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Multiple Sclerosis Reviews: 2005

Zivadinov, R. (2005). "Steroids and brain atrophy in multiple sclerosis." J Neurol Sci 233(1-2): 73-81.

            In this review, we focus on different pathogenetic mechanisms of corticosteroids that induce short- and long-term brain volume fluctuations in a variety of systemic conditions and disorders, as well as on corticosteroid-induced immunomodulatory, immunosuppressive and anti-inflammatory mechanisms that contribute to the slowdown of brain atrophy progression in patients with multiple sclerosis (MS). It appears that chronic low-dose treatment with corticosteroids may contribute to irreversible loss of brain tissue in a variety of autoimmune diseases. This side effect of steroid therapy is probably mediated by steroid-induced protein catabolism mechanism. Evidence is mounting that high-dose corticosteroids may induce reversible short-term brain volume changes due to loss of intracellular water and reduction of abnormal vascular permeability, without there having been axonal loss. Other apoptotic and selective inhibiting mechanisms have been proposed to explain the nature of corticosteroid-induced brain volume fluctuations. It has been shown that chronic use of high dose intravenous methylprednisolone (IVMP) in patients with MS may limit brain atrophy progression over the long-term via different immunological mechanisms, including downregulation of adhesion molecule expression on endothelial cells, decreased cytokine and matrix metalloproteinase secretion, decreased autoreactive T-cell-mediated inflammation and T-cell apoptosis induction, blood-brain barrier closure, demyelination inhibition and, possibly, remyelination promotion. Studies in nonhuman primates have confirmed that short-term brain volume fluctuations may be induced by corticosteroid treatment, but that they are inconsistent, potentially reversible and probably dependent upon individual susceptibility to the effects of corticosteroids. Further longitudinal studies are needed to elucidate pathogenetic mechanisms contributing to brain volume fluctuations in autoimmune diseases and multiple sclerosis.

Zivadinov, R. and T. P. Leist (2005). "Clinical-magnetic resonance imaging correlations in multiple sclerosis." J Neuroimaging 15(4 Suppl): 10S-21S.

            Conventional magnetic resonance imaging (MRI) has routinely been used to improve the accuracy of multiple sclerosis (MS) diagnosis and monitoring, detect the effects of disease-modifying therapy, and refine the utility of clinical assessments. However, conventional MRI measures, such as the use of lesion volume and count of gadolinium-enhancing and T2 lesions, have insufficient sensitivity and specificity to reveal the true degree of pathological changes occurring in MS. Newer metrics of MRI analysis, including T1-weighted hypointense lesions (black holes) and central nervous system (CNS) atrophy measures, are able to capture a more global picture of the range of tissue alterations caused by inflammation, demyelination, axonal loss, and neurodegeneration. There is mounting evidence that these MRI measures correlate well with existing and developing neurological impairment and disability. In so doing, these MRI techniques can help elucidate the mechanisms underlying the pathophysiology and natural history of MS. The current understanding is that T1 black holes and CNS atrophy more accurately reflect the neurodegenerative and destructive components of the MS disease process. Therefore, the short and long-term studies that aim to measure the degree and severity of the neurodegenerative MS disease process should incorporate these MRI metrics as part of their standard routine MRI protocols.

Zingg, W. (2005). "[Does vaccination cause disease?]." Ther Umsch 62(10): 665-74.

            Not many inventions in medical history have influenced our society as much as vaccination. The concept is old and simple. When Edward Jenner published his work on cowpox, "variolation" was quite common. In this procedure, pus of patients with mild smallpox was transferred to healthy individuals. Meanwhile smallpox has been eradicated worldwide. Diseases such as poliomyelitis, diphtheria or tetanus almost disappeared in industrialized countries. The same happened with epiglottitis and meningitis due to Haemophilus influenzae type b (Hib) after vaccination against Hib was introduced in Switzerland in 1990. This success was possible because of routine vaccination. Immunization is a save procedure and adverse events are much lower than complications in the natural course of the prevented diseases. However vaccinations were accused to cause diseases themselves such as asthma, multiple sclerosis, diabetes mellitus, chronic arthritis or autism. Hitherto no large cohort study or case-control-study was able to proof responsibility of vaccines in any of these diseases. Public media are eager to publish early data from surveillance reports or case reports which are descriptive and never a principle of cause and effect. In large controlled trials there was no proof that vaccination causes asthma, hepatitis-B-vaccination causes multiple sclerosis or macrophagic myofasciitis, Hib-vaccination causes diabetes mellitus, rubella-vaccination causes chronic arthritis, measles-mumps-rubella-vaccination causes gait disturbance or thiomersal causes autism. These results are rarely published in newspapers or television. Thus, many caring parents are left with negative ideas about immunization. Looking for the best for their children they withhold vaccination and give way to resurgence of preventable diseases in our communities. This must be prevented. There is more evidence than expected that vaccination is safe and this can and must be told to parents.

Zijdenbos, A. P., J. P. Lerch, et al. (2005). "Brain imaging in drug R&D." Biomarkers 10 Suppl 1: S58-68.

            Magnetic resonance imaging (MRI), used as a clinical diagnostic tool since the early 1980s, is rapidly gaining traction as an integral part of the drug development process. Brain imaging research spans a wide area, covering both structure and function, and ranging from the physics and physiology associated with novel acquisition techniques, to the development of sophisticated image processing algorithms. This paper briefly describes two methods on either end of this spectrum: the "pipeline" framework for the fully automated morphometric analysis of brain imaging data, and molecular MRI, which holds promise for the non-invasive detection of molecular targets of new pharmacological compounds. The potential use of these technologies is illustrated by examples of their applications in multiple sclerosis, Alzheimer's disease, and oncology.

Ziemssen, T. and F. Ziemssen (2005). "The role of the humoral immune system in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE)." Autoimmun Rev 4(7): 460-7.

            The pathogenic events in multiple sclerosis (MS) that result in immune cell infiltration, multifocal demyelination and axonal loss have been focused by the strong impact of the classical MS model experimental autoimmune encephalomyelitis (EAE) towards the hypothesis that MS is an entirely T cell-mediated disease. Although conspicuous humoral immune responses have been known since Kabal's seminal finding of elevated immunoglobulins (Igs) in the cerebrospinal fluid (CSF), only in the past few years evidence derived from recent studies of the MS lesion of anti-myelin antibodies (Abs) in patients with early MS and of MS animal models has led to a renewed interest in the role for B cells, plasma cells and their products in the pathogenesis of MS. This review surveys the actual data concerning the role of the humoral immune system in MS and EAE and explains potential modes of action and long-time persistence in the inflamed brain tissue as a B cell-supportive microenvironment in MS. These mechanisms include the modulation of antigen presentation and costimulation to T cells, increased myelin opsonisation und recruitment of inflammatory cells to the CNS, but also immunoregulatory influences on the remyelination by anti-myelin B cells and Abs. So, affecting the humoral immune system in MS would be a reasonable therapeutic option.

Ziemssen, T. (2005). "Modulating processes within the central nervous system is central to therapeutic control of multiple sclerosis." J Neurol 252 Suppl 5: v38-45.

            Historically considered to be an autoimmune demyelinating disease, multiple sclerosis is now recognized to be characterized by significant axonal and neuronal pathology. Addressing this neurodegenerative component of the disease is an important treatment objective, since axonal injury is believed to underlie the accumulation of disability and disease progression. The precise relationship between the inflammatory and neurodegenerative components in multiple sclerosis remains poorly elucidated, although neurodegeneration appears to be at least partially independent from neuroinflammation. The mechanisms underlying axonal injury appear complex and are likely to be multifactorial. Specific treatment strategies need to be developed that act within the central nervous system to prevent neurodegeneration and need to be provided from the earliest stages of disease. It is likely that immunomodulatory treatments acting purely in the periphery will provide only indirect and not direct neuroprotection. A promising approach is to enhance neuroprotective autoimmunity inside the brain, believed to be mediated, at least in part, by the release of neurotrophic factors within the nervous system from infiltrating immune cells. Such a beneficial process would be inhibited by a non-selective immunosuppressive strategy. In summary, treatments of multiple sclerosis should take into account the heterogeneous pathophysiology of the disease. The pathogenic process in the central nervous system itself should be the major focus in multiple sclerosis therapy in order to protect against demyelination and axonal loss and to promote remyelination and regeneration directly in the target tissue, independently of peripheral immune status. In conclusion, selective treatment strategies aimed at preventing axonal injury within the central nervous system are required to complement existing, peripherally acting treatments targeting the immune system.

