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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 relapses have been substantiated. However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIg in MS are supported by the new data.

Sriram, S. and I. Steiner (2005). "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis." Ann Neurol 58(6): 939-45.

            Despite many years of intensive research, multiple sclerosis (MS) defies understanding and treatment remains suboptimal. The prevailing hypothesis is that MS is immune mediated and that experimental allergic encephalomyelitis (EAE) is a suitable model to elucidate pathogenesis and devise therapy. This review examines critically the validity that EAE is an adequate and useful animal model of MS and finds credible evidence lacking. EAE represents more a model of acute central nervous system inflammation than the counterpart of MS. We propose to reconsider the utilization of EAE, especially when this model is used to define therapy. This will also force us to examine MS without the restraints imposed by EAE, as to what it is, rather than what it looks like.

Spitsberg, V. L. (2005). "Invited review: Bovine milk fat globule membrane as a potential nutraceutical." J Dairy Sci 88(7): 2289-94.

            For the last 15 yr, a great deal of knowledge has been accumulated on health beneficial factors, protein and nonprotein, of bovine milk fat globule membrane (MFGM). Among the health-beneficial components of the MFGM are cholesterolemia-lowering factor, inhibitors of cancer cell growth, vitamin binders, inhibitor of Helicobacter pylori, inhibitor of beta-glucuronidase of the intestinal Escherichia coli, xanthine oxidase as a bactericidal agent, butyrophilin as a possible suppressor of multiple sclerosis, and phospholipids as agents against colon cancer, gastrointestinal pathogens, Alzheimer's disease, depression, and stress. All of the above compel us to consider bovine MFGM as a potential nutraceutical.

Sospedra, M. and R. Martin (2005). "Immunology of multiple sclerosis." Annu Rev Immunol 23: 683-747.

            Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

Sospedra, M. and R. Martin (2005). "Antigen-specific therapies in multiple sclerosis." Int Rev Immunol 24(5-6): 393-413.

            During recent years, many new therapies for human autoimmune diseases such as multiple sclerosis (MS) have been considered based on promising in vitro data or animal experiments. A number of them have proceeded to early clinical testing. However, very few finally advanced to approval by the regulatory agencies and are currently available to patients. The main reasons for failure were either lack of efficacy in humans and/or unexpected and untolerable adverse events. Although previous attempts toward antigen-specific immunomodulation have often been disappointing, these difficulties have led to renewed interest in therapies that aim at reestablishing tolerance to autoantigens at the level of either T cell-mediated or antibody-mediated immune responses or both. Such antigen-specific immunotherapies offer the prospect of correcting pathological immune reactivity against autoantigens in a highly specific and effective manner and also achievement of this goal with relatively little side effects. Here we will review the various approaches that are currently being considered for antigen-specific immunotherapies in MS.

Sorensen, P. S., F. Deisenhammer, et al. (2005). "Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis." Eur J Neurol 12(11): 817-27.

            Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Solari, A. (2005). "Role of health-related quality of life measures in the routine care of people with multiple sclerosis." Health Qual Life Outcomes 3: 16.

            Health-related quality of life instruments are expected to be of particular value in routine care of people with multiple sclerosis (MS), where they may facilitate the detection of disease aspects that would otherwise go unrecognised, help clinicians appreciate patient priorities particularly in terms of treatment goals, facilitate physician-patient communication, and promote shared decision-making. However, it appears that these instruments are little used routine clinical approaches to people with MS. To address this issue, I performed a bibliographic search of studies that evaluated the efficacy of generic or disease-specific health-related quality of life (HRQOL) instruments in MS clinical practice from clinicians' or patients' perspectives. I found only one cross-sectional study, which compared preferences for three instruments, and assessed acceptability in people with MS.Reasons for lack of transfer of HRQOL measurements to clinical practice may be cultural, methodological, or practical. With regard to MS, the proliferation of instruments seems to constitute a barrier, with no particular instrument having gained wide popularity or consensus. Other barriers are lack of resources for the administration, collection and storage of the data, and inability of clinicians to score, interpret, and use HRQOL instrument to guide clinical care. It is therefore important to refine existing tools, extending clinical validation to wider contexts and cultures. More studies assessing acceptability and clinicians' and patients' preferences for different instruments are also required.

Solanky, M., D. Van Engel, et al. (2005). "Aggressive central nervous system demyelination in an adolescent." Rev Neurol Dis 2(1): 35-8.

            A 15-year-old boy diagnosed with a severe, active, and aggressive form of multiple sclerosis (MS) failed conventional, evidence-based therapy. The optimal treatment of the child or adolescent failing federally approved therapy for MS is unclear, similar to the situation in adults. This case history demonstrates that aggressive immunosuppression might be of at least short-term value in controlling disease acutely in an adolescent, as in adults with MS, when evidence-based therapies do not provide an adequate response.

Sobel, R. M., S. Lotkowski, et al. (2005). "Update on depression in neurologic illness: stroke, epilepsy, and multiple sclerosis." Curr Psychiatry Rep 7(5): 396-403.

            The risk of depression is increased in chronic neurologic illness and can adversely affect the course of disease. Recent literature is reviewed for depression in stroke, epilepsy, and multiple sclerosis. Depression can share pathophysiologic aspects of the comorbid illness, such as neurotransmitter pathway disturbances, hypothalamus-pituitary-adrenal pathway disturbances, and changes in immunologic function. Depression also can be a psychologic reaction to the burden of the neurologic condition. Risk factors for development of depression are reviewed. Depression and other medical conditions can have shared symptoms (eg, fatigue, psychomotor retardation) that can complicate the diagnosis of depression in neurologic illness. Proper selection of antidepressant treatment is necessary to avoid worsening the neurologic disorder.

Smith, P. F. (2005). "The safety of cannabinoids for the treatment of multiple sclerosis." Expert Opin Drug Saf 4(3): 443-56.

            The evidence for the therapeutic efficacy of cannabinoids in the treatment of multiple sclerosis (MS) is increasing but is not as yet convincing. Although several trials have reported no significant effect, the majority of the evidence which supports a beneficial effect on spasticity and pain is based on subjective measurements in trials where unblinding was likely to be a problem. The available clinical trial data suggest that the adverse side effects associated with using cannabis-based medicinal extracts (CBMEs) are generally mild, such as dry mouth, dizziness, somnolence, nausea and intoxication, and in no case did toxicity develop. However, most of these trials were run over a period of months and it is possible that other adverse side effects, not seen in these short-term studies, could develop with long-term use. Despite the evidence that cannabinoids can disrupt cognitive function and promote depression, on the basis of current data, such adverse effects seem unlikely to be associated with the use of CBMEs. Likewise, there is no evidence to suggest that their effects on balance and motor control, or immune function, may be clinically significant. There is, however, reason to be concerned about the use of therapeutic cannabinoids by people predisposed to psychosis and by pregnant women, given the increasing evidence of their adverse effects on the fetus. In conclusion, given the modest therapeutic effects of cannabinoids demonstrated so far, and the risk of long-term adverse side effects, there is reason to be cautious about their use in the treatment of MS.

Sloka, J. S. and M. Stefanelli (2005). "The mechanism of action of methylprednisolone in the treatment of multiple sclerosis." Mult Scler 11(4): 425-32.

            Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state.

Skundric, D. S. (2005). "Experimental models of relapsing-remitting multiple sclerosis: current concepts and perspective." Curr Neurovasc Res 2(4): 349-62.

            Multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE) are debilitating paralytic diseases caused by inflammation, demyelination and axonal degeneration of the central nervous system (CNS). Whilst the autoimmune nature of MS is strongly suggested by evidence of myelin specific autoreactive T cells and antibodies, EAE is an experimentally induced CNS specific autoimmune disease. As opposed to the majority of MS patients, which exhibit a relapsing-remitting course of the disease, only a handful of available EAE models displays relapsing-remitting course. In this review, we will summarize differences in regulation of acute and relapsing disease with emphasis on relapsing-remitting EAE models, and outline advantages and limitations of available relapsing EAE models pertinent for studies of relapsing human disease. We will discuss current concepts of relapse regulation by focusing on immune and molecular mechanisms of neuroinflammation, oligodendrocyte damage, myelin loss and axonal degeneration. This review will compare our present understanding of relapse regulation in human versus experimental autoimmune disease. Translation of mechanisms learned from relapsing EAE into development of new therapies for MS will be evaluated. Finally, perspectives in further optimization and development of more suitable experimental models to study human relapsing-remitting MS will be discussed.

Sipe, J. C. (2005). "Cladribine for multiple sclerosis: review and current status." Expert Rev Neurother 5(6): 721-7.

            In the 1990s, cladribine was developed as an adenosine deaminase-resistant nucleoside analog with selective lymphotoxic specificity in the hope that it might become useful in the treatment of some lymphoid neoplasms and autoimmune disorders. Several clinical trials demonstrated very significant effectiveness and safety of cladribine in the cure of hairy-cell leukemia, and the control of many other lymphoid malignancies. Cladribine was also extensively tested in selected autoimmune disorders, most notably in multiple sclerosis, with evidence of efficacy, tolerability and acceptable side effects/toxicity. The previous clinical studies and current status of cladribine for the treatment of multiple sclerosis are considered in this drug profile. In January 2005, Serono and IVAX announced plans to initiate a Phase III study of a specially formulated oral tablet of cladribine (Mylinax, Serono and IVAX) for the treatment of relapsing forms of multiple sclerosis. The proposed study will be the first large multicenter randomized controlled clinical trial of oral cladribine in multiple sclerosis.

Simon, J. H. (2005). "MRI in multiple sclerosis." Phys Med Rehabil Clin N Am 16(2): 383-409, viii.

            MRI provides multiple uses and applications in multiple sclerosis(MS). The basic features of the MRI-detected lesions, including the underlying pathology, are discussed. MRI allows assessment of the normal-appearing white and gray matter, and neuronal tract and functional system disturbances. An overview of the clinical significance of these MRI measures is included, as a basis for understanding their role as outcome measures in clinical trials. MRI recently assumed greater importance in its role in establishing an earlier diagnosis of MS after a first clinical event, and in monitoring subclinical disease before or subsequent to the formal diagnosis.The background to these applications and practical issues are discussed.

Simmons, D. L. (2005). "Anti-adhesion therapies." Curr Opin Pharmacol 5(4): 398-404.

            Cell adhesion molecules are key mediators of inflammatory processes and are attractive targets for discovery of novel therapeutics. There have been significant positive advances in both basic research and clinical development in this area. Basic research has yielded detailed insight into the structural basis of cell adhesion molecule function, especially the interaction of integrins with their ligands. Co-crystals of several integrin-ligand complexes have been published, including alpha v beta3 with ligand fragments, alpha IIb beta3 with multiple therapeutic ligands and alpha L beta2 (leukocyte function-associated antigen-1 [LFA-1]) with its cell-based ligand intercellular adhesion molecule-1. This has stimulated development of models of integrin function and also the mode of action of small-molecule inhibitors. The most exciting recent advances in the field of clinical development have come with the successful approval of two new anti-adhesion therapeutics: efalizumab (Raptiva) targeting LFA-1 for the treatment of chronic plaque psoriasis, and natalizumab (Tysabri/Antegren) targeting very late antigen-4 for the treatment of relapsing-remitting multiple sclerosis. However, the latter therapeutic ran into a surprising safety issue earlier this year and was withdrawn from the market, casting a shadow over what had seemed a promising new drug.

Siegert, R. J. and D. A. Abernethy (2005). "Depression in multiple sclerosis: a review." J Neurol Neurosurg Psychiatry 76(4): 469-75.

            Several studies have reported high rates of depression in multiple sclerosis (MS) with a lifetime prevalence of approximately 50% and an annual prevalence of 20% not uncommon. Concern about the potential of new drug treatments to exacerbate or precipitate depression in MS has led to increased interest in the relation between MS and depression. This review on MS and depression identifies the following key issues: How common is depression in people with MS? Is depression in MS associated with lesions in specific regions of the central nervous system? Is there an increased risk of suicide in MS? Is there a higher than expected incidence of anxiety disorders in MS? Are fatigue and depressed mood related in MS? Is there a relation between depression and cognitive impairment in MS? Which psychosocial variables affect the development of depression in MS? Does treatment with interferon increase the risk of depression? How effective are treatments for MS patients with depression? Each of these issues is briefly reviewed with critical commentary, and some priorities for future research are suggested.

Siddiqui, M. A. and K. Wellington (2005). "Intramuscular interferon-beta-1a: in patients at high risk of developing clinically definite multiple sclerosis." CNS Drugs 19(1): 55-61; discussion 63-4.

            Intramuscular interferon-beta-1a, a recombinant interferon-beta approved in the US for the treatment of relapsing forms of multiple sclerosis (MS), has also been evaluated in the treatment of patients with a first clinical demyelinating episode and brain lesions consistent with MS confirmed by magnetic resonance imaging (MRI). In a randomised, double-blind trial, patients at high risk of developing clinically definite MS who received intramuscular interferon-beta-1a 30 microg once weekly had a 44% reduction in the cumulative probability of developing MS, compared with placebo recipients (rate ratio 0.56; p = 0.002), over a 3-year period after a first, MRI-confirmed demyelinating event. These results were supported by MRI findings that showed significantly smaller increases in the volume of brain lesions and the number of new/enlarging and gadolinium-enhancing lesions in interferon-beta-1a recipients than in those receiving placebo. A nonblind extension of this trial demonstrated that early treatment with interferon-beta-1a significantly reduced the probability of developing MS by 35% (p = 0.03), compared with delayed treatment, over a 5-year period. Intramuscular interferon-beta-1a was generally well tolerated; however, influenza-like syndrome was documented in >50% of patients at high risk of developing clinically definite MS who received the drug.

Shternshis Iu, A., V. V. Sveranovskaia, et al. (2005). "[Epitope mimicry and its role in the development of autoimmune reactions]." Zh Mikrobiol Epidemiol Immunobiol(1): 96-100.

            The role of molecular mimicry in the development of some autoimmune diseases, such as rheumatism, rheumatoid arthritis, the Julian-Barre syndrome, the antiphospholipid syndrome, multiple sclerosis, is reviewed. The data on the presence in bacteria and viruses antigenic determinants similar to those in human tissues are presented. The phenomenon of epitope mimicry is considered in the light of the latest research in the field of IgE autoreactivity, which may take part in the pathogenesis of allergic diseases.

Sheremata, W. A., A. Minagar, et al. (2005). "The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications." CNS Drugs 19(11): 909-22.

            Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease.Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS.Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market.The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

Shaw, P. J. (2005). "Molecular and cellular pathways of neurodegeneration in motor neurone disease." J Neurol Neurosurg Psychiatry 76(8): 1046-57.

            The process of neuronal degeneration in motor neurone disease is complex. Several genetic alterations may be involved in motor neurone injury in familial amyotrophic lateral sclerosis, less is known about the genetic and environmental factors involved in the commoner sporadic form of the disease. Most is known about the mechanisms of motor neurone degeneration in the subtype of disease caused by SOD1 mutations, but even here there appears to be a complex interplay between multiple pathogenic processes including oxidative stress, protein aggregation, mitochondrial dysfunction excitotoxicity, and impaired axonal transport. There is new evidence that non-neuronal cells in the vicinity of motor neurones may contribute to neuronal injury. The final demise of motor neurones is likely to involve a programmed cell death pathway resembling apoptosis.

