed at helping a patient get restorative sleep, alleviating the somatic pains that ail the patient, keeping a person productive, regulating schedules or through goal oriented agreements made with the patient. Since this syndrome is chronic and may effect all areas of a persons functioning the family and social support system of the person being treated need to be evaluated. Patients often seek alternative medical treatments for this problem including diet therapy, acupuncture, and herbal therapy. Treatment must involve more than just the symptoms presented and the patient can only be treated successfully if they are willing to work at changing their own perceptions, and ways of relating to stressors in their world.