Zhao, C., S. P. Fancy, et al. (2005). "Mechanisms of CNS remyelination--the key to therapeutic advances." J Neurol Sci 233(1-2): 87-91.

            There are two components to the treatment of multiple sclerosis (MS); the first is to prevent damage occurring, and the second is to repair the residual damage. While considerable progress has been made in the recent years with the former through the development of anti-inflammatory and immunomodulatory therapies, there are currently no effective repair therapies routinely used in MS patients. This represents a significant gap in the MS clinician's therapeutic armoury. In this article we argue that a clear understanding of the repair mechanisms following CNS demyelination is fundamental to filling this gap. We discuss (1) the cellular events involved in remyelination, (2) changes in transcription factor expression within oligodendrocyte precursor cells associated with their activation in response to demyelination, (3) the role of platelet derived growth factor in the OPC recruitment phase of remyelination, and (4) the significance of the inflammatory response associated with demyelination in creating a signalling environment that favours remyelination.

Zhao, C., S. P. Fancy, et al. (2005). "Stem cells, progenitors and myelin repair." J Anat 207(3): 251-8.

            Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured central nervous system (CNS). This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets will depend on a detailed understanding of the cellular and molecular mechanisms of remyelination. In this article we address two important issues. First, we consider the nature of the cell or cells that respond to demyelination and generate new oligodendrocytes, identifying current areas of uncertainty and addressing the role of adult CNS stem and progenitor cells. Second, we discuss the concept of adult progenitor activation following demyelination, focusing on the increased expression of (1) olig transcription factors, (2) bone morphogenetic proteins and (3) fyn, a member of the src-family of tyrosine kinases.

Zhang, J. and G. Hutton (2005). "Role of magnetic resonance imaging and immunotherapy in treating multiple sclerosis." Annu Rev Med 56: 273-302.

            Significant advances in magnetic resonance imaging (MRI) technology and treatment of multiple sclerosis (MS) have been made during the past decade. These advances have revealed evidence of profound heterogeneity in MS. There is a clear need to revisit the key issues in MS pathogenesis and treatment strategies, taking new data into consideration. This paper provides an overview of recent progress in MS research, including (a) a review of clinical, pathologic, and immunologic aspects of MS, (b) a discussion of the mechanism of action of currently available disease-modifying drugs for MS, (c) an account of the role of MRI in clinical management and clinical trials in MS, and (d) an overview of some emerging treatments for MS.

Zajicek, J. (2005). "Diagnosis and disease modifying treatments in multiple sclerosis." Postgrad Med J 81(959): 556-61.

            Multiple sclerosis (MS) refers to scattered areas of hardening found on sectioning central nervous system tissue of affected people, usually after many years of illness. It rarely causes early death but is the commonest cause of neurological disability among young people. Overall results from controlled trials over the past 50 years have been rather disappointing but the comparatively recent licensing of drugs such as interferon beta and glatiramer acetate has led to a reappraisal of many aspects of MS. There are now new diagnostic criteria, which encompass developments in magnetic resonance imaging. Older clinical methods of measuring disease impact are now being re-evaluated to facilitate clinical trials of the approximate 150 new products currently being developed as potential disease modifying agents. The success and failure of agents that should be effective on theoretical grounds, together with advances in neuropathology, have led to fundamental questions regarding our basic understanding of disease pathogenesis being re-addressed.

Zaffaroni, M. (2005). "Treatment optimisation in multiple sclerosis." Neurol Sci 26 Suppl 4: S187-92.

            Not all patients with multiple sclerosis (MS) respond equally to available disease modifying agents (DMA). Rational and reliable criteria are needed to identify responders and non responders in order to optimize the treatment. Natural history of the disease, clinical evolution and magnetic resonance imaging are the putative indicators to be considered with this respect, but neutralizing antibodies, possible immunological markers and pathological or genetic diversity may also represent future additional indicators. Clinical recommendations and consensus criteria for defining a suboptimal response to DMA have been proposed by different international panels of experts, but all need validation in experimental settings to provide solid guidelines for establishing when and how to take action on MS treatment with DMA.

Yorkston, K. M., K. L. Johnson, et al. (2005). "Taking part in life: enhancing participation in multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 583-94.

            Health care professionals participating in rehabilitation for people with MS can play a critical role in enhancing limited outcomes such as enhanced mobility, reductions in symptoms such as pain and depression, and the metaoutcome-participation. This role will be significantly more effective if the health care professional acknowledges and validates the different perspectives of the professional and the patient and recognizes the expertise of the patient who has lived with MS in the context of his or her life.Assuming this role effectively requires that the health care professional develop a collaborative relationship with the patient and understand that the role may change depending on the stage of MS and the individual's circumstances.

Yang, C. C. (2005). "[Diagnosis of multiple sclerosis]." Acta Neurol Taiwan 14(4): 213-20.

            Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. The disorder displays marked clinical heterogeneity. In certain cases, making diagnosis can be challenging. Diagnosis of MS has become more important in the era of treatments that change the natural history of the disease. Several general diagnostic principles are useful to guide the diagnostic approach to MS. Clinically, MS requires neurological problems associated with objective abnormalities. Certain basic principles, first outlined by Schumacher et al. (1965) are still pertinent. Poser et al. (1983) have further modified the criteria using data derived from clinical evaluation and laboratory studies, including cerebrospinal fluid analysis, evoked potentials, and imaging studies. Poser criteria have long been familial for most neurologists. The most recent addition to our diagnostic armamentarium are the McDonald criteria (2001), which are the first attempt to incorporate standardized MRI criteria into the MS diagnostic process. The most innovative use of MRI to support an MS diagnosis is dissemination of demyelination can be demonstrated by MRI alone, in the absence of any new clinical attacks. Diagnosing MS by such sensitive MRI criteria will occur more quickly than waiting for a second clinical event. This has added some sensitivity, some controversy, and a lot of confusion. The application of the new criteria on Asian MS patients remains to be validated. Each of the criteria will be discussed, with major emphasis on the McDonald criteria.

Yamamura, T., K. Takahashi, et al. (2005). "[Multiple sclerosis and regulatory cells]." Nippon Rinsho 63 Suppl 5: 422-6.

Yamamura, T. (2005). "[Synthetic glycolipid ligands as novel therapeutics for multiple sclerosis]." Rinsho Shinkeigaku 45(11): 909-11.

            Our previous works indicate that regulatory cells such as natural killer (NK) cells and NKT cells could play an active role in maintaining the remission state of MS. We have therefore adopted a strategy for developing the future MS therapy by targeting NKT cells. The unique glycolipid-reactive lymphocytes are known to produce a large quantity of Th2 cytokines such as IL-4 when encountering their ligands like alpha-galactosylceramide (alpha-GC). Whereas most of the NKT ligands so far described would stimulate both Th1 and Th2 cytokine production by NKT cells, the synthetic compound OCH, an analogue of alpha-GC with a shorter lipid tail, is the one which selectively induces IL-4 production. Given this property, oral or intraperitoneal OCH administration would prohibit the development of a variety of Th1-meediated pathology, including EAE, collagen-induced arthritis, type 1 diabetes, DSS-induced colitis and acute GVHD by inducing Th2 bias. This review paper summarizes the recent publications and our unpublished results related to the efficacy of OCH and to the molecular mechanism accounting for the Th2 inducing property of OCH.