Sergott, R. C. (2005). "Optical coherence tomography: measuring in-vivo axonal survival and neuroprotection in multiple sclerosis and optic neuritis." Curr Opin Ophthalmol 16(6): 346-50.

            PURPOSE OF REVIEW: This review considers the latest developments in the use of optical coherence tomography in neuro-ophthalmology. RECENT FINDINGS: Optical coherence tomography can accurately and reproducibly quantitate the micron thickness of the peripapillary retinal nerve fiber layer, as well as the thickness and volume of the macula. It is able to perform both cross-sectional and longitudinal studies in patients with multiple sclerosis and optic neuritis. It is able to measure and assess axonal preservation and protection when used in clinical trials. SUMMARY: Specific guidelines when undertaking optical coherence tomography analyses for patients with multiple sclerosis and optic neuritis are needed to ensure uniformity among clinical trials; this development would be similar to the parameters devised when magnetic resonance imaging emerged as an important technology.

Seifert, T., C. Enzinger, et al. (2005). "Relapsing acute transverse myelitis: a specific entity." Eur J Neurol 12(9): 681-4.

            Acute transverse myelitis (ATM) not related to systemic disease may present in a relapsing manner. Data in the literature about this condition are scarce. We describe three patients suffering from relapsing myelitis in whom no association with systemic disease, i.e. infectious or connective tissue disease was found. Magnetic resonance imaging (MRI) findings were also distinctly different from multiple sclerosis and consistent with a necrotizing type of inflammation. Despite various treatment strategies, all patients became severely disabled. Relapsing ATM not related to systemic disease appears to be a specific entity which accounts for severe disability and currently lacks effective treatment.

Scott, T. F., S. L. Kassab, et al. (2005). "Acute partial transverse myelitis with normal cerebral magnetic resonance imaging: transition rate to clinically definite multiple sclerosis." Mult Scler 11(4): 373-7.

            OBJECTIVE: To determine the long-term risk of developing clinically definite multiple sclerosis (CDMS) in patients with acute partial transverse myelitis (APTM) and normal cerebral magnetic resonance imaging (MRI) scans. METHODS: We retrospectively studied 30 consecutive patients with clinical evidence of APTM. Patients with symmetric severe acute transverse myelitis were considered to have complete transverse myelitis and were excluded. All patients underwent spinal and cerebral MRIs, 13 underwent cerebrospinal fluid analysis and 11 patients underwent evoked potential studies. Various other studies were performed to assess for connective tissue disease and causes of APTM other than demyelinating disease. RESULTS: After an average follow-up of 61 months, all laboratory and clinical evidence, including relapse history, indicated that three patients developed lesions on cerebral MRI and could be classified as CDMS by either Poser criteria (two patients) or MacDonald criteria (one patient). Relapses limited to the spinal cord seen clinically were seen in 14/30 (46.6%) patients. Oligoclonal bands were seen in 8/13 (62%) patients; one patient transitioned to CDMS. Unifocal lesions of the cord were seen in 19/30 (63%) patients, multifocal lesions were seen in 8/30 (27%) and 3/30 (10%) had negative MRIs. The three patients who converted to CDMS did so within five years of the onset of myelitis. CONCLUSION: APTM with normal cerebral MRI had a low rate of conversion to CDMS in this long-term study. To date, there have been only a few follow-up studies that have addressed this issue.

Schwarz, S. and H. Leweling (2005). "Multiple sclerosis and nutrition." Mult Scler 11(1): 24-32.

            Benefits from any particular diet in multiple sclerosis (MS) have not yet been proven. It is, however, frequent that malnutrition may potentially exacerbate the symptoms of MS. There is some evidence that a high intake of saturated fat increases the incidence of MS. Epidemiological studies imply that unsaturated fatty acids may have a positive effect on the course of MS. However, the results of controlled studies are ambiguous. A meta-analysis of three small controlled clinical trials suggests a benefit from linoleic acid. Intake of Vitamin D is associated with a lower incidence of MS. In MS, the risk of osteoporosis is high, and prophylactic vitamin D and calcium should be considered at an early stage. The role of minerals, trace elements, antioxidants, vitamins or fish oil is unclear. The possible relationships between diet and MS have not been subjected to adequate study. It seems possible that in the future, diets or dietary supplements may become recommended forms of treatment for MS.

Schwarz, S., H. Leweling, et al. (2005). "[Alternative and complementary therapies in multiple sclerosis]." Fortschr Neurol Psychiatr 73(8): 451-62.

            Most MS patients use unconventional therapies, usually as complementary measures in addition to the conventional treatment. Only a few adequate clinical trials exist in this field. By definition, the efficacy of these therapies is unproven. Moreover, the possible risks are also largely unknown. Some therapies rely on rational pathophysiological considerations, other must be regarded as potentially harmful. The influence of diet on MS is unproven. Possibly, unsaturated fatty acids are beneficial. However, a few randomized trials yielded inconclusive results. Long-term supplementation of Vitamin D is associated with a decreased MS incidence. There is, however, insufficient evidence for an influence of Vitamin D on the course of the disease. Because of the high prevalence of osteoporosis in MS patients, prophylaxis with Vitamin D and Calcium is widely accepted. The effects of various minerals, selenium, antioxidant compounds, fish oil or vitamins remain speculative. Many patients use cannabis to alleviate spasticity and pain. Small series indicated positive effects, but randomized trials were negative for spasticity. However, many patients report subjective improvement under cannabis even if their objective parameters remain unchanged. Hyperbaric oxygenation was the subject of several small studies with heterogeneous results which, overall, do not support its use. Generally, physical therapies are perceived as an established therapy for MS. Short-term effects are probable, whereas the possible favourable long-term effects are unclear.

Schwartz, M. and J. Kipnis (2005). "Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases." J Neurol Sci 233(1-2): 163-6.

            Autoimmune diseases are traditionally viewed as an outcome of a malfunctioning of the immune system, in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis (MS), a disease of the white matter of the central nervous system (CNS), the attack is directed against myelin proteins. In this article we summarize a paradigm shift proposed by us in the perception of autoimmune disease. Observations by our group indicating that an autoimmune response is the body's mechanism for coping with CNS damage led us to suggest that all individuals are apparently endowed with a purposeful autoimmune response to CNS injuries, but have only limited inherent ability to control this response so that its effect will be beneficial. In animals susceptible to autoimmune diseases, the same autoimmune T cells are responsible both for neuroprotection and for disease development; the timing and strength of their activity will determine which of these effects is expressed. Individuals with non-inflammatory neurodegenerative diseases need a heightened autoimmunity. We discovered that autoimmunity could be boosted without risk of disease induction, even in susceptible strains, by the use of Copolymer-1 (Copaxone(R)), a weak agonist of a wide range of self-reactive T cells. Here we summarize the basic findings that led us to formulate the concept of protective autoimmunity, the mechanisms underlying its constitutive presence and its on/off regulation, and its therapeutic implications. We also offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals.

Schulz, K. H. and C. Heesen (2005). "[Effects of exercise in chronically ill patients. Examples from oncology and neurology]." Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 48(8): 906-13.

            Epidemiologic studies increasingly have demonstrated a correlation between physical inactivity and certain chronic diseases. Already in the 1970s exercise programs for cardiovascular patients were established, whereas in other severe chronic illnesses such as breast cancer or multiple sclerosis exposure to physical stress seemed to be a contraindication. Today there is a grow ing body of evidence demonstrating positive physical as well as psychic effects of exercise training in patients with these diseases. These studies are summarized and complementary studies of our group are described in more detail. In patients with breast cancer we were able to demonstrate persistent psychosocial effects even 1 year after completion of the training program. In patients with multiple sclerosis we could confirm an induction of neurotrophic factors in trained individuals. Correspondingly, there is accumulating evidence showing positive effects of exercise on cognitive function, especially in the aged. Potential pathophysiological pathways regarding a progression to dementia are presented. Consequently exercise programs could play a pivotal role in the prevention and therapy of the cognitive decline in the aged in an aging society.

Schulz, K. H., C. Heesen, et al. (2005). "[The concept of allostasis and allostatic load: psychoneuroimmunological findings]." Psychother Psychosom Med Psychol 55(11): 452-61.

            Classical theories have conceptualized stress as a reaction to threat to the homeostasis within the organism requiring an adaptive response. However, postulating mechanisms that could link such responses to long-term detrimental health outcomes remains difficult. The allostatic load concept enables us to think about how mediators can be protective in the short run but may have damaging effects when overused and/or not shut off. It further facilitates the formulation of cause-effects cascades to explain the link of dysregulations in stress mediators such as glucocorticoids and catecholamines and increased susceptibility for certain diseases. In the first section, we briefly summarize the theoretical background. We then employ the concept to integrate findings from basic and clinical research on dysregulations of the stress response systems in multiple sclerosis and breast cancer. Based on this model, it seems likely that such dysregulations are implicated in progression and possibly pathogenesis of these diseases. When using allostatic load as a heuristic model, one needs to consider that stress mediators and outcomes are interconnected in a non-linear network.

Schroeter, M. and S. Jander (2005). "T-cell cytokines in injury-induced neural damage and repair." Neuromolecular Med 7(3): 183-95.

            T-cell cytokines are involved in beneficial immune responses, pathological autoimmunity, and tissue inflammation. In this review, we focus on the role of interferon-gamma, interleukin (IL)-2, IL-4, IL-6, and IL-10 in autoimmune diseases such as multiple sclerosis, and primarily "nonimmune" injury of the central nervous system (CNS), in particular focal ischemia and trauma. Resident CNS cells such as microglia and astroglia are additional, and on some occasions major, cellular sources of T-cell cytokines in CNS disease. Collectively, they mediate harmful as well as beneficial functions that depend on the dynamics, cellular source, and compartmental site of their release, the pathophysiological context, and the presence of coexpressed factors. Furthermore, direct neurotoxic and neuroprotective effects of cytokines are evident that are independent from their immunoregulating properties. Whereas these complex interactions are only beginning to be understood, T-cell cytokines nevertheless hold promise as therapeutic targets in a variety of neurological disease conditions.

Schreiner, B., B. C. Kieseier, et al. (2005). "[Blocking adhesion molecules with natalizumab in multiple sclerosis]." Nervenarzt 76(8): 999-1005.

            Natalizumab is a humanized, monoclonal antibody, that inhibits adhesion molecules (alpha(4)-integrins) on the surface of immune cells. These adhesion molecules are important for binding of lymphocytes to endothelial cells of blood vessels and infiltration of inflammatory cells into tissues. Natalizumab is currently being tested in large clinical trials for the treatment of multiple sclerosis (MS) and other autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis). After demonstrating the safety and potential effectiveness of natalizumab in MS therapy during shorter treatment periods (</=6 months) in clinical phase I and II studies, two ongoing large, double-blinded, placebo-controlled phase III trials (named AFFIRM and SENTINEL) are evaluating its efficacy for patients with relapsing-remitting MS in respect to primary clinical endpoints (relapse rate, disease progression). Based a 1-year interim analysis of these studies, natalizumab was recently authorized by the U.S. Food and Drug Administration for treatment in reducing the frequency of clinical surges in multiple sclerosis, and an application was also made for its use in Europe. After more than 2 years of combined natalizumab (Tysabri) and interferon beta-1a (Avonex) therapy in the so-called Sentinel Study, there was one unexpected death and one appearance of progressive multifocal leukoencephalopathy. As a result, in February 2005 the manufacturers (Biogen/Elan) stopped all running studies of natalizumab and removed the drug from the market. New studies are underway to gain more understanding and especially to determine the risk to patients treated in the Sentinel Study. This article summarizes and updates the results of previous and ongoing natalizumab trials in the context of MS.

Schofield, P. (2005). "Dementia associated with toxic causes and autoimmune disease." Int Psychogeriatr 17 Suppl 1: S129-47.

            Toxic causes of dementia include exposure to heavy metals such as lead, mercury and aluminum as well as to carbon monoxide and solvents. Autoimmune conditions include such entities as multiple sclerosis, systemic lupus erythematosus, Behcet's disease and Sjogren's syndrome. These conditions share broadly similar cognitive effects giving rise to impairments with subcortical features. Individuals are often affected at a relatively young age. Optimal preventative strategies include avoidance of toxic substances. Comprehensive neuropsychological assessment is valuable not only diagnostically and for monitoring but also to identify the patients' strengths and weaknesses, so that compensatory strategies can be recommended.

Schneider, U., J. Seifert, et al. (2005). "[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders]." Nervenarzt 76(9): 1062, 1065-6, 1068-72 passim.

            For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.

Schneider, K. M. (2005). "AANA Journal course: update for nurse anesthetists--an overview of multiple sclerosis and implications for anesthesia." Aana J 73(3): 217-24.

            Multiple sclerosis is the most common demyelinating, chronic disease of the central nervous system diagnosed in and affecting young adults. This disease can significantly alter the life of affected people, and there is no known cure. It is important to understand and review this disease process because anesthesia providers are likely to encounter patients with multiple sclerosis in their practice. The purpose of this AANA Journal course is to present an overview of multiple sclerosis. The pathophysiologic features, symptoms, manifestations, diagnosis, and pharmacologic treatment are discussed, with a focus on the implications of multiple sclerosis for general and regional anesthesia.

Schmidt, E. Z., P. Hofmann, et al. (2005). "Sexuality in multiple sclerosis." J Neural Transm 112(9): 1201-11.

            Sexuality and partnership have an important influence on the quality of life of every person and also on people with chronic disorders such as multiple sclerosis. The findings in literature show high evidence that people with multiple sclerosis experience high levels of sexual dysfunction, most of them with hypoactive sexual behaviour often associated with dissatisfaction in relationship, and also the partners seem to show lower sexual and partnership satisfaction. The most common problems in women are lack of sexual interest and decreased libido, often with problems in orgasmic capacity, while men report erectile dysfunction and also lack of sexual interest. The impact of the level of disability and duration of the illness remains unclear. Positive familial support can often help the patient in coping with the illness, nonetheless problems with changing roles and multiple-sclerosis-minimizing can improve the need of contacts to outstanding persons.

Scherder, E., E. Wolters, et al. (2005). "Pain in Parkinson's disease and multiple sclerosis: its relation to the medial and lateral pain systems." Neurosci Biobehav Rev 29(7): 1047-56.

            Although pain is one of the major clinical symptoms of Parkinson's disease (PD) and multiple sclerosis (MS), it is often neglected and therefore undertreated. The question why the perception of pain in stages without cognitive impairment is not affected by the neuropathology has not been addressed so far. Furthermore, changes in the experience of pain as a result of cognitive impairment have not been clinically studied in PD and MS. These issues which are very relevant for pain assessment and treatment, will be addressed by discussing the neuropathology in the medial and lateral pain systems in cognitively intact versus cognitively impaired patients with PD and MS. Since there are no clinical studies that specifically address pain in cognitively impaired PD and MS patients, hypotheses will be generated about the impact of cognitive impairment on pain experience in these patients. These hypotheses should be a challenge for new research in this important but neglected area.

Scheinfeld, N. (2005). "Adalimumab: a review of side effects." Expert Opin Drug Saf 4(4): 637-41.