Yamamoto, Y. (2005). "[Palmitoleic acid]." Nippon Rinsho 63 Suppl 8: 803-5.

Wucherpfennig, K. W. (2005). "The structural interactions between T cell receptors and MHC-peptide complexes place physical limits on self-nonself discrimination." Curr Top Microbiol Immunol 296: 19-37.

            The activation and expansion of T cells in an antimicrobial immune response is based on the ability of T cell receptors (TCR) to discriminate between MHC-bound peptides derived from different microbial agents as well as self-proteins. However, the specificity of T cells is constrained by the limited number of peptide side chains that are available for TCR binding. By considering the structural requirements for peptide binding to MHC molecules and TCR recognition of MHC-peptide complexes, we demonstrated that human T cell clones could recognize a number of peptides from different organisms that were remarkably distinct in their primary sequence. These peptides were particularly diverse at those sequence positions buried in pockets of the MHC binding site, whereas a higher degree of similarity was present at a limited number of peptide residues that created the interface with the TCR. These T cell clones had been isolated from multiple sclerosis patients with human myelin basic protein, demonstrating that activation of such autoreactive T cells by microbial peptides with sufficient structural similarity may contribute to the disease process. Similar findings have now been made for a variety of human and murine T cell clones, indicating that specificity and cross-reactivity are inherent properties of TCR recognition. The observations that particular TCR are highly sensitive to changes at particular peptide positions but insensitive to many other changes in peptide sequence are not contradictory, but rather the result of structural interactions in which a relatively flat TCR surface contacts a limited number of side chains from a peptide that is deeply embedded in the MHC binding site.

Wong, M. (2005). "Advances in the pathophysiology of developmental epilepsies." Semin Pediatr Neurol 12(2): 72-87.

            Pediatric epilepsies display unique characteristics that differ significantly from epilepsy in adults. The immature brain exhibits a decreased seizure threshold and an age-specific response to seizure-induced brain injury. Many idiopathic epilepsy syndromes and symptomatic epilepsies commonly present during childhood. This review highlights recent advances in the pathophysiology of developmental epilepsies. Cortical development involves maturational regulation of multiple cellular and molecular processes, such as neurogenesis, neuronal migration, synaptogenesis, and expression of neurotransmitter receptors and ion channels. These normal developmental changes of the immature brain also contribute to the increased risk for seizures and unique responses to seizure-induced brain injury in pediatric epilepsies. Recent technological advances, especially in genetics and imaging, have yielded exciting discoveries about the pathophysiology of specific pediatric epilepsy syndromes, such as the emergence of channelopathies as the cause of many idiopathic epilepsies and identification of malformations of cortical development as a major source of symptomatic epilepsies in children.

Wolfovitz, E. (2005). "[The pleiotropic effects of statins]." Harefuah 144(8): 577-82, 597.

            Statins (HMG-CoA reductase inhibitors) are the most commonly used lipid lowering drugs. Recent experimental evidence suggest that these agents appear to display additional cholesterol independent or pleiotropic effects, contributing to prevention and inhibition of atherosclerosis. In addition, clinical trials have demonstrated different effects of statins on diseases that are not directly related to accelerated atherosclerosis. The statins' vascular pleiotropic effects include improvement of endothelial function, slowing the inflammation process, inhibition of the thrombus formation, enhancement of plaque stability and decreasing oxidative stress. Clinical benefits were observed with statins therapy for cardiovascular diseases - ischemic heart disease, cerebral vascular accidents and peripheral vascular disease. Lately, clinical trials have suggested their role in Alzheimer's disease, multiple sclerosis, malignant diseases, osteoporosis, chronic renal diseases, transplantations, macular degeneration and autoimmune diseases. The objective of this review is to summarize the data related to the pleiotropic effects of the statin drugs, beyond their lipid lowering effect.

Wojtera, M., B. Sikorska, et al. (2005). "Microglial cells in neurodegenerative disorders." Folia Neuropathol 43(4): 311-21.

            Microglia are resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. It is widely accepted that microglia contribute to the neurodegeneration through a release of a variety of proinflammatory substances. In fact, they are not the only cells which contribute to immunological processes inside the nervous system. The CNS is composed of different cell populations that answer to pathological factors and influence each other and modulate their reactions. These complex interactions are responsible for the development of brain pathology. This paper reviews the available information on microglial cells contribution to AD, PD and prion diseases development.

Wirenfeldt, M., R. Ladeby, et al. (2005). "[Microglia--biology and relevance to disease]." Ugeskr Laeger 167(33): 3025-30.

            Microglia, the resting macrophage population in the brain and spinal cord, has a central role in inflammatory processes and in acute and chronic degenerative diseases of the central nervous system. The possibility of utilizing microglia diagnostically has emerged with the prospect of visualization of reactive microgliosis via positron emission tomography. Microglia might also have a therapeutic potential by way of recruitment of microglial precursors from the blood with the opportunity to introduce genetically modified cells lesion-specifically into the central nervous system via the bloodstream. Knowledge about microglial function has preferentially been obtained via studies in experimental animal models of the pathological central nervous system. In spite of the rather extensive knowledge regarding the pathophysiological implications of these cells, their function in the normal central nervous system remains rather unknown.

Wills, A. and S. Ormerod (2005). "Casebook: paraesthesia and numbness." Practitioner 249(1674): 604, 606, 608 passim.

Wessely, R. (2005). "Interference by interferons: Janus faces in vascular proliferative diseases." Cardiovasc Res 66(3): 433-43.

            Interferons (IFNs) display pleiotropic properties; not only do they protect cells from viral infections but they may also modulate cell growth and differentiation as well as innate and adaptive immune responses. Therapeutic applications of IFNs have proven efficacy in a variety of illnesses, including hepatitis, multiple sclerosis, and some forms of cancer. Emerging evidence has been obtained during recent years that interferons impact on molecular and cellular mechanisms implicated in the development of vascular proliferative diseases such as atherosclerosis, restenosis, and cardiac allograft vasculopathy. Further appreciation and delineation of the precise mechanisms on how interferons influence vascular proliferative disease processes could potentially facilitate the development of novel treatment options attenuating these common causes of cardiovascular morbidity and mortality.

Werner, H. (2005). "The benefits of the dysphagia clinical nurse specialist role." J Neurosci Nurs 37(4): 212-5.

            Dysphagia is a major health problem associated with multiple neurological diseases such as stroke, multiple sclerosis, and Parkinson's disease, among others. Staff nurses lack a consistent approach to managing dysphagia patients. A dysphagia clinical nurse specialist (CNS) may facilitate a consistent approach. As a member of the interdisciplinary team, the dysphagia CNS carries a caseload and serves as a liaison between the interdisciplinary team and the nursing staff to oversee dysphagia nursing care.

Welshman, A. (2005). "Palliative care. Some organisational considerations." Minerva Anestesiol 71(7-8): 439-43.

            Managing pain effectively is one of the biggest challenges in medicine, let alone when dealing with the dying patient and his family. For palliative care specialists this is a daily challenge. However, ''To cure when possible, to give comfort always'' is an empty credo if physicians don't use every weapon in the medical arsenal to relieve the suffering caused by chronic pain. It's of course the opioids: morphine, heroin, their synthetic derivatives and other narcotics, a class of medications that conjure up visions of drug addiction and narcotic squads. To say that opioids are stigmatised by such allusions is putting it mildly. An unhealthy proportion of doctors and patients alike are afraid to have anything to do with them, even in when facing their final stages of life. This is particularly so in the Mediterranean society. It is here in Italy that an effort must be made to educate both physicians and the general public, an arduous task to change a long standing belief which requires a quick cultural turn around. Those who refuse opioids because they are afraid of addiction, and the doctors who refuse to prescribe them out of fear or pure unwillingness to address an apprehensive attitude on behalf of his patient, need to be better informed. Most misconceptions about opioids have to do with terminology, because words like ''morphine, addiction, dependency'' and ''tolerance'' mean entirely different things in popular and medical parlance. Add to this the perceptions and attitudes the patient can have with this terminology which then can have a profound effect on the success or failure of a pain control programme. In fact, most people think that medication such as morphine are only for people who are dying and as a consequence is synonymous with death itself. Is this why Italian physicians are not prescribing morphine even though great efforts have been made recently by the Health Ministry to facilitate prescribing laws and costs? It is worthy of serious consideration. Another important issue faced daily by palliative care physicians is the broad number of chronic conditions which could make use of opioids. Severe cancer pain is the most obvious example of an appropriate use of opioids, but hardly the only one. The North American Chronic Pain Association of Canada (NACPAC) advocates the use of opioids for a wide range of conditions causing severe chronic pain, including lower back pain, inflammatory bowel disease, migraines, AIDS, multiple sclerosis and arthritis. Concerns regarding under treatment of chronic pain have captured the attention of patient advocacy groups, policy makers and scientific organisations. Misconceptions of opioid laws, negative social stigma and lack of valid prescribing alternatives to overcome this, together with paucity of formal provider education confound the issue. Much education needs to be done before opioids will be seen as a safe and reasonable treatment for chronic pain here in Italy.

Weiss, S. R. and S. Navas-Martin (2005). "Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus." Microbiol Mol Biol Rev 69(4): 635-64.

            Coronaviruses are a family of enveloped, single-stranded, positive-strand RNA viruses classified within the Nidovirales order. This coronavirus family consists of pathogens of many animal species and of humans, including the recently isolated severe acute respiratory syndrome coronavirus (SARS-CoV). This review is divided into two main parts; the first concerns the animal coronaviruses and their pathogenesis, with an emphasis on the functions of individual viral genes, and the second discusses the newly described human emerging pathogen, SARS-CoV. The coronavirus part covers (i) a description of a group of coronaviruses and the diseases they cause, including the prototype coronavirus, murine hepatitis virus, which is one of the recognized animal models for multiple sclerosis, as well as viruses of veterinary importance that infect the pig, chicken, and cat and a summary of the human viruses; (ii) a short summary of the replication cycle of coronaviruses in cell culture; (iii) the development and application of reverse genetics systems; and (iv) the roles of individual coronavirus proteins in replication and pathogenesis. The SARS-CoV part covers the pathogenesis of SARS, the developing animal models for infection, and the progress in vaccine development and antiviral therapies. The data gathered on the animal coronaviruses continue to be helpful in understanding SARS-CoV.

Weinberg, A. D. and R. Montler (2005). "Modulation of TNF receptor family members to inhibit autoimmune disease." Curr Drug Targets Inflamm Allergy 4(2): 195-203.

            Certain members of the TNF-receptor family have shown proinflammatory function during immune activation and can be directly involved with the pathogenic effects observed during an autoimmune episode. The TNF-R family members summarized in this review includes: TNF-RI + II, OX40, and 4-1BB and they are expressed on a variety of leukocytes within the body. Studies within the last decade suggest that all of these proteins or their natural ligands can be targeted with various agents designed to diminish clinical signs of disease in autoimmune models. The data from the preclinical models specifically involving TNF-blockade have led to the development of clinical trials for patients with multiple sclerosis and rheumatoid arthritis. This review will chronicle the preclinical development of agents designed to inhibit OX40 and 4-1BB functions in autoimmunity and discuss relevant preclinical and clinical data associated with TNF-blockade.

Wehman-Tubbs, K., S. H. Yale, et al. (2005). "Insight into multiple sclerosis." Clin Med Res 3(1): 41-4.

Weber, M. S., T. Prod'homme, et al. (2005). "Drug Insight: using statins to treat neuroinflammatory disease." Nat Clin Pract Neurol 1(2): 106-12.

            Statins, a family of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used primarily to reduce atherogenesis and cardiovascular morbidity. Surprisingly, they have also been shown to have immunomodulatory properties that might be of benefit for the treatment of autoimmune disorders. Statins can prevent and even reverse ongoing paralysis in experimental autoimmune encephalomyelitis--the mouse model for multiple sclerosis--and on the basis of these findings, statins are now being tested in patients with multiple sclerosis in clinical trials.

Waxman, S. G. (2005). "Cerebellar dysfunction in multiple sclerosis: evidence for an acquired channelopathy." Prog Brain Res 148: 353-65.

            Cerebellar dysfunction in multiple sclerosis (MS) is a significant contributor to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. Thus, there is a need for better understanding of its pathophysiology. This chapter reviews a growing body of evidence which suggests that mis-tuning of Purkinje cells, due to expression of an abnormal repertoire of sodium channels, contributes to cerebellar deficits in MS. Within the normal nervous system, sodium channel Na(v)1.8 is expressed in a highly specific manner within spinal sensory and trigeminal neurons, and is not present within Purkinje cells, Na(v)1.8 mRNA and protein are, however, expressed within Purkinje cells both in models of MS (experimenal autoimmume encephalomyelitis; EAE), and in postmortem tissue from humans with MS. Expression of Na(v)1.8 within Purkinje cells in vitro alters electrogenesis in these cells in several ways: first, by increasing duration and amplitude of action potentials; second, by decreasing the proportion of action potentials that are conglomerate and the number of spikes per conglomerate action potential; and third, by supporting sustained, pacemaker-like impulse trains in response to depolarization, which are not seen in the absence of Na(v)1.8. Similar changes are observed in recordings from Purkinje cells in vivo from mice with EAE. Taken together, these results suggest that expression of Na(v)1.8 within Purkinje cells distorts their pattern of firing in MS.

Warren, J. D., J. M. Schott, et al. (2005). "Brain biopsy in dementia." Brain 128(Pt 9): 2016-25.

            Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Virley, D. J. (2005). "Developing therapeutics for the treatment of multiple sclerosis." NeuroRx 2(4): 638-49.

            Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an alpha4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.

Viel, E., F. Pellas, et al. (2005). "[Peripheral neurolytic blocks and spasticity]." Ann Fr Anesth Reanim 24(6): 667-72.

            Peripheral nerve blockade is one of the therapeutic possibilities to treat 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 from having efficient rehabilitation. Test-blocks as well as 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 occurred and minor side effects are transient painful phenomena during injection. These approaches proved to be accurate, fast, simple, highly successful and reproducible. Percutaneous neurolytic procedures should be done 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 neuron.

Vermersch, P., T. Stojkovic, et al. (2005). "Mycophenolate mofetil and neurological diseases." Lupus 14 Suppl 1: s42-5.

            We describe experience with the use of mycophenolate mofetil (MMF) in neurological diseases. Although only small series of patients or case reports were described, MMF is promising in immune-mediated neuromuscular disorders. MMF has been used for the treatment of polymyositis, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. These studies showed that MMF is well tolerated and may be useful in some patients. MMF can be effective alone but mainly as an adjuvant therapy by reducing steroid requirements or the frequency of infusions of IVIg. MMF has also been tested alone as a single drug treatment or in combination with immunomodulatory drugs in multiple sclerosis in open surveillance trials or in phase II studies. None of these studies have been designed to demonstrate a clinical efficacy but preliminary results are very promising.

Verbeek, M. M., M. A. Willemsen, et al. (2005). "[Diagnosis in cerebrospinal fluid: possible applications in neurological practice]." Ned Tijdschr Geneeskd 149(33): 1833-8.