            Adalimumab (Humira) is a human monoclonal TNF-alpha antibody that blocks the effects of TNF-alpha. It is administered by subcutaneous injection. It has been approved alone or in combination with methotrexate for the treatment of rheumatoid arthritis in the EU and US. Approval for its use for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis is expected in the near future. Its side effect profile is favourable when compared with traditional systemic treatments for these diseases. It does not require laboratory monitoring. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. There is a two-fold risk of serious infections with the use of adalimumab, as reported in the Premier trial. This risk should not be minimised in this way. It should not be used during periods of active infection. Its most notable infectious complication is the reactivation of tuberculosis. Tuberculosis screening should be according to country standards and may or may not include purified protein derivative test or chest X-ray. Deep fungal and other serious and atypical infection can also be promoted by adalimumab. It has been associated infrequently with skin rashes. Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease. There has been reported pancytopenia and elevated transamines with the use of adalimumab, which suggest that laboratory monitoring blood counts and liver functions, at least intermittently, are useful. In patients with any of the foregoing problems, its use should be extremely carefully considered. Adalimumab is a useful medication which can be safely used if its side effects are recognised.

Schattner, A. (2005). "Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines." Vaccine 23(30): 3876-86.

            BACKGROUND: Viruses and virus-induced lymphokines may have an important role in the pathogenesis of autoimmunity (Schattner A. Clin Immunol Immunopathol; 1994). The occurrence and significance of autoimmune manifestations after the administration of viral vaccines remain controversial. METHODS: Medline search of all relevant publications from 1966 through June 2004 with special emphasis on search of each individual autoimmune manifestation and vaccination, as well as specifically searching each viral vaccine for all potential autoimmune syndromes reported. All relevant publications were retrieved and critically analyzed. RESULTS: The most frequently reported autoimmune manifestations for the various vaccinations, were: hepatitis A virus (HAV)--none; hepatitis B virus (HBV)--rheumatoid arthritis, reactive arthritis, vasculitis, encephalitis, neuropathy, thrombocytopenia; measles, mumps and rubella vaccine (MMR)--acute arthritis or arthralgia, chronic arthritis, thrombocytopenia; influenza--Guillain-Barre syndrome (GBS), vasculitis; polio--GBS; varicella--mainly neurological syndromes. Even these 'frequent' associations relate to a relatively small number of patients. Whenever controlled studies of autoimmunity following viral vaccines were undertaken, no evidence of an association was found. CONCLUSIONS: Very few patients may develop some autoimmune diseases following viral vaccination (in particular - arthropathy, vasculitis, neurological dysfunction and thrombocytopenia). For the overwhelming majority of people, vaccines are safe and no evidence linking viral vaccines with type 1 diabetes, multiple sclerosis (MS) or inflammatory bowel disease can be found.

Schapiro, R. T. (2005). "Managing symptoms of multiple sclerosis." Neurol Clin 23(1): 177-87, vii.

Scardi, S. and A. Cherubini (2005). "[Can we prevent the progression of aortic valve sclerosis and stenosis? The need for a prospective, randomized trial]." Ital Heart J Suppl 6(7): 403-12.

            Cardiologists long assumed that aortic valve sclerosis/stenosis is a wear-and-tear, degenerative process; recent studies suggested that lipoproteins can play a key role in the development of both sclerosis/stenosis in the aortic valve. Thus, sclerosis/stenosis cannot be considered as a simple degenerative process, but on the contrary it is complex and involves multiple pathogenetic mechanisms. Experimental, clinical and epidemiological data support the link between aortic valvulopathy and atherosclerosis: both are caused by inflammation, lipid deposition, and accumulation of extracellular bone matrix protein. In non-randomized clinical studies, hydroxy-methylglutaryl-coenzyme A reductase inhibitors minimized the progression of aortic valvulopathy. The major pharmacological effect, supposed to underlie the inferred (but still unproven) impact of statins on aortic sclerosis/stenosis is plasma cholesterol reduction. Lately, retrospective clinical studies supported this hypothesis and suggested a key role for statins in delaying the progression of aortic valvulopathy. However, the potential favorable effects of statins require confirmation. Prospective trials in Canada and Europe are now ongoing (ASTRONOMER--Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin; SEAS--Simvastatin and the Ezetimibe in Aortic Stenosis) and will address the use of cholesterol-lowering drugs in reducing the progression of aortic valve stenosis and in improving clinical outcomes.

Scalabrino, G. (2005). "Cobalamin (vitamin B(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories." Exp Neurol 192(2): 463-79.

            Subacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B(12)) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-alpha and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-alpha and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear.

Sayre, L. M., P. I. Moreira, et al. (2005). "Metal ions and oxidative protein modification in neurological disease." Ann Ist Super Sanita 41(2): 143-64.

            This review highlights the role of oxidative stress and imbalances in metal ion homeostasis in the neurodegenerative diseases Alzheimer's disease and Parkinson's disease and in the progressive demyelinating disease multiple sclerosis. The chemistry and biochemistry of oxidative stress-induced protein damage are first described, followed by the evidence for a pathological role of oxidative stress in these disease states. It is tempting to speculate that free radical oxygen chemistry contributes to pathogenesis in all these conditions, though it is as yet undetermined what types of oxidative changes occur early in the disease, and what types are secondary manifestations of neuronal degeneration.

Saunamaki, T., R. Hanninen, et al. (2005). "[Neuropsychologic examination and rehabilitation of multiple sclerosis patients]." Duodecim 121(5): 537-44.

Sastre-Garriga, J., I. Galan-Cartana, et al. (2005). "[Neurorehabilitation in multiple sclerosis.]." Neurologia 20(5): 245-54.

            Neurorehabilitation is predominantly an educational, dynamic process based on the adaptation of the individual and his environment to the actual neurological impairment and focuses on decreasing the impact of disabling neurological conditions on the individual in order to achieve optimum quality of life. It has been suggested by some that neurorehabilitation is the only approach available to us which can improve the limitations in activity and restrictions in social participation of people with multiple sclerosis. The neurorehabilitation approach is a holistic one and is a fundamental part of neurological care; it should not be forgotten by neurologists, especially when dealing with people with chronic disabling conditions such as multiple sclerosis. Together with the social model of disability, the concept of restorative neurology, as a scientific and therapeutic attempt to minimize those impairments directly responsible for the disability presented by the person, is recently gaining ground among neuroscientists and clinicians. In this review the conceptual basis for neurorehabilitation will be presented together with a review of the literature concerning the biological aspects of neurorehabilitative therapy (neuroplasticity) and the clinical trials evaluating the effectiveness of neurorehabilitation in people with multiple sclerosis. Finally, we will consider the practical aspects of neurorehabilitation.

Sarlani, E., E. G. Grace, et al. (2005). "Trigeminal neuralgia in a patient with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy." J Am Dent Assoc 136(4): 469-76.

            BACKGROUND: Trigeminal neuralgia (TN) is characterized by unilateral, severe, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Symptomatic or secondary TN involves TN-like pain that develops owing to a central nervous system lesion (benign or malignant) or to multiple sclerosis (MS). CASE DESCRIPTION: The authors present a report of a unique case of a 43-year-old patient with unilateral TN, MS and concomitant chronic inflammatory demyelinating polyneuropathy. The facial pain preceded any other manifestations of the systemic disorders, and only after repeated neurological examinations were these diagnoses established. CLINICAL IMPLICATIONS: Magnetic resonance imaging of the brain and repeated neurological evaluations should be implemented in all patients with TN to rule out the presence of underlying disease. The dental practitioner should be familiar with TN to avoid unnecessary dental interventions and ensure prompt initiation of appropriate treatment.

Sanders, S., C. Del Mar, et al. (2005). "Evidence in practice--number 8. What is the prognosis of optic neuritis? How often does it lead to multiple sclerosis?" Br J Gen Pract 55(521): 972-3.

Sandberg-Wollheim, M. (2005). "Interferon-beta1a treatment for multiple sclerosis." Expert Rev Neurother 5(1): 25-34.

            Although multiple sclerosis is probably the most common cause of neurologic disability in young adults, the cause is unknown, the prognosis uncertain and available treatments unsatisfactory. Multiple sclerosis is an inflammatory autoimmune disorder of the CNS and the result of both environmental factors and susceptibility genes. The prognosis is difficult or impossible to predict at the time of diagnosis. Treatments that modulate the course of the disease have only recently become available but the long-term aim to prevent disability and promote repair remains distant. Interferon-beta is the most widely used therapy. The efficacy of interferon-beta in the short term is well documented in many large treatment trials, but the treatment effects are only modest and many issues relating to efficacy in the long term are unresolved. These include uncertain benefit on conversion to secondary-progressive multiple sclerosis, the relevance of neutralizing antibodies and the controversial effect on multiple sclerosis-related brain atrophy.

Sandberg-Wollheim, M., D. Frank, et al. (2005). "Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis." Neurology 65(6): 802-6.

            BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Rzazewska-Makosa, B. (2005). "[The mechanism of glucocorticoid resistance in multiple sclerosis]." Postepy Hig Med Dosw (Online) 59: 457-63.

            Glucocorticoids (GCs) are used in the treatment of multiple sclerosis (MS) and other autoimmunological diseases due to their significant anti-inflammatory and immunosuppressive effects. In MS, GCs are mainly used in the treatment of clinical relapses. Most patients benefit from GCs, except for some who are resistant. These patients pose a serious clinical problem. GC resistance in MS has not been widely elaborated. Less than 5% of MS patients do not respond to GCs in the early phase of the disease, and these are considered as having primary resistance to GCs. There is also a group of patients who develop GC resistance later, after a good therapeutic response at the beginning of therapy. This secondary type of resistance is more common and may apply to as many as 30% of all patients. Primary GC resistance has a genetic origin and is associated with a mutation within the GR. The mechanisms of secondary GC resistance are more diverse. There is only one receptor for GCs, but it can occur in three isoforms: GR alpha, GR beta, and GR gamma. GR alpha secures the appropriate GC signaling transmission, whereas GR beta and gamma bind to GC, but prevent the GC/GR complex from DNA activation. Thus both these latter forms of GR inhibit GC activity. The beta and gamma isoforms of GR become more common in cells at the inflammatory foci. Another mechanism of secondary GC resistance depends on the induction of cytokines during inflammatory processes. Interleukins 2, 4, and 13 are overproduced and lead to the induction of transcriptional factor AP-1. AP-1 competes with the GC/GR complex for the binding site on DNA. In addition, IL-2 slows the transport of the GC/GR complex to cell nuclei. In assessing GC resistance it is important to consider additional factors, such as patient compliance with the treatment.

Rutella, S., F. Zavala, et al. (2005). "Granulocyte colony-stimulating factor: a novel mediator of T cell tolerance." J Immunol 175(11): 7085-91.

            In recent years, several investigators have unraveled a previously unrecognized role for G-CSF in the regulation of T cell and dendritic cell functions. The experimental evidence in favor of G-CSF-mediated immune regulation includes the ability to switch T cell cytokine secretion profile to Th2 responses and the promotion of regulatory T cell and tolerogenic dendritic cell differentiation. Interestingly, G-CSF is beneficial in animals for the prevention and/or treatment of immune-mediated diseases, e.g., graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes, suggesting a potential role in human autoimmune diseases. This review summarizes the growing body of evidence that supports a critical role for G-CSF as a novel mediator of T cell tolerance.

Rus, H., C. Cudrici, et al. (2005). "C5b-9 complement complex in autoimmune demyelination and multiple sclerosis: dual role in neuroinflammation and neuroprotection." Ann Med 37(2): 97-104.

            Complement system activation plays an important role in innate and acquired immunity. Activation of complement leads to the formation of C5b-9 terminal complex. While C5b-9 can promote cell lysis, sublytic assembly of C5b-9 on plasma membranes induces cell cycle activation and survival. Multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) are inflammatory demyelinating diseases of the central nervous system (CNS) mediated by activated lymphocytes, macrophages/microglia and the complement system. Complement activation may contribute to the pathogenesis of these diseases through its dual role: the ability of activated terminal complex C5b-9 to promote demyelination and the capacity of sublytic C5b-9 to protect oligodendrocytes (OLG) from apoptosis. By inducing EAE in C5-deficient mice, we showed that complement C5 promotes remyelination and protects oligodendrocytes from apoptotic cell death. These findings indicate that activation of complement C5b-9 plays a pro-inflammatory role in the acute phase of the disease, but may also be neuroprotective during the chronic phase of the disease.

Rowbotham, M. C. (2005). "Is fibromyalgia a neuropathic pain syndrome?" J Rheumatol Suppl 75: 38-40.

            The fibromyalgia syndrome (FM) seems an unlikely candidate for classification as a neuropathic pain. The disorder is diagnosed based on a compatible history and the presence of multiple areas of musculoskeletal tenderness. A consistent pathology in either the peripheral or central nervous system (CNS) has not been demonstrated in patients with FM, and they are not at higher risk for diseases of the CNS such as multiple sclerosis or of the peripheral nervous system such as peripheral neuropathy. A large proportion of FM sufferers have accompanying symptoms and signs of uncertain etiology, such as chronic fatigue, sleep disturbance, and bowel/bladder irritability. With the exception of migraine headaches and possibly irritable bowel syndrome, the accompanying disorders are clearly not neurological in origin. The impetus to classify the FM as a neuropathic pain comes from multiple lines of research suggesting widespread pain and tenderness are associated with chronic sensitization of the CNS. An examination of how the term neuropathic pain is defined reveals a conceptual split into 2 partially overlapping groups of disorders: those with demonstrable pathology in the nervous system and those characterized primarily by enduring dysfunction in the nervous system. Requiring demonstrable pathology in the nervous system in the definition of neuropathic pain is the traditional approach. The expansion of the definition to require only enduring nervous system dysfunction is less palatable because it opens the classification to many disorders of uncertain etiology, including complex regional pain syndrome. As it is uncertain which of the many different chronic pain syndromes include an enduring component of central sensitization, restricting the term "neuropathic pain" to those disorders with a primary etiology clearly related to the peripheral or CNS is prudent and consistent with clinical practice.

Rovaris, M., G. Comi, et al. (2005). "Can glatiramer acetate reduce brain atrophy development in multiple sclerosis?" J Neurol Sci 233(1-2): 139-43.

            The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of progressive atrophy reflecting the neurodegenerative aspects of multiple sclerosis (MS) pathology. The present article reviews the results of studies assessing the effect of glatiramer acetate (GA) treatment in preventing MS-related, MRI-measurable brain volume decrease. Whilst data from the extended, open-label follow-up of the US trial seem to indicate that long-term treatment with GA might prevent the loss of brain parenchyma in relapsing-remitting MS patients, longitudinal data from the European/Canadian MRI trial suggest that, over a short-term period of treatment, GA does not have a clear-cut impact on the decrease of brain volume. The effect of GA on MS-related brain atrophy might, therefore, be delayed and dissociated in time from those exerted on other clinical and MRI measures of disease activity. However, the modest magnitude of this effect makes it difficult to evaluate its impact on the actual disease progression. Further studies of adequate duration are now required to address this issue, as well as to confirm the sustained efficacy of GA treatment over long periods of follow-up.

Rovaris, M., A. Gass, et al. (2005). "Diffusion MRI in multiple sclerosis." Neurology 65(10): 1526-32.