            Examination of the cerebrospinal fluid (CSF) is part of the modern diagnostics of many neurological diseases. When an acute or chronic meningitis or encephalitis is suspected, the distinction between an acute viral and a bacterial intrathecal infection can generally be rapidly made via examination of the CSF. In case of a chronic infection this will determine the direction of further microbiological analysis. When there are clinical indications for subarachnoid haemorrhage but no abnormalities on the CT-scan, it can be either demonstrated or excluded by means of spectrophotometric analysis of blood pigments in the CSF. In case of possible multiple sclerosis (MS) and contraindications for MRI, or if the combination of the clinical symptoms and MRI does not yield a definitive diagnosis, then the demonstration of unique oligoclonal IgG-bands in the CSF is an important parameter in confirming a diagnosis of 'MS'. In practice, metastases to the leptomeninges are often detected by means of (repeated) cytopathological analysis of the CSF, which has a higher sensitivity and specificity than MRI. Examination of the CSF also plays an important role in the diagnosis of (hereditary) metabolic encephalopathies in childhood. In case of watery discharge from the nose or ear following trauma or neurosurgery, it can be determined whether or not this is leaking CSF. Analysis of certain brain-specific proteins in the CSF can contribute to the differential diagnosis of dementia syndromes. The added diagnostic value of examination of the CSF in hypokinetic rigidity syndromes is still unclear. The complications of a spinal puncture often remain limited to post-puncture headache. Contraindications include intracranial space-occupying abnormalities, compression of the spinal cord, haemorrhagic diathesis and abnormalities around the puncture site.

Vandevelde, M. and A. Zurbriggen (2005). "Demyelination in canine distemper virus infection: a review." Acta Neuropathol (Berl) 109(1): 56-68.

            Canine distemper virus (CDV) causes severe immunosuppression and neurological disease in dogs, associated with demyelination, and is a model for multiple sclerosis in man. In the early stage of the infection, demyelination is associated with viral replication in the white matter. In acute demyelinating lesions there is massive down-regulation of myelin transcription and metabolic impairment of the myelin-producing cells, but there is no evidence that these cells are undergoing apoptosis or necrosis. Oligodendroglial change is related to restricted infection of these cells (transcription but no translation) and marked activation of microglial cells in acute lesions. Concomitant with immunological recovery during the further course of the disease, inflammation occurs in the demyelinating plaques with progression of the lesions in some animals. A series of experiments in vitro suggests that chronic inflammatory demyelination is due to a bystander mechanism resulting from interactions between macrophages and antiviral antibodies. Autoimmune reactions are also observed, but do not correlate with the course of the disease. The progressive or relapsing course of the disease is associated with viral persistence in the nervous system. Persistence of CDV in the brain appears to be favored by non-cytolytic selective spread of the virus and restricted infection, in this way escaping immune surveillance in the CNS. The CDV Fusion protein appears to play an important role in CDV persistence. Similarities between canine distemper and rodent models of virus-induced demyelination are discussed.

Vandenbark, A. A. (2005). "TCR peptide vaccination in multiple sclerosis: boosting a deficient natural regulatory network that may involve TCR-specific CD4+CD25+ Treg cells." Curr Drug Targets Inflamm Allergy 4(2): 217-29.

            Vaccination with self peptides contained within T cell receptor (TCR) chains, expressed by pathogenic Th1 cells can induce a second set of regulatory T cells that can reverse paralysis in rodents with experimental encephalomyelitis, and similarly, may have the potential to regulate myelin-reactive Th1 cells in patients with multiple sclerosis (MS). In this review, we discuss our recent discovery that TCR-reactive T cells generally possess classical inhibitory activity associated with Treg cells. CD4+CD25+ TCR-reactive T cells can inhibit CD4+CD25- indicator cells stimulated with anti-CD3/anti-CD28 antibody in a dose-dependent and cell-contact-dependent manner. Additionally, CD4+CD25+ T cells from blood of healthy control donors have significant responses to a pool of discriminatory TCR peptides, including BV10S1P, BV19S20, BV13S7, BV12S2A2T, BV11S1A1T, BV21S3A1T, AV15S1, and BV12S1A1N1. Patients with MS have varying degrees of deficient responses to TCR peptides, and by association, a defect in Treg cell function as well. TCR peptide vaccination using a new tripeptide mixture emulsified in IFA produced strong T cell responses in 100% of MS recipients, a dramatic improvement over previous vaccines given i.d. in saline that induced TCR-reactive T cell responses in about 50% of recipients. Responders to vaccination had a tendency towards reduced MRI lesions, and an early indication of enhanced Treg activity mediated by TCR-reactive T cells that could provide suppression of target as well as bystander T cells. These data provide a strong foundation for future TCR vaccination studies that will critically test the ability of the tripeptide mixture to induce significantly enhanced Treg activity and possible clinical and MRI benefits in vivo.

van Meeteren, M. E., C. E. Teunissen, et al. (2005). "Antioxidants and polyunsaturated fatty acids in multiple sclerosis." Eur J Clin Nutr 59(12): 1347-61.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

van den Broek, H. H., J. G. Damoiseaux, et al. (2005). "The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review." Mult Scler 11(3): 349-59.

            The female predominance of multiple sclerosis (MS) has suggested that hormonal differences between the sexes must confer some protective effect on males or enhance the susceptibility of females to this disease. There has been evidence that gonadal hormones can modulate the immune response regulated by antigen presenting cells and T cells. These cells control the immune response by the production of interacting pro- and anti-inflammatory cytokines. The first include the acute phase pro-inflammatory cytokines of the innate immune response as well as the T-helper 1 (Th1) cytokines, while the later contain the Th2 cytokines as well as the suppressor cytokines. There is some evidence that MS and experimental autoimmune encephalitis (EAE) are Th1 cell-mediated diseases. For this reason many studies have been done to influence the pro-inflammatory cytokine production of these Th1 cells in favour of an anti-inflammatory immune response as mediated by Th2 cells. However the role of the regulatory T cells in this context is not clearly understood. Here we review the studies concerning the role of sex hormones on the cytokine production in relation to the disease course of MS and EAE and in particular in the light of the recent revival of the regulatory T cells and their suppressive cytokines.

Ursell, M. R. and P. W. O'Connor (2005). "Natalizumab and other monoclonal antibodies." Neurol Clin 23(1): 233-46, viii.

Tzakos, A. G., A. Troganis, et al. (2005). "Structure and function of the myelin proteins: current status and perspectives in relation to multiple sclerosis." Curr Med Chem 12(13): 1569-87.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and loss of neurological function, local macrophage infiltrate and neuroantigen-specific CD4(+)T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of myelin-specific antigens derived from myelin basic protein, the most abundant extrinsic myelin membrane protein, and/or another equally suitable myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of myelin proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted myelin multilayers, becomes central to understanding how and why myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the proteins and lipids within the myelin multilayers; (ii) on the structure-function relationships and characterization of the myelin proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments.

Tyndall, A. and R. Saccardi (2005). "Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions." Clin Exp Immunol 141(1): 1-9.

            Around 700 patients have received an autologous haematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease (AD). The majority of these have been within the context of phase I/II clinical trials and following international guidelines proposed 7 years ago. In general, a positive benefit/risk ratio has led to phase III prospective randomized controlled trials in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis (RA) in Europe. In the US, similar trials are being planned for SSc, MS and systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has fallen in all disease subgroups since the inception due to more appropriate patient selection, and so far a clear advantage of the more intense myeloablative regimens in terms of remission induction and relapse rate has not emerged. Although each AD has a different profile, over a third of patients have sustained a durable remission, often with no further need for immunosuppressive drugs. In those who relapsed, many responded to agents which pre transplant had been ineffective. The study of immune reconstitution and gene expression pre and post HSCT is being undertaken to further understand the mechanism of autoimmunity.

Tyndall, A. and T. Daikeler (2005). "Autologous hematopoietic stem cell transplantation for autoimmune diseases." Acta Haematol 114(4): 239-47.

            Ten years have passed since the first published consensus statement on the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe autoimmune disease (AD) appeared. During that time, around 700 patients suffering from severe AD have undergone HSCT in the frame of phase I/II clinical trials from over 20 countries including the US. The majority have received an autologous HSCT using one of a limited number of regimens, consistent with the original consensus statement. Long-term drug-free remissions, remission then relapse, no response and treatment-related mortality (TRM) were seen in all the subgroups of AD. An overall TRM of 7% was observed, with marked variation between ADs, i.e. 11% in systemic lupus erythematosus (SLE) and only 1 patient in rheumatoid arthritis (RA). Phase III prospective, comparative randomized trials are running or being planned in multiple sclerosis (MS), systemic sclerosis (SSc), SLE and RA. Basic science programs are also being undertaken to study the immunological mechanisms underlying the clinical events observed.

Tullman, M. J. and F. D. Lublin (2005). "Combination therapy in multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 245-8.

            Over the past decade, multiple sclerosis (MS) has become a treatable neurologic illness. However, given the rather modest benefit of the currently available disease-modifying agents, as well as the challenges associated with performing placebo-controlled, equivalence, and superiority trials, the logic of combining therapies in MS has considerable appeal. Selecting agents for combination requires careful consideration, as the immunomodulating activity of one drug could potentially interfere with the therapeutic effect of another, and certain combinations may be associated with unforeseen adverse effects. Rigorously controlled studies are needed to determine the safest and most effective use of new and existing MS therapies.

Trotter, J. (2005). "NG2-positive cells in CNS function and the pathological role of antibodies against NG2 in demyelinating diseases." J Neurol Sci 233(1-2): 37-42.

            NG2 is expressed by a variety of immature glia in the CNS including oligodendrocyte progenitor cells, paranodal astrocytes and perisynaptic glia. The protein has a large extracellular domain with two LNS/Lam G domains at the N-terminus and a short intracellular tail with a PDZ-recognition domain at the C-terminus. Experiments suggest that the protein plays a role in migration. The PDZ protein GRIP was identified as an intracellular binding partner of NG2 in immature glial cells. A complex is formed between GRIP, NG2 and the AMPA class of glutamate receptors: this may position these glial receptors towards sites of neuronal glutamate release at synapses and during myelination. Identification of neuronal receptors and links to the cytoskeleton of NG2 is of critical importance. Some Multiple Sclerosis patients have autoantibodies to NG2 in the cerebral spinal fluid: such antibodies could interfere with remyelination by lysing oligodendrocyte progenitor cells or blocking their migration but may also cause pathology by disrupting glial-neuronal signalling at synapses and paranodes.

Trebst, C. and M. Stangel (2005). "[Cannabinoids in multiple sclerosis -- therapeutically reasonable?]." Fortschr Neurol Psychiatr 73(8): 463-9.

            For centuries extracts from the Cannabis sativa plant have been used for recreational use and as remedies. Anecdotal reports from patients with multiple sclerosis (MS) experiencing relief of their spasticity and pain after smoking marihuana have prompted discussions about a potential therapeutic application of cannabis preparations in MS. Only recently the first large, multicenter, double-blind, placebo controlled study was conducted evaluating the use of cannabinoids for treatment of spasticity and other symptoms related to MS. Based on this trial and previous uncontrolled observations together with insights from basic research and animal experiments there is reasonable evidence for the therapeutical employment of cannabinoids in the treatment of MS related symptoms. Furthermore, data are arising that cannabinoids have immunomodulatory and neuroprotective properties. However, results from clinical trials do not allow the recommendation for the general use of cannabinoids in MS. This article summarizes the present knowledge of clinical and experimental research regarding the therapeutic potential of cannabinoids for the treatment of MS.

Traboulsee, A., G. Zhao, et al. (2005). "Neuroimaging in multiple sclerosis." Neurol Clin 23(1): 131-48, vii.

Totolian, N. A. (2005). "[Magnetic-resonance tomography in differential diagnosis of brain lesions in demyelinating and systemic autoimmune diseases]." Zh Nevrol Psikhiatr Im S S Korsakova 105(5): 42-6.

            An aim of the study was to establish MRT signs that may be useful for differential diagnosis of multiple sclerosis (MS). Three groups of patients have been examined: 300 patients with MS, 35 with demyelinating diseases (acute disseminated encephalomyelitis, neuromyelitis optica--Devic's syndrome); 90 patients with systemic autoimmune diseases (systemic lupus erythematosus, primary antiphospholipid syndrome, sclerodermatitis, Sjugren's syndrome, autoimmune thyroiditis, vasculitis and vasculopathy). Classification of MRT syndromes in MS and their frequency are presented: syndrome of chronic inflammatory demyelination (79%), syndrome of acute inflammatory demyelination (9%), syndrome of multifocal degenerative leucoencephalopathy (8%), syndrome of combined multifocal diffusive leucoencephalopathy (4%). The similarity and differences in MRT semiotics of the above diseases and MS are described.

Totolian, N. A. (2005). "[Betaferon in the treatment of multiple sclerosis: efficacy standards]." Zh Nevrol Psikhiatr Im S S Korsakova 105(7): 63-6.

Titelbaum, D. S., A. Degenhardt, et al. (2005). "Anti-tumor necrosis factor alpha-associated multiple sclerosis." AJNR Am J Neuroradiol 26(6): 1548-50.

            A case of multiple sclerosis presenting during anti-tumor necrosis factor treatment for rheumatoid arthritis is discussed. This association has been reported in the nonradiological literature, but is an important association for radiologists to be aware of, as they may be in a position to first suggest the diagnosis.

Thomson, T. D. and W. J. Taylor (2005). "Evidence for inpatient rehabilitation as an effective intervention." Hosp Med 66(4): 200-4.

            Rehabilitation in inpatient settings is expensive and staff-intensive. It is necessary for such services to demonstrate effectiveness to justify this. In contrast to popular notions, evidence for the effectiveness of inpatient rehabilitation does exist and is reviewed in this article. In particular, there is very good evidence for specialized inpatient stroke care and rehabilitation.

Thompson, A. J. (2005). "Neurorehabilitation in multiple sclerosis: foundations, facts and fiction." Curr Opin Neurol 18(3): 267-71.

            PURPOSE OF REVIEW: This review of recent work in the area of neurorehabilitation of multiple sclerosis patients surveys progress and underscores the need for further work to evaluate the effectiveness of treatments. RECENT FINDINGS: Several recent review documents have summarized the current position regarding neurorehabilitation and symptomatic management in multiple sclerosis. They have highlighted the paucity of evidence underpinning current practice, thereby identifying the need for more scientifically sound studies in both neurorehabilitation and symptomatic treatment. However, as will be apparent from this review, there has been a welcome increase in studies evaluating both aspects of neurorehabilitation and specific areas such as the role of cannabinoids in spasticity and pain and new treatments for cognitive impairment. SUMMARY: Overall, there is an encouraging trend both in questioning our current practice and in designing more scientifically sound trials incorporating new and more appropriate outcome measures. There is, however, much more to be done before we are in a position to provide the expert, comprehensive, joined-up, care that is required to meet the complex, ever-changing needs of patients with multiple sclerosis.

Thaut, M. H., D. A. Peterson, et al. (2005). "Temporal entrainment of cognitive functions: musical mnemonics induce brain plasticity and oscillatory synchrony in neural networks underlying memory." Ann N Y Acad Sci 1060: 243-54.