            Diffusion imaging is a quantitative, MR-based technique potentially useful for the study of multiple sclerosis (MS), due to its increased pathologic specificity over conventional MRI and its ability to assess in vivo the presence of tissue damage occurring outside T2-visible lesions, i.e., in the so-called normal-appearing white and gray matter. The present review aims at critically summarizing the state-of-the-art and providing a background for the planning of future diffusion studies of MS. Several pieces of evidence suggest that diffusion-weighted and diffusion tensor MRI are sensitive to MS damage and able to detect its evolution over relatively short periods of time. Although a significant relationship between diffusion-weighted MRI findings and MS clinical disability was not found in the earliest studies, with improved diffusion imaging technology correlations between diffusion abnormalities and MS clinical aspects are now emerging. However, the best acquisition and postprocessing strategies for MS studies remain a matter of debate and the contribution of newer and more sophisticated techniques to diffusion tensor MRI investigations in MS needs to be further evaluated. Although changes in diffusion MRI indices reflect a net loss of structural organization, at present we can only speculate on their possible pathologic substrates in the MS brain. Postmortem studies correlating diffusion findings with histopathology of patients with MS are, therefore, also warranted.

Rovaris, M. and M. Filippi (2005). "Defining the response to multiple sclerosis treatment: the role of conventional magnetic resonance imaging." Neurol Sci 26 Suppl 4: S204-8.

            During the last two decades, conventional MRI (cMRI) has been extensively used in the diagnostic workup of multiple sclerosis (MS) patients, to monitor the natural history of the disease and to evaluate the efficacy of experimental treatments in randomised, controlled clinical trials. In the latter context, a major issue is represented by the high intra- and inter-individual heterogeneity of the MS patterns of disease activity and evolution. Such heterogeneity might explain, at least partially, the weak correlations found between clinical and cMRI aspects in patients with established MS, which is particularly evident when individual patients are considered. As a consequence, the definition of response to MS treatment, when based upon cMRI aspects, is still a challenging task. Although the use of cMRI-derived quantities as a standalone approach to define treatment options and strategies at an individual patient level should be discouraged, an evidence-based integration of clinical and cMRI data might be helpful in selected cases for an optimal work-up of patients undergoing immunomodulating or immunosuppressive treatments.

Rostasy, K. M. (2005). "Inflammation and neuroaxonal injury in multiple sclerosis and AIDS dementia complex: implications for neuroprotective treatment." Neuropediatrics 36(4): 230-9.

            Multiple sclerosis (MS) and AIDS dementia complex (ADC), also termed HIV-associated dementia (HAD), are two examples of CNS diseases with a strong inflammatory component. In particular, macrophage/microglia activation in the deep white matter (DWM) is a key feature of both diseases. Activated macrophages/microglia have been shown to produce multiple cellular substances which can cause injury and apoptosis to all cell types in the CNS. This potentially provides a link between the initial pathogenic event and subsequent widespread neuroaxonal injury, which recent studies have found to be an early finding and an important determinant of clinical burden in both diseases. This review summarizes important immunopathological and neurobiological aspects of MS and ADC, with a special focus on the relation between macrophage/microglia activation and neuroaxonal injury, and discusses potential neuroprotective strategies.

Rosenberg, J. H. and R. Shafor (2005). "Fatigue in multiple sclerosis: a rational approach to evaluation and treatment." Curr Neurol Neurosci Rep 5(2): 140-6.

            With the publication of the Multiple Sclerosis Council Guideline on the management of multiple sclerosis (MS) fatigue, there has been increased appreciation for the role fatigue can play in MS. Secondary fatigue is fatigue caused by other etiologies than those directly related to MS. Once these causes are ruled out, fatigue is related to MS. Secondary MS-related fatigue comes as result of the symptoms of MS that drain energy. Once secondary MS causes are ruled out, then the patient is deemed as having primary MS fatigue. Fatigue management is both nonpharmacologic and pharmacologic. Occupational therapists are the major allied health providers that address the role fatigue plays in MS patients. Over the past two decades, numerous clinical trials have been conducted on drugs for treating MS-related fatigue. Of these agents, amantadine has been studied for the longest period, and has shown efficacy in about one third of patients with MS-related fatigue on several commonly used scales. Two randomized -trials of the central nervous system stimulant pemoline have yielded unimpressive results; efficacy was seen at higher doses but coupled with an unacceptable risk of adverse events. The wake-promoting agent modafinil is the only agent to show efficacy compared with placebo on the Fatigue Severity Scale, a measure that is highly resistant to "impulse answering" and is thus viewed as one of the most difficult scales on which to show -benefit. This article reviews fatigue in MS and proposes a rational strategy for evaluation and management of this most common MS symptom.

Rooney, W. D. and P. K. Coyle (2005). "Recent advances in the neuroimaging of multiple sclerosis." Curr Neurol Neurosci Rep 5(3): 217-24.

            Neuroimaging studies continue to provide important insights into the central nervous system disease pathology of multiple sclerosis (MS). Although conventional magnetic resonance imaging remains the mainstay of diagnosis and laboratory assessment of therapeutic response in MS, quantitative techniques continue to extend our understanding of both macroscopic and microscopic disease processes. Over the past year, many published studies have investigated measures of brain atrophy, gray matter involvement, vascular properties, and myelin and neuronal loss and have examined their relationship to clinical disease expression, genotype, and therapy. An important trend continuing over the past year is the development of targeted agents to improve the pathologic specificity of imaging measures. Specific disease measures such as endothelial activation, microglial activation, and cell trafficking are accessible to neuroimaging and offer significant promise for improved characterization of central nervous system involvement in MS.

Romeo, M. J., V. Espina, et al. (2005). "CSF proteome: a protein repository for potential biomarker identification." Expert Rev Proteomics 2(1): 57-70.

            Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Rodi, D., R. Couture, et al. (2005). "Targeting kinin receptors for the treatment of neurological diseases." Curr Pharm Des 11(10): 1313-26.

            Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B(1) receptor antagonists as antiepileptic agents, and for B(2) receptor antagonists (and/or B(1) agonists) in the treatment of stroke. Functional B(1) receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.

Rode, G., C. Thomas-Anterion, et al. (2005). "[Assessment of disability and quality of life in patients with cognitive disorders]." Ann Readapt Med Phys 48(6): 376-91.

            OBJECTIVE: To identify disability, handicap and quality of life questionnaires available for patients with cognitive impairment. MATERIALS AND METHODS: We systematically reviewed the literature in Medline using the keywords assessment, evaluation, deficiency, disability, disadvantage, handicap, quality of life, scale, index, questionnaire, ICIDH-1, and ICIDH-2, combined with the cognitive deficits dysexecutive syndrome, memory deficits, attention deficits, neglect, apraxia, aphasia, agnosia and mood disorders. We focused on validated scales and distinguished scales dedicated to assess disability, handicap and quality of life. RESULTS: At the level of disability, global and specific scales are available. Specific scales exist for dysexecutive syndrome, memory deficits, attention deficits, unilateral neglect, aphasia and mood disorders. French adaptations of foreign language tests and original tests developed in French have been validated in these areas. No specific tool is available for isolated apraxia or agnosia. Generic scales and pathology-specific scales (for stroke, traumatic brain injury, and multiple sclerosis) are available for quality of life. For aphasia, specific tools are available for incapacity handicap and quality of life. CONCLUSION: Previous results show the impact of the ICIDH-1 framework on functional outcome assessment of cognitive impairments. This approach is often limited by the lack of theoretical background and by the difficulty to assess the involvement of environment and anosognosia.

Rocca, M. A., S. J. Hickman, et al. (2005). "Imaging the optic nerve in multiple sclerosis." Mult Scler 11(5): 537-41.

            Although multiple sclerosis (MS) frequently involves the optic nerves, imaging this structure is not yet performed routinely in clinical practice. The recent improvement of magnetic resonance (MR) technology and the development of new MR strategies, capable of providing an, in vivo, overall assessment of MS pathology has allowed objective metrics to be obtained for monitoring disease evolution, essentially in the brain. However, despite this progress, the correlation between brain MR metrics of the disease and clinical disability are still disappointing. An objective and accurate estimate of the presence and extent of optic nerve involvement might help to overcome this clinical/MRI paradox. This review summarizes the main results obtained from the application of conventional and modern MR-based techniques for the evaluation of optic nerve damage in MS.

Rocca, M. A., S. J. Hickman, et al. (2005). "Imaging spinal cord damage in multiple sclerosis." J Neuroimaging 15(4): 297-304.

            During the past 2 decades, the considerable improvement of magnetic resonance (MR) technology and the development of new MR strategies capable of providing an in vivo overall assessment of multiple sclerosis (MS) pathology have allowed us to obtain important novel pieces of information on disease evolution in the brain. However, despite this, the correlation between brain MR imaging metrics and clinical disability are still suboptimal. A reason for this discrepancy might be the involvement of clinically eloquent structures, such as the spinal cord, which owing to technical challenges have not been extensively studied using MR imaging until very recently. An objective and accurate estimate of the presence and extent of spinal cord damage might indeed contribute to increasing the strength of the correlations between clinical and MRI metrics. This review summarizes the main results obtained from the application of conventional and modern MR-based techniques for the evaluation of spinal cord damage in MS.

Robson, P. (2005). "Human studies of cannabinoids and medicinal cannabis." Handb Exp Pharmacol(168): 719-56.

            Cannabis has been known as a medicine for several thousand years across many cultures. It reached a position of prominence within Western medicine in the nineteenth century but became mired in disrepute and legal controls early in the twentieth century. Despite unremitting world-wide suppression, recreational cannabis exploded into popular culture in the 1960s and has remained easily obtainable on the black market in most countries ever since. This ready availability has allowed many thousands of patients to rediscover the apparent power of the drug to alleviate symptoms of some of the most cruel and refractory diseases known to humankind. Pioneering clinical research in the last quarter of the twentieth century has given some support to these anecdotal reports, but the methodological challenges to human research involving a pariah drug are formidable. Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability. As a result, the scientific evaluation of medicinal cannabis in humans is still in its infancy. New possibilities in human research have been opened up by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions. This chapter will begin with an outline of the development and current status of legal controls pertaining to cannabis, following which the existing human research will be reviewed. Some key safety issues will then be considered, and the chapter will conclude with some suggestions as to future directions for human research.

Roberts-Thomson, P. J., R. A. Roberts-Thomson, et al. (2005). "Immune dysfunction in Australian Aborigines." Asian Pac J Allergy Immunol 23(4): 235-44.

            An examination of the prevalence and phenotype of immune disorders in different ethnic groups may provide important clues to the etiopathogenesis of these disorders. Whilst still conjectural the restricted and somewhat unique polymorphisms of the MHC (and other genetic loci involving host defences) of the Australian Aborigines may provide an explanation for their apparent heightened susceptibility to newly encountered infections and their resistance to many (auto) immune and allergic disorders. In comparison with non-Aboriginal Australians, Australian Aborigines have heightened frequencies of rheumatic fever, systemic lupus erythematosus, various infections and post-streptococcal glomerulonephritis. In contrast various autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis, CREST, biliary cirrhosis, coeliac disease, pernicious anaemia, vitiligo), B27 related arthropathies, psoriasis, lymphoproliferative disorders and atopic disorders appear infrequent or absent. Similarly various autoantibodies occur with increased or diminished frequency. With continuing racial admixture, social deprivation and deleterious lifestyles of these people it is likely that further changes in both the frequencies and phenotype of these immune disorders will occur. It is only with a full understanding of the pathogenic mechanisms involved in these immune disorders that meaningful and clinical relevant interventions will be possible.

Roberts, R. (2005). "Lysosomal cysteine proteases: structure, function and inhibition of cathepsins." Drug News Perspect 18(10): 605-14.

            Lysosomal cysteine proteases, a subgroup of the cathepsin family, are critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. In the past decade, the number of identified human cathepsins has more than doubled and their known role in several pathologies has expanded rapidly. Increased understanding of the structure and mechanism of this class of enzymes has brought on a new fervor in the design of small molecule inhibitors with the hope of producing specific, therapeutic drugs for diseases such as arthritis, allergy, multiple sclerosis, atherosclerosis, Alzheimer's disease and cancer.

Rio, J. and X. Montalban (2005). "Interferon-beta 1b in the treatment of multiple sclerosis." Expert Opin Pharmacother 6(16): 2877-86.

            Ever since IFN-beta1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-beta1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-beta1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.

Rinaldi, L. and P. Gallo (2005). "Immunological markers in multiple sclerosis: tackling the missing elements." Neurol Sci 26 Suppl 4: S215-7.

            Multiple sclerosis (MS) is a complex disease in which several pathophysiological mechanisms are involved: inflammation, demyelination, axonal damage and repairing. Further complicating the picture, such processes are variably represented in MS patient populations, thus accounting for the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. In the last decade a huge effort has been made in the attempt to "capture" the gold fish, i. e., biological markers either specific for the disease and/or capable to predict, in newly diagnosed MS patients, disease course and response to therapy. Moreover, these biomarkers would be extremely useful in the development of new process-specific therapies. Unfortunately such markers are far from being "fished", but recent studies have pointed out new interesting candidates, driving new energies and hopes in the MS research community. In this review we briefly discuss the latest news on immune markers in MS.

Rietberg, M. B., D. Brooks, et al. (2005). "Exercise therapy for multiple sclerosis." Cochrane Database Syst Rev(1): CD003980.

            BACKGROUND: No intervention has proven effective in modifying long-term disease prognosis in Multiple Sclerosis (MS) but exercise therapy is considered to be an important part of symptomatic and supportive treatment for these patients. OBJECTIVES: To assess the effectiveness of exercise therapy for patients with MS in terms of activities of daily living and health-related quality of life. SEARCH STRATEGY: We searched the Cochrane MS Group Specialised Register (searched: March 2004), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004), MEDLINE (from 1966 to March 2004), EMBASE (from 1988 to March 2004 ), CINAHL (from 1982 to March 2004), PEDro (from 1999 to March 2004) . Manual search in the journal 'Multiple Sclerosis' and screening of the reference lists of identified studies and reviews. We also searched abstracts published in proceedings of conferences. SELECTION CRITERIA: Randomised Controlled Trials (RCTs) that reported on exercise therapy for adults with MS, not presently experiencing an exacerbation; outcomes that include measures of activity limitation or health-related quality of life or both. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and methodological quality of the included trials. Disagreements were resolved by discussion. The results were analysed using a best-evidence synthesis based on methodological quality. MAIN RESULTS: Nine high-methodological-quality RCTs(260 participants) met the inclusion criteria. Six trials focussed on comparison of exercise therapy versus no exercise therapy, whereas three trials compared two interventions that both met our definition of exercise therapy. Best evidence synthesis showed strong evidence in favour of exercise therapy compared to no exercise therapy in terms of muscle power function, exercise tolerance functions and mobility-related activities. Moderate evidence was found for improving mood. No evidence was observed for exercise therapy on fatigue and perception of handicap when compared to no exercise therapy. Finally, no evidence was found that specific exercise therapy programmes were more successful in improving activities and participation than other exercise treatments. No evidence of deleterious effects of exercise therapy was described in included studies. AUTHORS' CONCLUSIONS: The results of the present review suggest that exercise therapy can be beneficial for patients with MS not experiencing an exacerbation. There is an urgent need for consensus on a core set of outcome measures to be used in exercise trials. In addition, these studies should experimentally control for 'dose' of treatment, type of MS and should include sufficient contrast between experimental and control groups.

Rieckmann, P. (2005). "Multiple sclerosis therapy: new strategies." Neurol Sci 26 Suppl 1: S20.

Rickards, H. (2005). "Depression in neurological disorders: Parkinson's disease, multiple sclerosis, and stroke." J Neurol Neurosurg Psychiatry 76 Suppl 1: i48-52.

Rice, G. P., H. P. Hartung, et al. (2005). "Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale." Neurology 64(8): 1336-42.

            The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Restrepo, C. S., A. Largoza, et al. (2005). "CT and MR imaging findings of benign cardiac tumors." Curr Probl Diagn Radiol 34(1): 12-21.

            This imaging review describes the appearance of benign cardiac tumors on CT and MRI. Although rare, benign tumors outnumber their primary malignant counterparts three to one. Since mortality varies directly with invasion, identifying the neoplasm at an early stage helps focus treatment, especially in benign cases, which generally respond well to surgical resection. In adults and children, myxomas and rhabdomyomas, respectively, represent the most common benign tumors, which can be grouped into tissue-specific subtypes, such as rhabdomyomas, fibromas, lipomas, teratomas, etc. Besides their variable prevalence in particular age groups, these tumors also differ with regard to their gender predilection, location, and number. For example, myxomas appear predominantly in women and generally as a solitary mass in the left or right atrium, whereas rhabdomyomas present equally in boys and girls and chiefly as multiple masses in the ventricles. Despite their differences, however, both types share an association with heritable syndromes like the Carney complex for myxomas and tuberous sclerosis for rhabdomyomas. As with all cardiac tumors, echocardiographic findings usually suggest the initial diagnosis but cross-sectional imaging with CT and MRI can help resolve diagnostically challenging cases. For example, with its direct multiplanar capability, excellent contrast resolution, and large field of view, MRI permits a detailed examination of the entire mediastinum, helping to rule out an equivocal mass on echocardiography. Through dynamic techniques, MRI, in addition to morphologic characterization, can depict the pathophysiological effects of these tumors, for instance, with regard to myocardial contraction, valvular function, or blood flow.

Reske, D., H. F. Petereit, et al. (2005). "Difficulties in the differentiation of chronic inflammatory diseases of the central nervous system--value of cerebrospinal fluid analysis and immunological abnormalities in the diagnosis." Acta Neurol Scand 112(4): 207-13.

            OBJECTIVES: A number of neurological syndromes may be evoked by involvement of the nervous system due to systemic diseases such as lupus erythematodes, sarcoidosis, Behcet's disease and Sjogren's syndrome (SS) and may be confounded with another chronic inflammatory disease which is restricted to the central nervous system, e.g. multiple sclerosis (MS). Because of different treatment strategies, it is important to distinguish between these different autoimmune diseases. RESULTS: Neither clinical signs nor additional analyses such as serological findings or cerebrospinal fluid (CSF) analysis are able to differentiate between the diseases with certainty. Nevertheless, taking all findings together, diagnosis may be possible. CONCLUSION: Here we compare typical clinical and CSF findings in MS, neurosarcoidosis, neurolupus, neuro-Behcet and nervous system involving SS with special emphasis on those findings allowing differentiation of the respective diseases by reviewing the literature.

Regenauer, A. (2005). "[New challenges in multiple sclerosis]." Versicherungsmedizin 57(3): 115-21.

            After decades of prevailing fatalism concerning multiple sclerosis new hopes emerge at the horizon of both the diagnostic and therapeutic section catalyzed by a new understanding of the neurodegenerative disease process. The rapidly evolving MRI techniques enabled an analysis of CNS tissue injury in terms of structure and chemical composition. Based on studies with serial MRI scans, multiple sclerosis is increasingly considered as a dynamic disease process, in which not only the myelin but also the axons are damaged already in a very early stage. The introduction of interferon therapy caused much attention and great hope both among patients and clinicians. Unfortunately clinical studies require a large number of patients and long periods. Obviously if treated early enough and consistently, patients with the relapsing-remitting form of multiple sclerosis suffer less exacerbations, MRI lesions and disease progression in comparison to patients not treated by interferons. But sustained improvement in terms of extramortality and extramorbidity can only be expected in the medium term.

Ray, K. K. and C. P. Cannon (2005). "The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes." J Am Coll Cardiol 46(8): 1425-33.

            Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS.

Ray, A. and E. Wyllie (2005). "Treatment options and paradigms in childhood temporal lobe epilepsy." Expert Rev Neurother 5(6): 785-801.

            Temporal lobe epilepsy in adults is a relatively homogenous syndrome with hippocampal sclerosis being its most common pathologic substrate. In the pediatric age group, low-grade neoplasms and cortical dysplasia are much more common than hippocampal sclerosis. Pediatric temporal lobe epilepsy has distinct semiologic, electrophysiologic and imaging characteristics as compared with its adult counterpart. The various treatment options for pediatric temporal lobe epilepsy include antiepileptic drugs, resective surgery, vagal nerve stimulation and the ketogenic diet. In spite of the multiple antiepileptic drugs currently available, 5-10% of all newly diagnosed cases will remain intractable to medical therapy and should be referred for presurgical evaluation. Resective surgery offers the best chance of seizure freedom in carefully selected patients. Future areas of research include new drug development, better imaging and localization techniques, and brain stimulation.

Ransohoff, R. M. (2005). "Immunologic correlates of MS pathologic subtypes." Mult Scler 11(1): 101-2.

Ramos-Casals, M., A. Pares, et al. (2005). "Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature." J Viral Hepat 12(6): 648-54.

            To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjogren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjogren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.

Racke, M. K., W. Hu, et al. (2005). "PTX cruiser: driving autoimmunity via TLR4." Trends Immunol 26(6): 289-91.

            Although the cause of autoimmune diseases is unknown, it has long been speculated that an infectious agent might have a role in their initiation and progression. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been used to study factors in disease pathogenesis. A recent study shows that pertussis toxin, which is used as an adjuvant in EAE, uses Toll-like receptor 4 signaling to mediate its disease-inducing effect.

Quintana, H. (2005). "Transcranial magnetic stimulation in persons younger than the age of 18." J Ect 21(2): 88-95.

            OBJECTIVES: To review the use of transcranial magnetic stimulation (single-pulse TMS, paired TMS, and repetitive TMS [rTMS]) in persons younger than the age of 18 years. I discuss the technical differences, as well as the diagnostic, therapeutic, and psychiatric uses of TMS/rTMS in this age group. METHODS: I evaluated English-language studies from 1993 to August 2004 on nonconvulsive single-pulse, paired, and rTMS that supported a possible role for the use of TMS in persons younger than 18. Articles reviewed were retrieved from the MEDLINE database and Clinical Scientific index. RESULTS: The 48 studies reviewed involved a total of 1034 children ages 2 weeks to 18 years; 35 of the studies used single-pulse TMS (980 children), 3 studies used paired TMS (20 children), and 7 studies used rTMS (34 children). Three studies used both single and rTMS. However, the number of subjects involved was not reported. CONCLUSIONS: Single-pulse TMS, paired TMS, and rTMS in persons younger than 18 has been used to examine the maturation/activity of the neurons of various central nervous system tracts, plasticity of neurons in epilepsy, other aspects of epilepsy, multiple sclerosis, myoclonus, transcallosal inhibition, and motor cortex functioning with no reported seizure risk. rTMS has been applied to psychiatric disorders such as ADHD, ADHD with Tourette's, and depression. Adult studies support an antidepressant effect from repetitive TMS, but there is only one study that has been reported on 7 patients that used rTMS to the left dorsal prefrontal cortex on children/adolescents with depression (5 of the 7 subjects treated responded). Although there are limited studies using rTMS (in 34 children), these studies did not report significant adverse effects or seizures. Repetitive TMS safety, ethical, and neurotoxicity concerns also are discussed.

Pryce, G. and D. Baker (2005). "Emerging properties of cannabinoid medicines in management of multiple sclerosis." Trends Neurosci 28(5): 272-6.

            Use of cannabis as a medicine for numerous conditions has a well-documented history stretching back thousands of years. With the identification of an endogenous system of receptors and ligands in recent years, abundant experimental data have reinforced the anecdotal claims of people who perceive medicinal benefit from the currently illegal consumption of cannabis. This, combined with data from recent clinical trials, points to the prospect of cannabis as a medication in the treatment of multiple sclerosis and numerous other medical conditions.

Provenzale, J. M., M. Escolar, et al. (2005). "Quantitative analysis of diffusion tensor imaging data in serial assessment of Krabbe disease." Ann N Y Acad Sci 1064: 220-9.

            Krabbe disease is a rare autosomal recessive pediatric white matter (WM) disorder that is due to deficiency of a specific enzyme, beta-galactocerebrosidase. This report reviews our experience with use of diffusion tensor imaging (DTI) in serial assessment of WM changes in Krabbe disease following stem cell transplantation. DTI appears to be a sensitive means to monitor effects of stem cell transplantation on WM development in Krabbe disease. The group of early transplantation infants was clearly distinguishable from the group of late transplantation infants based on anisotropy measurements. Good correlation also was seen between neurodevelopmental scores and anisotropy measurements. The work described here in Krabbe disease may serve as a model for application of DTI to other therapies in various WM disorders such as multiple sclerosis and dysmyelinating disorders of childhood.

Prince, H. E. (2005). "Biomarkers for diagnosing and monitoring autoimmune diseases." Biomarkers 10 Suppl 1: S44-9.

            The goal of studies of autoimmune disease biomarkers is to identity markers that fluctuate with disease development and severity, but then normalize following successful therapy. The perfect marker could thus serve as a diagnostic tool, as well as a monitoring device for therapeutic drug efficacy. Current biomarker discovery efforts are focused on three groups of proteins reflective of the autoimmune disease process: (1) degradation products arising from destruction of affected tissues, (2) enzymes that play a role in tissue degradation and (3) cytokines and other proteins associated with immune activation. Potential biomarkers for two autoimmune diseases, rheumatoid arthritis and multiple sclerosis, have been described in recent publications. For rheumatoid arthritis, these markers (by group) include (1) aggrecan fragments, C-propeptide of type II collagen and cartilage oligomeric matrix protein, (2) matrix metalloprotease (MMP)-1, MMP-3 and MMP-1/inhibitor complexes and (3) thioredoxin, IL-16 and tumour necrosis factor (TNF)-alpha. For multiple sclerosis, they include (1) neurofilament light protein and glial fibrillary acidic protein, (2) MMP-2 and MMP-9 and (3) TNF-alpha and soluble vascular adhesion molecule-1. The utility of most of these markers is limited by their restriction to relatively inaccessible anatomic sites (synovial or cerebrospinal fluid). Thus, from a practical standpoint, the most useful autoimmune biomarkers will be those measurable in serum or plasma.

Prat, A. and J. Antel (2005). "Pathogenesis of multiple sclerosis." Curr Opin Neurol 18(3): 225-30.

            PURPOSE OF REVIEW: The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of multiple sclerosis. RECENT FINDINGS: A current debate is where and what initiates the neuroinflammatory reaction that characterizes the acute multiple sclerosis lesion. Immune sensitization to neural antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly viral derived, peptides (molecular mimicry). Although CD4 T cells are considered central to initiating central nervous system inflammation, the actual extent and specificity of tissue injury reflects the array of adaptive (CD8 T cells and antibody) and innate (microglia/macrophages) immune constituents present in the lesions. Neuropathologic studies indicate that lethal changes in neural cells (oligodendrocytes) could also be the initiating event, reflecting as yet unidentified acquired insults (e.g. exogenous virus or reactivated endogenous retrovirus) or intrinsic abnormalities ('neurodegenerative' hypothesis). Recurrence or persistence of the disease process can reflect events occurring at multiple sites including expansion of the immune repertoire in response to neural antigens transported to regional lymph nodes (determinant spreading), especially if immune regulatory mechanisms are defective; alterations in blood-brain barrier properties consequent to initial cellular transmigration; and participation of endogenous (microglia, astrocytes) or long lived infiltrating cells (macrophages, B cells in ectopic germinal centers) in regulating and effecting immune functions within the central nervous system. Accumulating neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (trophic support and clearance of tissue debris) impacted by inflammatory processes. SUMMARY: Understanding the full spectrum of multiple sclerosis presents a continuing challenge for both immunology and neurobiology.

Poser, C. M. (2005). "The diagnosis and management of multiple sclerosis." Acta Neurol Scand 112(3): 199-201.

Poppe, A. Y., Y. Lapierre, et al. (2005). "Neuromyelitis optica with hypothalamic involvement." Mult Scler 11(5): 617-21.

            We describe two cases of neuromyelitis optica (NMO) with clinical and radiographically confirmed features of hypothalamic involvement, in the absence of other parenchymal brain lesions. Their course is otherwise typical of Devic's form of NMO. A review of the literature identifies additional cases of NMO in which clinical features attributable to under-recognized dysfunction of the hypothalamic-pituitary axis were present. We propose that the currently accepted criteria for the diagnosis of NMO could be revisited to recognize the possibility of lesions developing within hypothalamic structures.

Ponsonby, A. L., R. M. Lucas, et al. (2005). "UVR, vitamin D and three autoimmune diseases--multiple sclerosis, type 1 diabetes, rheumatoid arthritis." Photochem Photobiol 81(6): 1267-75.

            We review the evidence indicating a possible beneficial role for UVR on three Th1-mediated autoimmune diseases: multiple sclerosis, type 1 diabetes and rheumatoid arthritis in relation to recent developments in photoimmunology. Recent work suggests that UVR exposure may be one factor that can attenuate the autoimmune activity leading to these three diseases through several pathways involving UVB and UVA irradiation, UVR-derived vitamin D synthesis and other routes such as alpha-melanocyte-stimulating hormone, calcitonin gene related peptide and melatonin. Ecological features, particularly a gradient of increasing prevalence of multiple sclerosis and type 1 diabetes with higher latitude, provide some support for a beneficial role of UVR. Analytical studies provide additional support, particularly as low vitamin D has been prospectively associated with disease onset for all three diseases, but are not definitive. Randomized controlled trial data are required. Further, we discuss how associated genetic studies may assist the accumulation of evidence with regard to the possible causal role of low UVR exposure and/or low vitamin D status in the development of these diseases.

Pompeii, L. A., S. D. Moon, et al. (2005). "Measures of physical and cognitive function and work status among individuals with multiple sclerosis: a review of the literature." J Occup Rehabil 15(1): 69-84.

            The purpose of this review was to critically evaluate the multiple sclerosis (MS) literature that has examined physical and cognitive function in relation to ability to work. Although numerous factors may be considered when determining work ability, physical and/or cognitive functional limitations associated with MS are presumably the primary determinants of work capacity. An exhaustive search of the literature produced 20 research articles that described 18 studies. Findings from these studies support that limitations in physical or cognitive function can hinder one's ability to work; however, ability to work could not be based solely on these measures of function. Work ability among individuals extended beyond measures of impairment to include level of education, job characteristics, and disease symptoms such as fatigue. In summary, measures of physical and cognitive function can guide physicians when clinically evaluating an individual with MS, but are poor indicators for precluding an individual from working.

Polman, C. H., J. S. Wolinsky, et al. (2005). "Multiple sclerosis diagnostic criteria: three years later." Mult Scler 11(1): 5-12.

            New diagnostic criteria for multiple sclerosis (MS) were developed by an International Panel in 2001 and have had wide distribution and discussion since publication. These provided the first formal incorporation of magnetic resonance imaging (MRI) in a diagnosis work-up for patients suspected of having MS. The so-called McDonald criteria have been studied in retrospective and prospective analyses for sensitivity, specificity and utility, and have been proven to compare favourably or to be an improvement upon prior MS diagnostic criteria. The purpose of the current review is to present and evaluate the key studies that have been performed using the McDonald criteria since 2001 and to set the stage for an upcoming re-evaluation of the new criteria based on data-driven information gathered since their development.