            In a series of experiments, we have begun to investigate the effect of music as a mnemonic device on learning and memory and the underlying plasticity of oscillatory neural networks. We used verbal learning and memory tests (standardized word lists, AVLT) in conjunction with electroencephalographic analysis to determine differences between verbal learning in either a spoken or musical (verbal materials as song lyrics) modality. In healthy adults, learning in both the spoken and music condition was associated with significant increases in oscillatory synchrony across all frequency bands. A significant difference between the spoken and music condition emerged in the cortical topography of the learning-related synchronization. When using EEG measures as predictors during learning for subsequent successful memory recall, significantly increased coherence (phase-locked synchronization) within and between oscillatory brain networks emerged for music in alpha and gamma bands. In a similar study with multiple sclerosis patients, superior learning and memory was shown in the music condition when controlled for word order recall, and subjects were instructed to sing back the word lists. Also, the music condition was associated with a significant power increase in the low-alpha band in bilateral frontal networks, indicating increased neuronal synchronization. Musical learning may access compensatory pathways for memory functions during compromised PFC functions associated with learning and recall. Music learning may also confer a neurophysiological advantage through the stronger synchronization of the neuronal cell assemblies underlying verbal learning and memory. Collectively our data provide evidence that melodic-rhythmic templates as temporal structures in music may drive internal rhythm formation in recurrent cortical networks involved in learning and memory.

Thakur, G. A., S. P. Nikas, et al. (2005). "CB1 cannabinoid receptor ligands." Mini Rev Med Chem 5(7): 631-40.

            The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

Teunissen, C. E., M. P. van Boxtel, et al. (2005). "Homocysteine in relation to cognitive performance in pathological and non-pathological conditions." Clin Chem Lab Med 43(10): 1089-95.

            Elevated serum homocysteine has been associated with increased risk of Alzheimer's disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimer's and Parkinson's disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=-0.36 to -0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinson's disease on L-Dopa therapy (18.9 vs. 16.5 micromol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0 micromol/L, n=39, compared to 12.0 micromol/L in 45 controls) and correlated to both cognitive and motor function (r=-0.33 and -0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Tepavcevic, V. and W. F. Blakemore (2005). "Glial grafting for demyelinating disease." Philos Trans R Soc Lond B Biol Sci 360(1461): 1775-95.

            Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.

Tench, C. R., P. S. Morgan, et al. (2005). "Spinal cord imaging in multiple sclerosis." J Neuroimaging 15(4 Suppl): 94S-102S.

            Multiple sclerosis (MS) is a chronic neurological condition characterized pathologically by axonal loss, demyelination, inflammation, and gliosis. Magnetic resonance imaging (MRI) has had a major impact on diagnosing MS, understanding the condition, and monitoring the effects of treatments. Recently, spinal cord MRI has received increased attention. Advanced techniques have been used to image the spinal cord, particularly the cervical cord, and measure quantitative parameters such as T1 relaxation time, magnetization transfer ratio, and diffusivity. These metrics show central nervous system abnormalities in MS patients and various correlations with disability and might reflect specific pathological processes. Image analysis techniques have also been developed and combined with high-resolution MRI to measure the cord cross-sectional area (CSA), a metric that relates to cord atrophy. The cord CSA is reduced in MS patients compared to normal controls and correlates with disability. Furthermore, changes in CSA are detectable and correlate with changes in disability. Despite the technical difficulties of performing spinal cord MRI, imaging studies, particularly of the cervical cord, are becoming more common. Significant focus has been placed on measuring cord atrophy, and reproducible techniques have been developed to measure the cervical cord CSA. Spinal cord MRI may provide information about disease progression that is not readily available from brain MRI scans and could be useful in diagnosing MS in some cases, as well as for monitoring the effects of treatments.

Tedeschi, G. and A. Gallo (2005). "Multiple sclerosis patients and immunomodulation therapies: the potential role of new MRI techniques to assess responders versus non-responders." Neurol Sci 26 Suppl 4: S209-12.

            Disease-modifying drugs (DMD) are effective in reducing relapses and magnetic resonance imaging (MRI) lesions in multiple sclerosis (MS). Nevertheless, individual treatment responses are variable, and accurate and reliable methods to identify DMD responsiveness have not been validated. Although extremely relevant in the study and management of MS, MRI data have not been systematically tested to answer this question yet. Here we present non-conventional MRI data, including magnetisation transfer imaging (MTI), diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy ((1)HMRS). As these techniques are more sensitive to microstructural tissue changes and more specific for the heterogeneous pathological substrates of MS lesions, we anticipate their potential role for detecting relevant changes of tissue pathology during treatment of MS patients and, consequently, for a better definition of response status to therapy.

Teare, L. and J. Zajicek (2005). "The use of cannabinoids in multiple sclerosis." Expert Opin Investig Drugs 14(7): 859-69.

            Naturally occurring cannabinoids including Delta9-tetrahydrocannabinol and cannabidiol as well as endocannabinoids and synthetic cannabinoids may have a role in modulating experimental models of multiple sclerosis. Recent clinical studies to treat symptoms of multiple sclerosis have shown varying results, which may reflect issues relating to the way in which such studies were conducted. There is now increasing interest in the potential role of cannabinoids not only in symptom relief, but also for their possible neuroprotective actions.

t Hart, B. A., J. Bauer, et al. (2005). "Non-human primate models of experimental autoimmune encephalomyelitis: Variations on a theme." J Neuroimmunol 168(1-2): 1-12.

            Despite years of intensive research into multiple sclerosis (MS) scientists have not yet succeeded in developing an absolute therapy for the treatment of this disabling disease of the human central nervous system. The wide immunological gap between inbred rodent strains and the heterogeneous human population is probably the single most important factor that hampers the translation of scientific principles developed in rodents into effective therapies for MS. Because of the closer immunological proximity to humans, non-human primates provide useful experimental models that may help to bridge this gap. Here we review the models of experimental autoimmune encephalomyelitis in rhesus macaques and common marmosets. We will discuss the salient points of the models and suggest how these may represent the spectrum of inflammatory demyelinating diseases of the central nervous system in humans.

t Hart, B. A. and K. Heije (2005). "Broad spectrum immune monitoring in immune-mediated inflammatory disorders." Drug Discov Today 10(20): 1348-51.

Szczepanik, M., M. Tutaj, et al. (2005). "[Experimental methods in the treatment of multiple sclerosis--new possibilities and hopes]." Przegl Lek 62(2): 115-8.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelinization. Although our knowledge on the pathomechanism of MS has evolved dramatically in recent years; however there is still no effective cure for MS. So far, non-specific immune suppressive agents are used to slow down the disease. Recently, there are many efforts to find a new method that would allow to control specifically unwanted immune response. It might be achieved by affecting antigen recognition or induction of "immune deviation".

Sykes, M. and B. Nikolic (2005). "Treatment of severe autoimmune disease by stem-cell transplantation." Nature 435(7042): 620-7.

            Transplantation of haematopoietic stem cells--cells capable of self renewing and reconstituting all types of blood cell--can treat numerous lethal diseases, including leukaemias and lymphomas. It may now be applicable for the treatment of severe autoimmune diseases, such as therapy-resistant rheumatoid arthritis and multiple sclerosis. Studies in animal models show that the transfer of haematopoietic stem cells can reverse autoimmunity, and several mechanistic pathways may explain this phenomenon. The outcome of ongoing clinical trials, as well as of studies in patients and animal models, will help to determine the role that stem-cell transplantation can play in the treatment of autoimmune diseases.

Suchkov, S. V., Z. S. Alekberova, et al. (2005). "[Achievements and prospects of clinical abzymology]." Vestn Ross Akad Med Nauk(9): 38-43.

            Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

Suarez Alvarez, L., G. R. Hughes, et al. (2005). "[Neurological manifestations of the antiphospholipid syndrome]." Med Clin (Barc) 124(16): 630-3.