Polman, C. H., S. C. Reingold, et al. (2005). "Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"." Ann Neurol 58(6): 840-6.

            New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Pollmann, W., C. Busch, et al. (2005). "[Quality of life in multiple sclerosis. Measures, relevance, problems, and perspectives]." Nervenarzt 76(2): 154-69.

            Measuring quality of life (QOL) has made essential contributions for the management of patients with multiple sclerosis (MS). QOL measures may be used for helping to assess the complex changes which patients with MS have to go through during the disease trajectory, and they may be used for pharmacoeconomic research. The large number of tests available includes generic ones such as Short Form SF-36 and Sickness Impact Profile, health-related ones such as MSQOL-54, FAMS, or HAQUAMS, and patient generated measures such as the Patient Generated Index and SEIQOL-DW. Depression, cognitive impairment, and fatigue are important factors influencing QOL. Since the different tests measure quite different facets of QOL, this review intends to help the reader select a tool suited to the aim and specific question. It is hoped that QOL measures may help to better understand patients, to become a more helpful medical partner, to assist patients to develop perspectives for their future, and to decide about therapies or even palliative interventions.

Pollmann, W., W. Feneberg, et al. (2005). "[Therapy of pain syndromes in multiple sclerosis -- an overview with evidence-based recommendations]." Fortschr Neurol Psychiatr 73(5): 268-85.

            While pain is a common problem in multiple sclerosis (MS) patients, it is frequently overlooked and has to be asked for actively. Pain can be classified into 4 diagnostically and therapeutically relevant categories. 1. PAIN DIRECTLY RELATED TO MS: Painful paroxysmal symptoms like trigeminal neuralgia or painful tonic spasms are treated with carbamazepine as first choice, or lamotrigine, gabapentin, oxcarbazepine and other anticonvulsants. Painful "burning" dysaesthesia, the most frequent chronic pain syndrome, are treated with tricyclic antidepressants or carbamazepine, further options include gabapentin or lamotrigine. While escalation therapy may require opioids, the role of cannabinoids in the treatment of pain still has to be determined. 2. PAIN INDIRECTLY RELATED TO MS: Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents like baclofen or tizanidine, alternatively gabapentin. In severe cases botulinum toxin injections or intrathecal baclofen merit consideration. Physiotherapy and physical therapy may ameliorate malposition-induced joint and muscle pain. Moreover, painful pressure lesions should be avoided using optimally adjusted aids. 3. Treatment-related pain can occur with subcutaneous injections of beta interferons or glatiramer acetate and may be reduced by optimizing the injection technique and by local cooling. Systemic side effects of interferons like myalgias can be reduced by paracetamol or ibuprofen. 4. Pain unrelated to MS such as back pain or headache are frequent in MS patients and may be worsened by the disease. Treatment should be follow established guidelines. In summary, a careful analysis of the pain syndrome will allow the design of the appropriate treatment plan using various medical and non-medical options and thus will help to ameliorate the patients' quality of life.

Pluchino, S. and G. Martino (2005). "The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders." J Neurol Sci 233(1-2): 117-9.

            Spontaneous remyelination occurs in multiple sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture in demyelinated areas of the central nervous system (CNS). As a consequence of this incomplete reparative process, the disease invariably progresses and patchy areas of demyelination-in which axonal damage and/or loss is a constant accompanying factor-increase over time and lead to the accumulation of irreversible neurological deficits. Thus, the development of cell-based therapies aimed to promote multifocal remyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years. However, most of these therapeutic approaches-although consistently able to form new myelin sheaths around the transplantation site-are unrealistic owing to the multifocality of the demyelinating process and the inability to in vitro growth and differentiate large number of myelin-forming cells. Recently, promising cell-replacement therapies based on the use of stem cells have been proposed. However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: (i) the ideal stem cell source for transplantation, (ii) the route of cell administration, (iii) the differentiation and persistence of stem cells into the targeted tissue and, last but not least, (iv) the functional and long-lasting integration of transplanted cells into the host tissue.

Piedrola Angulo, G. (2005). "[Human herpesvirus 6 and multiple sclerosis]." An R Acad Nac Med (Madr) 122(2): 377-89; discussion 389-92.

            In this work the possible etiologic relationship among the multiple sclerosis and the herpesvirus 6 (VHH-6) has been studied, subject debated in the last years. They have been carried out two studies using blood and LCR of sick of multiple sclerosis, and control in healthy fellows and with other neurological illnesses. The followed techniques are described to isolate the virus, their DNA, and the antibodies IgG and IgA in front of the VHH-6. The presente of the VHH-6 has not been demonstrated neither of its DNA in any case, but if it has been proved, with statistical significance that in the sick persons with buds of multiple sclerosis, the antibodies of the type IgG, as much in plasm as in LCR, was more present and in higher levels that in the controls.

Pickett, G. E., D. Bisnaire, et al. (2005). "Percutaneous retrogasserian glycerol rhizotomy in the treatment of tic douloureux associated with multiple sclerosis." Neurosurgery 56(3): 537-45; discussion 537-45.

            OBJECTIVE: Patients with multiple sclerosis (MS) have a relatively high incidence of tic douloureux (TD) and often do not tolerate medical therapy well. The minimally invasive nature of percutaneous retrogasserian glycerol rhizotomy (PRGR) renders it ideal for first-line surgical treatment of TD. We sought to ascertain the benefits of PRGR in patients with MS and to determine whether hypalgesia after PRGR correlates with efficacy. METHODS: We assessed 97 glycerol procedures performed in 53 patients followed prospectively for treatment of TD associated with MS. Factors assessed included degree of pain relief, postoperative hypalgesia, procedural morbidity, medication use, time to pain recurrence, and number and type of subsequent procedures. RESULTS: Complete pain relief was obtained in 78% of patients after the initial glycerol injection, and partial relief was obtained in 13% of patients. Long-term follow-up (mean, 81 mo) demonstrated a recurrence rate of 59%, with a mean time to recurrence of 17 months. Actuarial recurrence rates were 50% at 12 months and 60% at 24 months. Twenty-four patients underwent a second or subsequent PRGR for recurrent pain and achieved similar rates of pain relief and time to recurrence. Facial sensory loss was associated with a higher likelihood of pain relief (P < 0.05), with longer time to pain recurrence (P < 0.05), and with decreased use of medication after surgery (P < 0.01.) CONCLUSION: PRGR is an effective, low-morbidity surgical procedure in the management of TD complicating MS. The presence of facial sensory loss after PRGR is associated with prolonged efficacy.

Phillips, W. J., D. J. Smith, et al. (2005). "Recombinant immunoglobulin-based epitope delivery: a novel class of autoimmune regulators." Int Rev Immunol 24(5-6): 501-17.

            Over the past decades, there has been significant progress in understanding the mechanisms of autoimmune diseases at a molecular level. Diseases such as juvenile diabetes, multiple sclerosis, celiac disease, rheumatoid arthritis, and others appear to be mediated by pathogenic T cells that recognize self-epitopes and escape natural tolerance. Seminal observations correlating autoimmunity with HLA and disease-associated epitopes, in conjunction with recent characterization of T regulatory (Treg) cells, promoted a renewed interest in antigen or epitope-based methods of interfering with pathogenic autoimmune reactions. Recombinant immunoglobulin-peptides encompassing disease-associated self-epitopes (IgPP) integrate effective targeting of antigen-presenting cells (APCs) with a potential to generate Treg cells and thus are being developed for treatment of selected autoimmune disorders. In the current review, we outline the main features of this new class of active immunotherapeutics and directions of future development.

Petzold, A. (2005). "Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss." J Neurol Sci 233(1-2): 183-98.

            This review on the role of neurofilaments as surrogate markers for axonal degeneration in neurological diseases provides a brief background to protein synthesis, assembly, function and degeneration. Methodological techniques for quantification are described and a protein nomenclature is proposed. The relevance for recognising anti-neurofilament autoantibodies is noted. Pathological implications are discussed in view of immunocytochemical, cell-culture and genetic findings. With reference to the present symposium on multiple sclerosis, the current literature on body fluid levels of neurofilaments in demyelinating disease is summarised.

Peterson, J. W. and B. D. Trapp (2005). "Neuropathobiology of multiple sclerosis." Neurol Clin 23(1): 107-29, vi-vii.

Peterlik, M. and H. S. Cross (2005). "Vitamin D and calcium deficits predispose for multiple chronic diseases." Eur J Clin Invest 35(5): 290-304.

            There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-Dihydroxyvitamin D(3) and extracellular Ca(++) are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1alpha-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D(3). Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine.

Perennou, D., P. Decavel, et al. (2005). "[Evaluation of balance in neurologic and geriatric disorders]." Ann Readapt Med Phys 48(6): 317-35.

            OBJECTIVE: To analyse the clinical usefulness and metrological properties of the main techniques and indices used to assess balance disorders. METHODS: More than 4000 abstracts referenced in MEDLINE and dealing with postural control and postural disorders (wide screening) were reviewed to determine the main postural techniques and indices used in a clinical context. We retained abstracts with a high citation frequency and those with interesting findings. Corresponding key words were identified for a specific search of articles that we analysed. RESULTS: Postural assessment tools can be classified as scales of ordinal items, tests based on metric or chronometric measurement, posturography, and verticality perception. These techniques are complementary, and their association is recommended in a clinical context. Regarding generic tools, the Falls-related Efficacy Scale (FES) and the Activities-specific Balance Confidence scale (ABC scale) would be enhanced if comparatively analysed and reworked to allow for a feasible and reliable assessment of the fear of falling. Despite a wide diffusion in numerous postural fields worldwide, the Berg Balance Scale (BBS) and the Functional Reach Test (FRT) do not have the required criteria to remain the gold standards they were in the 1990s. Static posturography should be normalised and yield more reliable indices. The clinical relevance of the subjective assessment of visual, haptic, and postural verticals are questionable, especially to explain postural disability. Regarding specific tools, the Tinetti test (TT) and the Time Up and Go test (TUG) are the most suited to assess postural capacities in very elderly people, in whom the predictive validity of the postural assessment of falls is still modest. In stroke patients, the Postural Assessment Scale for Stroke (PASS), posturography, lateropulsion assessment, and vertically perception are interesting and complementary techniques. Postural assessment relies mainly upon the 5 postural items of the Unified Parkinson Disease Rating Scale (UPDRS) in people with Parkinson disease and upon the Romberg test and posturography in patients with cerebellar or proprioceptive ataxia. Some novel postural scales for patients with multiple sclerosis or spinal cord injury are also emerging. CONCLUSION: Among numerous tools that contribute to the assessment of postural disorders, only the most recent ones (developed in the last 10 years) have undergone complete validation. It is now crucial to compare these tools, not only in terms of reproducibility and internal consistency, but also overall, in terms of feasibility, responsiveness, and predictive validity for a given population.

Pepping, M. and D. M. Ehde (2005). "Neuropsychological evaluation and treatment of multiple sclerosis: the importance of a neuro-rehabilitation focus." Phys Med Rehabil Clin N Am 16(2): 411-36, viii.

            This article describes the components of a neuropsychologic evaluation and some of the primary indications for its use in multiple sclerosis (MS). We also detail the kinds of neurocognitive and neurobehavioral problems that are cited commonly in the relevant literature and seen in the clinical setting. We provide a brief overview of the brain structures that are affected commonly by MS, and their implications for neuropsychologic function. We have included an overview of some of the current medications that are used to target cognitive and emotional symptoms that can be a direct result of the disease. We also present four representative case examples of composite patients, and briefly review the ways in which neuropsychologic evaluation and neuro-rehabilitation treatments can help people who have MS.

Pelczynska, K., I. Jaroszewicz, et al. (2005). "[Biological activity of calcitriol and its new analogues -- potential therapeutic applications]." Postepy Hig Med Dosw (Online) 59: 129-39.

            Calcitriol is effective not only in the regulation of calcium-phosphate homeostasis, but also in promoting the differentiation and inhibition of proliferation of various cells. Calcitriol seems to be a potent drug with various therapeutic applications, such as regulation of calcium-phosphate homeostasis and treatment of psoriasis, autoimmune diseases, and cancer. Since clinical use of calcitriol is largely limited, due to its undesirable side effect of hypercalcemia, numerous calcitriol analogues have been synthesized to obtain compounds with better therapeutic profiles. This paper summarizes the current state of knowledge concerning the cellular mechanisms of calcitriol's biological activity and their clinical implications. Such medical application includes treatment (as a single-drug or in combination) of osteoporosis, renal osteodystrophy, psoriasis (calcipotriol or tacalcitol ointment), autoimmunological diseases (including multiple sclerosis), and some cancers. The efforts to obtain new vitamin D3 analogues are also briefly reviewed. The structures and roles of vitamin D receptors in the biological effects of calcitriol and its analogues are discussed.

Pease, J. E. and R. Horuk (2005). "CCR1 antagonists in clinical development." Expert Opin Investig Drugs 14(7): 785-96.

            Chemokines (chemotactic cytokines) are a family of low-molecular-weight proteins that direct the cellular migration of leukocytes by binding to and activating the G protein-coupled receptors displayed on the leukocyte cell surface. The inadvertent or excessive generation of chemokines has been associated with the inflammatory component of several disease processes, and consequently, considerable efforts have been made to characterise chemokine/chemokine receptor interactions with the ultimate aim of therapeutic intervention. This review focuses on the biology of CC chemokine receptor 1, which together with its ligands is thought to recruit leukocytes during the progression of rheumatoid arthritis, multiple sclerosis and organ transplant rejection. The developments made in antagonising this receptor and efficacies of these compounds in the clinical setting are also highlighted.

Pearce, J. M. (2005). "Neuromyelitis optica." Spinal Cord 43(11): 631-4.

            The combination of optic neuritis and myelitis, the so-called Neuromyelitis optica is an uncommon pattern of demyelinating disorder. In 1870, Sir Thomas Clifford Allbutt first reported the association and Erb published a comparable report. Gowers and Dreschfeld described other instances in the 19th century. This paper attempts to review the syndrome to consider whether it merits recognition as a disease, sui generis, or rather as a syndrome symptomatic of multiple sclerosis, acute disseminated encephalomyelitis, and other immunological disorders. Two forms are distinguished: a monophasic illness, and a relapsing form. The claimed differential features separating it from classical multiple sclerosis are appraised. Modern immunology suggests an antibody-dependent, complement-mediated pathogenesis.

Patwardhan, M. B., D. B. Matchar, et al. (2005). "Cost of multiple sclerosis by level of disability: a review of literature." Mult Scler 11(2): 232-9.

            We performed a review of the economic literature to identify what is known about the relationship between Expanded Disability Status Scale (EDSS) categories and cost of multiple sclerosis (MS). We sought cohort studies of patients with multiple sclerosis that described the costs attributed to each EDSS score and utilized specific inclusion criteria for the selection of 10 studies. We found that both direct and indirect costs rise continuously with increasing EDSS category, and this rise is qualitatively exponential. The rise in indirect costs appears at lower EDSS scores. The cost of a relapse occurring in any given EDSS category exceeds that associated with that particular EDSS category. Few studies comprehensively assessed the entire spectrum of the costs, and much of the literature is based on EDSS categories in coarse groupings. In spite of several variations between studies, one important conclusion that we can draw is that rise in cost is positively correlated to scores on the EDSS categories, and therefore agents with a capacity to prevent or arrest the rate of MS progression may affect the overall cost of MS.

Patten, S. B. (2005). "Treatment of neuropsychiatric syndromes in multiple sclerosis." Expert Rev Neurother 5(3): 413-20.

            The treatment of multiple sclerosis has been revolutionized during the past 10 years by the introduction of disease-modifying therapies. However, day-to-day management of the symptoms and complications of this condition will, for the foreseeable future, continue to be important management concerns. Among the most problematic and troublesome manifestations of multiple sclerosis are its neuropsychiatric manifestations. Most prominent among these are depression, pathologic laughing and crying, fatigue, cognitive problems, sleep disorders and disorders of sexual function. There have been relatively few randomized controlled trials of pharmacologic treatments for these conditions. Available treatments for the management of fatigue and cognitive deficits remain inadequate and patients must often accommodate these symptoms in their lifestyle.

Panyi, G. (2005). "Biophysical and pharmacological aspects of K+ channels in T lymphocytes." Eur Biophys J 34(6): 515-29.

            Voltage-gated Kv1.3 and Ca2+-activated IKCa1 K+ channels play a pivotal role in antigen-dependent activation and proliferation of lymphocytes.These channels primarily determine the membrane potential of T cells, and thus regulate the magnitude of the Ca2+ signal required for efficient gene transcription and subsequent proliferation. Although these facts are generally well described and acknowledged, some recent discoveries have motivated research in this field, which is reviewed herein along with the basic biophysical characterization of Kv1.3 and IKCa1. The discovery of T cell subset-specific expression of Kv1.3 points towards the potential therapeutic use of high affinity and high specificity Kv1.3 inhibitors as specific immunosuppressors in the management of autoimmune diseases, such as Multiple Sclerosis. In meeting the demands for an ideal immunosuppressor, several laboratories have discovered potent natural Kv1.3- specific inhibitors and engineered peptides which have a better pharmacological profile based on the biophysical characterization of the interaction surface between the channel pore and the toxins. In contrast to the generally accepted permissive role of Kv1.3 during lymphocyte activation, the discovery of the localization of Kv1.3 in the immunological synapse might open new opportunities in the regulation of T cell activation by this channel species.

Ozgen, H. M., W. C. Overweg-Plandsoen, et al. (2005). "Cerebellar hypoplasia-endosteal sclerosis: a long term follow-up." Am J Med Genet A 134(2): 215-9.

            Cerebellar hypoplasia with endosteal sclerosis is an infrequent entity that has been described in only four cases. Major clinical symptoms are cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, microcephaly, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. We report on a girl with this entity, whom we followed for 11 years. The endosteal sclerosis remained stationary over time, as were the clinical neurological symptoms, but neuroadiological symptoms were slowly progressive. We provide a short review of this probably autosomal recessively inherited disorder. (c) 2005 Wiley-Liss, Inc.

Osoegawa, M. (2005). "[Atopic myelitis]." Nippon Rinsho 63 Suppl 5: 125-30.

Oppenheim, J. J., H. F. Dong, et al. (2005). "Autoantigens act as tissue-specific chemoattractants." J Leukoc Biol 77(6): 854-61.

            We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function.

Olsson, T., F. Piehl, et al. (2005). "Genetic dissection of neurodegeneration and CNS inflammation." J Neurol Sci 233(1-2): 99-108.

            Inflammation and neurodegeneration characterize multiple sclerosis, as well as many other diseases of the central nervous system (CNS). The understanding of the molecular pathways that regulate these processes is of fundamental importance for the development of new therapies. Nerve lesions paradigms in animals can serve as important tools to dissect central features of human CNS disease and by using these models certain key regulators have also been identified. However, our knowledge of how aspects of neurodegeneration and CNS inflammation are regulated on a genomic level is very limited. Such knowledge may help to unravel disease mechanisms. By using a standardized nerve trauma model, ventral root avulsion (VRA), in a series of inbred rat strains we here demonstrate a potent genetic regulation of the degree of neuron death and glial activation. Genome wide mapping of these phenotypes in experimental rat strain crosses identifies several quantitative trait loci (QTLs) controlling nerve lesion-induced nerve cell death, local T cell accumulation and expression of MHC class II on microglia. This approach may lead to the identification of evolutionary conserved genetic polymorphisms in key controlling genes, which can serve as prime candidates for association studies in several human CNS diseases.

Olson, J. K., A. M. Ercolini, et al. (2005). "A virus-induced molecular mimicry model of multiple sclerosis." Curr Top Microbiol Immunol 296: 39-53.

            Multiple sclerosis1 (MS) is an immune-mediated autoimmune demyelinating disease in humans. The initiating event in MS is unknown, but epidemiological evidence suggests that virus infections may be important and one possible mechanism for induction of infection-induced autoimmune disease is molecular mimicry. To test the ability of a virus encoding a self myelin mimic epitope to induce an autoimmune response, we have developed a mouse model wherein the immunodominant myelin epitope PLP139-151, or mimics of this epitope, were inserted into a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV). SJL mice infected with TMEV containing PLP139-151 or a mimic of PLP139-151 expressed by the protease IV protein of Haemophilus influenzae, sharing only 6/13 amino acids with the native epitope, developed an early-onset demyelinating disease associated with activation of CD4+ T cells reactive with PLP139-151. We have used this molecular mimicry model to further address the requirements for mimic epitope processing and presentation during infection and the requirements for TCR recognition and MHC binding of mimic epitopes. We have also investigated whether molecular mimicry may require multiple infections, with either the mimic-encoding virus or an unrelated virus, to initiate autoimmune disease. Finally, we have asked whether a virus encoding a molecular mimic has to directly infect the target organ to induce autoimmune disease. Overall, this virus-induced molecular mimicry model has provided critical information regarding the mechanisms by which infection-induced molecular mimicry can induce autoimmune diseases.

Oksenberg, J. R. and S. L. Hauser (2005). "Genetics of multiple sclerosis." Neurol Clin 23(1): 61-75, vi.

Oksenberg, J. R. and L. F. Barcellos (2005). "Multiple sclerosis genetics: leaving no stone unturned." Genes Immun 6(5): 375-87.

            Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

Ohta, M. and K. Ohta (2005). "[Immunologic tests: Myelin basic protein and anti-myelin basic protein antibody]." Nippon Rinsho 63 Suppl 7: 596-8.

Offner, H. and A. A. Vandenbark (2005). "Congruent effects of estrogen and T-cell receptor peptide therapy on regulatory T cells in EAE and MS." Int Rev Immunol 24(5-6): 447-77.

            Both estrogen (E2) and T-cell receptor (TCR) peptides have beneficial effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS) that involve distinct but congruent mechanisms. Of interest, these two approaches share an ability to enhance expression of the FoxP3 gene and associated activity of regulatory T (Treg) cells. E2 increases the number and activity of FoxP3(+) T cells through Esr-1 signaling during TCR activation of CD4(+)CD25(-) T cells. In contrast, TCR peptide therapy appears to increase the frequency of regulatory FoxP3(+) T cells specific for self-TCR determinants expressed by targeted pathogenic T cells. The combined effects on Treg expansion and activation induced by these distinct immunoregulatory approaches may account for their potent effects on clinical EAE and argue for a similar combined therapeutic approach for MS.

Oertelt, S., C. Selmi, et al. (2005). "Genes and goals: an approach to microarray analysis in autoimmunity." Autoimmun Rev 4(7): 414-22.

            A significant body of data on gene expression patterns in autoimmune diseases has been generated by microarray analysis. Although results are very promising, there are many factors that have detracted from the data. Indeed, no common methodological directions are available. Similarly, collection techniques, processing methods, and statistical approaches are often different. The impact of future studies will depend on the comparison of large datasets to validate results and must include rigorous statistical analysis. To better illustrate the issue we review herein the gene expression patterns observed in five representative autoimmune diseases, i.e. systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, dermatomyositis, and primary biliary cirrhosis. We also emphasize how, once potential chromosome regions or pathways are identified, specific array design will be a powerful resource when used on large and representative populations.

Norman, M. U. and M. J. Hickey (2005). "Mechanisms of lymphocyte migration in autoimmune disease." Tissue Antigens 66(3): 163-72.

            The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naive lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Nishino, S. and T. Kanbayashi (2005). "Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system." Sleep Med Rev 9(4): 269-310.

            Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

Nicholson, M. J., M. Hahn, et al. (2005). "Unusual features of self-peptide/MHC binding by autoimmune T cell receptors." Immunity 23(4): 351-60.

            Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II beta chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection.

Neuhaus, O., O. Stuve, et al. (2005). "Putative mechanisms of action of statins in multiple sclerosis--comparison to interferon-beta and glatiramer acetate." J Neurol Sci 233(1-2): 173-7.

            Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-beta. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-beta and glatiramer acetate (GA).

Natarajan, N. and R. Weinstein (2005). "Therapeutic apheresis in neurology critical care." J Intensive Care Med 20(4): 212-25.

            Therapeutic apheresis has been widely accepted in the treatment of neurological disorders that are understood to be mediated by humoral and/or cellular immunity. The clinical presumption is that well-established and/or unknown insults cause damage to nerves or their myelin sheaths. The rationale for apheresis treatments for these neurological disorders relates to removal of offending immune (or other) mediators, thus blunting the attack and permitting recovery of nerve and/or myelin. This review will concentrate on the role of therapeutic apheresis, in particular therapeutic plasma exchange, in neurological disorders that may frequently be seen by intensivists.

Nash, P. T. and T. H. Florin (2005). "Tumour necrosis factor inhibitors." Med J Aust 183(4): 205-8.

            The cytokine, tumour necrosis factor-alpha (TNF-alpha) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn's disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18 000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

Narayana, P. A. (2005). "Magnetic resonance spectroscopy in the monitoring of multiple sclerosis." J Neuroimaging 15(4 Suppl): 46S-57S.

            In addition to providing information on tissue structure, magnetic resonance (MR) technology offers the potential to investigate tissue metabolism and function. MR spectroscopy (MRS) offers a wealth of data on the biochemistry of a selected brain tissue volume, which represent potential surrogate markers for the pathology underlying multiple sclerosis (MS). In particular, the N-acetylaspartate peak in an MR spectrum is a putative marker of neuronal and axonal integrity, and the choline peak appears to reflect cell-membrane metabolism. On this basis, a diminished N-acetylaspartate peak is interpreted to represent neuronal/axonal dysfunction or loss, and an elevated choline peak represents heightened cell-membrane turnover, as seen in demyelination, remyelination, inflammation, or gliosis. Therefore, MRS may provide a unique tool to evaluate the severity of MS, establish a prognosis, follow disease evolution, understand its pathogenesis, and evaluate the efficacy of therapeutic interventions, which complements the information obtained from the various forms of assessment made by conventional MR imaging.

Napoli, S. Q. and R. Bakshi (2005). "Magnetic resonance imaging in multiple sclerosis." Rev Neurol Dis 2(3): 109-16.

            Magnetic resonance imaging (MRI) has played a central role in the clinical management and scientific investigation of multiple sclerosis (MS) and has become the most important ancillary tool for diagnosing and monitoring the disease. Conventional MRI techniques are used to assess overt lesions and atrophy in the central nervous system and include spin-echo T2-weighted, pre- and post-gadolinium-enhanced spin-echo T1-weighted, and fluid-attenuated inversion-recovery images. Advanced MRI techniques such as diffusion-weighted imaging, magnetization transfer imaging, magnetic resonance spectroscopy, and functional MRI have increased our understanding of the pathogenesis of MS. The role of these newer techniques in clinical practice remains under investigation. In this review, we will focus on the role of MRI in the diagnosis and management of MS. We will also review how advanced MRI techniques contribute to our understanding of MS.

Nakasaka, Y., M. Atsumi, et al. (2005). "[Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with relapsing multiple sclerosis]." No To Shinkei 57(1): 51-5.

            We report a 47-year-old man with multiple sclerosis (MS) with previous history of recurrent sensorimotor disturbance and visual deficit. The patient developed bilateral motor weakness in the upper limbs, and systemic malaise. An administration of 20 mg/day of prednisolone was ineffective for his symptoms and he complained dyspnea a week later. On admission, his clinical findings included brainstem dysfunction with optic nerve atrophy, motor disturbance in the bilateral upper limbs, hyperreflexia, and superficial sensory disturbance. Biochemical examination revealed marked reduction in serum Na (117 mEq/l) and C1 (85 mEq/l) with increased urinary Na excretion. Although his plasma osmotic pressure decreased to 233 mOsm/kg, urinary osmotic pressure increased to 409 mOsm/kg. Serum antidiuretic hormone (ADH) concentration was 26.1 pg/ml and plasma renin activity was 0.1 ng/ml/ hour. Renal function and adrenal function were normal. Cerebrospinal fluid contained increased protein concentration, IgG, and myelin basic protein. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with MS was diagnosed. Intravenous Na infusion with restricted supplemental fluid and serial administration of methylprednisolone (1,000 mg/day for three days) improved his neurological abnormalities and normalized his serum serum Na level and plasma osmotic pressure. This suggests that demyelinating lesions in the hypothalamus due to MS may cause the transient increased ADH secretion.

Nagpal, S., S. Na, et al. (2005). "Noncalcemic actions of vitamin D receptor ligands." Endocr Rev 26(5): 662-87.

            1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.

Mutter, J., J. Naumann, et al. (2005). "[Amalgam risk assessment with coverage of references up to 2005]." Gesundheitswesen 67(3): 204-16.

            Amalgam, which has been in use in dentistry for 150 years, consists of 50 % elemental mercury and a mixture of silver, tin, copper and zinc. Minute amounts of mercury vapour are released continuously from amalgam. Amalgam contributes substantially to human mercury load. Mercury accumulates in some organs, particularly in the brain, where it can bind to protein more tightly than other heavy metals (e. g. lead, cadmium). Therefore, the elimination half time is assumed to be up to 1 - 18 years in the brain and bones. Mercury is assumed to be one of the most toxic non-radioactive elements. There are pointers to show that mercury vapour is more neurotoxic than methyl-mercury in fish. Review of recent literature suggests that mercury from dental amalgam may lead to nephrotoxicity, neurobehavioural changes, autoimmunity, oxidative stress, autism, skin and mucosa alterations or non-specific symptoms and complaints. The development of Alzheimer's disease or multiple sclerosis has also been linked to low-dose mercury exposure. There may be individual genetical or acquired susceptibilities for negative effects from dental amalgam. Mercury levels in the blood, urine or other biomarkers do not reflect the mercury load in critical organs. Some studies regarding dental amalgam reveal substantial methodical flaws. Removal of dental amalgam leads to permanent improvement of various chronic complaints in a relevant number of patients in various trials. Summing up, available data suggests that dental amalgam is an unsuitable material for medical, occupational and ecological reasons.

Mutch, K. (2005). "Information for young people when multiple sclerosis enters the family." Br J Nurs 14(14): 758-67.

            Multiple sclerosis (MS) typically affects people aged 20-40 years and, by its very nature, is characterized by unpredictability, uncertainty and variability, and is therefore bound to have an impact on children who have a parent with MS. There has been little work done to assess the needs of young people living with MS in their family. A series of workshops specifically aimed at 9-14-year-olds who have a parent with MS have been successfully conducted. This article reviews the background to setting up the workshop and identifies implications for future MS specialist nurses to help this potentially vulnerable group of people. By breaking the silence and talking about MS with young people, the myths can be removed and the anxieties reduced.