            Antiphospholipid syndrome can be associated with several neurological manifestations. The most common symptom is headache. It has also been associated with cognitive dysfunction, probably due to ischemia. A high prevalence of antiphospholipid antibodies has been found in patients with epilepsy and in transverse myelitis. The most common thrombotic manifestation is stroke. Venous thrombosis can also be found, yet it is less frequent. A stroke in a young person obliges to rule out the antiphospholipid syndrome. The neurological manifestations can mimic multiple sclerosis. Thus, determination of antiphospholipid antibodies is recommended in the study of patients with atypical manifestations of multiple sclerosis. Other manifestations associated with antiphospholipid antibodies include chorea, neurosensorial deafness, Guillain-Barre syndrome, and psychotic disorders.

Stys, P. K. (2005). "General mechanisms of axonal damage and its prevention." J Neurol Sci 233(1-2): 3-13.

            Axonal degeneration is a prominent pathological feature in multiple sclerosis observed over a century ago. The gradual loss of axons is thought to underlie irreversible clinical deficits in this disease. The precise mechanisms of axonopathy are poorly understood, but likely involve excess accumulation of Ca ions. In healthy fibers, ATP-dependent pumps support homeostasis of ionic gradients. When energy supply is limited, either due to inadequate delivery (e.g., ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g., conduction along demyelinated axons), ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload. During Na pump dysfunction, Na can enter axons through non-inactivating Na channels, promoting axonal Na overload and depolarization by allowing K egress. This will gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchange, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Neurotransmitters such as glutamate can be released by reverse operation of Na-dependent transporters, in turn activating a variety of ionotropic and metabotropic receptors, further exacerbating overload of cellular Ca. Together, this Ca overload will inappropriately stimulate a variety of Ca-dependent enzyme systems (e.g., calpains, phospholipases), leading to structural and functional axonal injury. Pharmacological interruption at key points in these interrelated injury cascades (e.g., at voltage-gated Na channels or AMPA receptors) may confer significant neuroprotection to compromised central axons and supporting glia. Such agents may represent attractive adjuncts to currently available immunomodulatory therapies.

Strupp, M. and T. Brandt (2005). "[Neurology--current treatment concepts]." Dtsch Med Wochenschr 130(25-26): 1536-9.

Strong, M. J., S. Kesavapany, et al. (2005). "The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?" J Neuropathol Exp Neurol 64(8): 649-64.

            Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies that have in common progressive degeneration of both upper and lower motor neurons, ultimately giving rise to a relentless loss of muscle function. This progressive degeneration is associated with heightened levels of oxidative injury, excitotoxicity, and mitochondrial dysfunction--all occurring concurrently. In this article, we review the evidence that suggests, in common with other age-dependent neurodegenerative disorders, that ALS can be considered a disorder of protein aggregation. Morphologically, this is evident as Bunina bodies, ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates in familial ALS variants harboring mutations in SOD1, peripherin-immunoreactive aggregates within spinal motor neurons and as neuroaxonal spheroids, and in an increasingly greater population of patients with ALS with cognitive impairment, both intra- and extraneuronal tau aggregates. We review the evidence that somatotopically specific patterns of altered kinase and phosphatase activity are associated with alterations in the phosphorylation state of these proteins, altering either solubility or assembly characteristics. The role of nonneuronal cells in mediating motor neuronal injury is discussed in the context of alterations in tyrosine kinase activity and enhanced protein phosphorylation.

Stewart, T. M. and A. C. Bowling (2005). "Polyunsaturated fatty acid supplementation in MS." Int MS J 12(3): 88-93.

            This article focuses on polyunsaturated fatty acid (PUFA) supplementation, which is a popular form of complementary and alternative therapy among people with MS. Owing to their popularity, clinicians should be knowledgeable about the PUFA supplements that are widely available, and the efficacy and safety data from clinical studies. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA supplementation is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant caution. A review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials are required to confirm the benefits.

Steultjens, E. M., J. Dekker, et al. (2005). "Evidence of the efficacy of occupational therapy in different conditions: an overview of systematic reviews." Clin Rehabil 19(3): 247-54.

            OBJECTIVE: To summarize the research evidence available from systematic reviews of the efficacy of occupational therapy (OT) for practitioners, researchers, purchasing organizations and policy-makers. DATA SOURCE: The search for systematic reviews was conducted in PubMed and the Cochrane Library (October 2004). METHODS: The reviews included were those that utilized a systematic search for evidence with regard to OT for specific patient groups. Data were summarized for patient group, interventions, outcome domains, type of study designs included, method of data synthesis and conclusions. RESULTS: Fourteen systematic reviews were included. Three reviews related to rheumatoid arthritis, four reviewed stroke and four focused on elderly people. Reviews of Parkinson's disease, multiple sclerosis, Huntington's disease, cerebral palsy and mental illnesses were also identified. The reviews of rheumatoid arthritis, stroke and elderly people showed evidence of the efficacy of OT in increasing functional abilities. Positive results were presented for quality of life and social participation in elderly people and stroke respectively. The efficacy of OT in all other patient groups is unknown due to insufficient evidence. CONCLUSION: This summary shows that elderly people and people with stroke or rheumatoid arthritis can expect to benefit from comprehensive OT. Evidence of the efficacy of specific interventions is sparse and should be addressed in future research. The evidence that does exist should be incorporated into OT practice.

Stepien, K., M. Tomaszewski, et al. (2005). "Neuroprotective properties of statins." Pharmacol Rep 57(5): 561-9.

            Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.

Steinman, L. (2005). "Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab." Nat Rev Drug Discov 4(6): 510-8.

            Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, alpha4beta1 integrin was identified as the key molecule involved in homing to inflamed regions of the brain. An antibody to alpha4beta1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds alpha4beta1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.

Steinman, L. and S. S. Zamvil (2005). "Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis." Trends Immunol 26(11): 565-71.

            Experimental autoimmune encephalomyelitis (EAE) is a useful model for aiding the development of new treatments for MS. All therapies approved for MS ameliorate EAE. Two approved medications, glatiramer acetate and Natalizumab, were developed directly from studies in EAE. Several trials are ongoing in MS after success in EAE, including altered peptide ligands of myelin, DNA vaccines and statins. However, EAE has failed to predict the outcome of certain approaches. The reasons underlying such failures are discussed here.

Steinman, L., P. J. Utz, et al. (2005). "Suppression of autoimmunity via microbial mimics of altered peptide ligands." Curr Top Microbiol Immunol 296: 55-63.

            Molecular mimics of self-antigens can behave as altered peptide ligands and serve to ameliorate autoimmune disease. Analysis of experimental autoimmune encephalomyelitis with proteomic autoantibody microarrays reveals that there might exist a wide variety of microbes with features that mimic self-epitopes. Autoimmunity could therefore be modulated via microbial immunity, which may account for relapse and remission of ongoing disease.

Steck, A. J. (2005). "[Use of intravenous immunoglobulin in neurological disorders]." Rev Med Suisse 1(17): 1167-70.

            The use of intravenous immunglobulin in the treatment of Guillain-Barre-Syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathies is well established. Other conditions, such as dysglobulinemic neuropathy, myasthenia gravis, multiple sclerosis and inclusion body myositis may also benefit from the administration of intravenous immunoglobulins.

Stangel, M. and R. Gold (2005). "[High-dose intravenous immunoglobulins in the treatment of multiple sclerosis. An update]." Nervenarzt 76(10): 1267, 1269-70, 1272.

            The immunomodulatory treatment of multiple sclerosis (MS) with high-dose intravenous immunoglobulins (IVIg) has been discussed with some controversy in the context of evidence-based medicine. The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIg treatment in MS. Here we summarize and critically discuss the new data in the context of previous studies on this treatment. In relapsing-remitting MS, IVIg remain a second-line treatment when other licensed treatments are not possible. Currently there is no role for IVIg in secondary progressive MS. Similarly, the use of IVIg during an acute relapse shows no benefit in addition to standard steroid treatment. The initiation of IVIg therapy after a clinically isolated syndrome has delayed the occurrence of definite MS, and this may become a new indication. Furthermore, previous data suggesting that IVIg can reduce the incidence of postpartal rel