Murdoch, D. and K. A. Lyseng-Williamson (2005). "Subcutaneous recombinant interferon-beta-1a (Rebif): a review of its use in relapsing-remitting multiple sclerosis." Drugs 65(9): 1295-312.

            Subcutaneous recombinant interferon-beta-1a (Rebif) 22 or 44 microg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-beta-1a three times weekly over intramuscular interferon-beta-1a 30 microg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-beta-1a 44 microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

Muller-Forell, W. (2005). "[Neuroradiology of the intracranial visual pathway. Part II]." Radiologe 45(11): 1043-55.

            Part 2 mainly presents intrinsic lesions as the most common brain tumors (astrocytoma of all grades, ependymoma), arising in the region of the visual pathway. A second focus is on vascular pathology, not only infarction, but cavernoma and venous malformation in Sturge-Weber syndrome. The third topic deals with inflammatory processes such as multiple sclerosis or sarcoidosis.

Mukhtar, M., E. Acheampong, et al. (2005). "T-Cells and excitotoxicity: HIV-1 and other neurodegenerative disorders." Neuromolecular Med 7(3): 265-73.

            Until recently the central nervous system (CNS) was considered an immune-privileged site, however, technological and immunological advances have resulted in the CNS being reclassified as an "immune-specialized site." The immune cells, particularly T-cells, continuously patrol the brain and are involved in neuroimmune responses. As such, any changes in the brain microenvironment could affect the physiological functioning of T-cells. Particularly, neurotransmission- associated abnormalities, such as excitotoxicity associated with hypersecretion of glutamate, could severely affect the neuroimmune function of T-cells. Excitotoxicity is involved in the pathogenesis of a number of neurodegenerative disorders. The specific excitotoxicity triggered by the excitatory amino acid neurotransmitter, glutamate, is considered a key mechanism involved in neuronal death. The inability of brain immune cells to overcome these aberrant changes is an active area of investigation. In the systemic circulation, glutamate is inversely related to the number of CD4+ T-cells; however, the effects of elevated glutamate and glutamate-induced exicitotoxicity on cells homing in the brain are critical for understanding neuropathogenesis of neurodegenerative disorders.

Moynagh, P. N. (2005). "The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain." J Anat 207(3): 265-9.

            A dysregulated inflammatory response in the central nervous system (CNS) lies at the heart of many neuropathological conditions such as multiple sclerosis and Alzheimer's disease. A key component of these inflammatory conditions is the accumulation of leukocytes in the CNS. The infiltration of leukocytes into the brain is dependent on the induction of leukocyte adhesion molecules and chemoattractant chemokines. Recent studies have suggested the astrocyte to be a key cell in mediating the inflammatory process in the brain and in expressing adhesion molecules and chemokines. Here I overview work in my laboratory and others that demonstrates interleukin-1 (IL-1) to be a key inducer of the expression of these molecules in astrocytes. The temporal expression is sustained in nature and this is due to prolonged activation of the transcription factor NFkappaB. The molecular basis to the sustained activation of NFkappaB is also discussed. The IL-1 signalling pathway thus emerges as a valuable therapeutic target in the treatment of presently incurable neuropathological conditions.

Mouzaki, A., S. Deraos, et al. (2005). "Advances in the treatment of autoimmune diseases; cellular activity, type-1/type-2 cytokine secretion patterns and their modulation by therapeutic peptides." Curr Med Chem 12(13): 1537-50.

            Autoimmune diseases are many, have an overall prevalence of about 3% of the world population, affecting more women than men, and their incidence is influenced by genetics and the environment. It is currently thought that the immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate or non-functional immunoregulatory mechanisms, can lead to the development of an autoimmune disease. Advances in the treatment of autoimmune diseases follow a better understanding of the abnormalities in the cellular activity pathways and the resulting, often permanent, imbalance of the pro- and anti-inflammatory cytokine expression profiles. Over the past few years, there has been a dramatic change in the therapeutic regimens employed in autoimmune diseases, with soluble receptors, monoclonal antibodies and molecular mimetics enhancing or gradually replacing conventional immunosuppressive therapies. New biologicals have been developed, targeting defined pathways of the adaptive immune response. One approach towards the therapeutic management of autoimmune diseases involves the design and use of peptide analogs of disease-associated epitopes to be used as immunomodulatory drugs. Peptides can target cell-functions directly, by interfering with the formation of the tri-molecular complex MHC-Peptide-TCR, and/or they can target soluble mediators such as cytokines or their receptors, eventually replacing monoclonal antibody therapies. This review offers an update on the treatment modalities of certain prototypic autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on cell activation and cytokine expression profiles.

Mourich, D. V. and N. B. Marshall (2005). "Antisense approaches to immune modulation for transplant and autoimmune diseases." Curr Opin Pharmacol 5(5): 508-12.

            Antisense oligomers have been shown to be effective tools for inhibiting gene expression in a highly specific manner. This technology has proven to be invaluable for determining gene function in conventional molecular and cellular studies. However, the promise of an antisense-based drug technology, suggested by antiviral efficacy shown nearly 25 years ago, is just now coming of age. Since then, numerous antisense approaches have been shown to be effective in animal models against numerous viruses and some tumors. Not surprisingly, antisense agents targeting these diseases are taking the lead in human clinical trials and FDA approval. Although comparatively smaller in scope, approaches for modulating immune responses to treat Crohn's disease, diabetes, multiple sclerosis and transplant rejection appear to be the next burgeoning phase of development in antisense therapy.

Morrissey, S. P., E. Le Page, et al. (2005). "Mitoxantrone in the treatment of multiple sclerosis." Int MS J 12(3): 74-87.

            Mitoxantrone is useful for the treatment of cancer and MS and, as with other chemotherapeutic agents, many studies have examined its tolerability. The suitability of mitoxantrone in MS is particularly interesting because of its role in treating various stages of the disease. Evidence shows that mitoxantrone could be a first-line treatment for malignant forms of MS, and a second-line drug in relapsing-remitting or secondary progressive MS that is unresponsive to interferon beta-1a, -1b or glatiramer acetate. Mitoxantrone should, however, be restricted to patients with demonstrable inflammatory disease activity, and should only be prescribed by neurologists with previous experience in both MS and mitoxantrone therapy. This review examines the properties of mitoxantrone, its tolerability, and discusses its suitability for treating various forms of MS, referring to several important studies.

Morand, E. F. (2005). "New therapeutic target in inflammatory disease: macrophage migration inhibitory factor." Intern Med J 35(7): 419-26.

            The cytokine macrophage migration inhibitory factor (MIF) participates in fundamental events in innate and adaptive immunity. The profile of activities of MIF in vivo and in vitro is strongly suggestive of a role for MIF in the pathogenesis of many inflammatory diseases, including rheumatoid arthritis (RA), and hence antagonism of MIF is suggested as a potential therapeutic strategy in inflammatory disease. The best developed case for therapeutic antagonism of MIF is in RA. In RA, MIF is abundantly expressed in serum and synovial tissue. MIF induces synovial expression of key pro-inflammatory genes, regulates the function of endothelial cells and leucocytes, and is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumour suppressor protein p53. In animal models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. A similar case has been made, for example using MIF-deficient mice, in models of atheroma, colitis, multiple sclerosis and other inflammatory diseases. The relationship with p53 also means MIF may be important in the link between inflammatory disease and cancer, such as is seen in RA or colitis. MIF also has a unique relationship with glucocorticoids, in that despite antagonizing their effects, the expression of MIF is in fact induced by glucocorticoids. Thus, MIF functions as a physiological counter-regulator of the anti-inflammatory effects of glucocorticoids. This may be entrained by selective activation of mitogen-activated protein kinases rather than nuclear factor kappa B. Therapeutic MIF antagonism may therefore provide a specific means of 'steroid sparing'. Exploitation of antibody, soluble receptor or small molecule technologies may soon lead to the ability to test in the clinic the importance of MIF in human inflammatory diseases.

Moore, G. R. (2005). "Mri correlates of MS pathologic subtypes." Mult Scler 11(1): 103-5.

Moon, S. J., A. A. Fryer, et al. (2005). "Ultraviolet radiation, vitamin D and risk of prostate cancer and other diseases." Photochem Photobiol 81(6): 1252-60.

            Most common diseases appear to result from complex, poorly understood interactions between genetic and environmental factors. Relatively few factors have been unequivocally linked with disease risk or outcome. Evidence from various studies using different experimental approaches has been interpreted as showing that, apart from its harmful effects on the pathogenesis of the common skin cancers, ultraviolet radiation (UVR) may exert a beneficial effect on development of various internal cancers and other pathologies. This concept is supported by parallel studies showing that hypovitaminosis D is linked with increased risk of various diseases including insulin resistance and multiple sclerosis. These findings suggest that, first, host factors such as skin pigmentation that affect UVR-induced synthesis of vitamin D and, second, polymorphism in genes that mediate the effectiveness of vitamin D action are susceptibility candidates for a variety of diseases. Collectively, these data suggest the hypothesis that, via effects on vitamin D synthesis, UVR exposure has beneficial effects on susceptibility and outcome to a variety of complex diseases. We describe evidence from studies in various diseases, but mainly from prostate cancer patients, that supports this hypothesis, but we emphasize that, although supportive data are available, the concept is unproven. Indeed, other explanations are possible. However, given the potentially important public health implications of the hypothesis and the potential for the development of novel therapeutic modalities, we believe the concept is worthy of further investigation.

Montalban, X. (2005). "Primary progressive multiple sclerosis." Curr Opin Neurol 18(3): 261-6.

            PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate on the specific characteristics of primary progressive multiple sclerosis. RECENT FINDINGS: The most important observations come from the studies using magnetic resonance imaging showing involvement of the normal-appearing brain tissue and also from the clinical and magnetic-resonance-imaging descriptions in longitudinal studies. SUMMARY: Progress in the diagnosis of primary progressive multiple sclerosis has been made. Long- and short-term natural history are now better known, which will allow the designing of clinical trials in the near future. Magnetic-resonance-imaging studies have demonstrated damage of the normal-appearing brain tissue, which may explain in part the apparent clinical and radiological paradox, common to all clinical forms of multiple sclerosis but perhaps more evident in the primary progressive form. Preliminary results from exploratory trials seem to indicate that these patients should no longer be excluded from therapeutic trials.

Miyake, S. and T. Yamamura (2005). "Therapeutic potential of glycolipid ligands for natural killer (NK) T cells in the suppression of autoimmune diseases." Curr Drug Targets Immune Endocr Metabol Disord 5(3): 315-22.

            NKT cells emerge as important regulatory cells in autoimmune responses. Abnormalities in the numbers and functions of natural killer T (NKT) cells have been observed in patients with autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the non-polymorphic MHC class I-like protein, CD1d. Recently, we and other groups have demonstrated that administration of glycolipid ligands such as alpha-galactosylceramide (alpha-GC ) or its sphingosine truncated derivative, OCH suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), diabetes in NOD mice and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. OCH is a unique ligand to stimulate NKT cells to selectively produce Th2 cytokines whereas alpha-GC induces both interleukin (IL)-4 and interferon (IFN)-gamma, and is more beneficial for treatment of a wide variety of Th1-mediated autoimmune diseases. The lack of polymorphism of CD1d and cross-reactive responses of mouse and human NKT cells to the same ligand indicates that targeting NKT cells with this ligand may be an attractive means for intervening in human autoimmune diseases such as type I diabetes (T1D), multiple sclerosis (MS) and rheumatoid arthritis (RA). The present review will focus on the potential roles of NKT cells in the pathogenesis of autoimmune diseases and the recent advances in glycolipid therapy for autoimmune disease models. The molecular mechanism of OCH-induced Th2-selective cytokine secretion will also be discussed.

Mitchell, A. J., J. Benito-Leon, et al. (2005). "Quality of life and its assessment in multiple sclerosis: integrating physical and psychological components of wellbeing." Lancet Neurol 4(9): 556-66.

            Health-related quality of life (HRQoL) has been more intensively studied in multiple sclerosis (MS) than in any other neurological disorder. Traditional medical models of impairment and disability are an incomplete summary of disease burden. Quality of life can be thought of as the sum of all sources of satisfaction (including anticipated sources) minus all threats (including anticipated threats). Many psychosocial factors-including coping, mood, self-efficacy, and perceived support-influence the quality of life of patients with MS more than biological variables such as weakness or extent of MRI lesions. Neuropsychiatric complications such as cognitive impairment and fatigue are also important predictors, even in those patients in the early stages of the disease. We review generic and specific HRQoL measures to help clinicians choose the most appropriate therapies. Subjective (self-report) HRQoL measures may serve to alert clinicians to areas that would otherwise be overlooked. Studies of new interventions should include an assessment of HRQoL not just impairment or disability alone.

Mitchell, R. J., P. B. Osborne, et al. (2005). "Dental amalgam restorations: daily mercury dose and biocompatibility." J Long Term Eff Med Implants 15(6): 709-21.

            Over the past 150 years, silver-tin-copper amalgam has been the most frequently used dental restorative material. Amalgam may be the single most frequently used implant material. In the early 1980s, researchers discovered that amalgam restorations release mercury vapor during chewing. This review describes the research that has led to an estimate of the daily dose of mercury that will be absorbed by a subject with a large number of amalgam restorations. Along the way, the history and chemistry of dental amalgam are outlined. The routes of absorption of liquid mercury, ionic mercury, organic mercury, and mercury vapor are also briefly described. The daily dose is found to be 14% of the threshold above which observable adverse neurological symptoms are expected. The review concludes with a summary of the research on the adverse effects of dental amalgam. As expected from the low daily dose, few adverse neurological symptoms have been reported. There is also little evidence of an association of amalgam restorations with neurodegenerative diseases, altered renal function, adverse pregnancy outcomes, or autoimmune diseases. There is a lack of data on neurobiological and neurodevelopmental effects on children who may be exposed to mercury from maternal amalgam restorations during gestation. Additional data on the role of amalgam, if any, in Alzheimers disease and multiple sclerosis are needed.

Minagar, A., E. Gonzalez-Toledo, et al. (2005). "Neuroimaging in multiple sclerosis." Int Rev Neurobiol 67: 165-201.

Miller, A. E. (2005). "Glatiramer acetate in the treatment of multiple sclerosis." Neurol Clin 23(1): 215-31, viii.

Miller, D., F. Barkhof, et al. (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis." Lancet Neurol 4(5): 281-8.

            In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Methods of assessing the prognosis for patients who present with a CIS have been sought, because only 30-70% of patients with a CIS develop MS. When clinically silent brain lesions are seen on MRI, the likelihood of developing MS is high. MS can be diagnosed within 3 months of CIS presentation with certain MRI and CSF criteria. Disability from MS is less likely in patients with a CIS of optic neuritis or sensory symptoms only, few or no MRI lesions, a long period to the first relapse, and no disability after the first 5 years. Development of more reliable prognostic markers will enable new treatments to be targeted for those who are most likely to benefit. We encourage continued clinical and laboratory assessment of patients with a CIS.

Miller, A., M. Korem, et al. (2005). "Vitamin B12, demyelination, remyelination and repair in multiple sclerosis." J Neurol Sci 233(1-2): 93-7.

            Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.

Miller, D., F. Barkhof, et al. (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery processes, and management." Lancet Neurol 4(6): 341-8.

            The onset of multiple sclerosis (MS) in 85% of young adults is with a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Whereas multifocal brain lesions are present on MRI in many patients with a CIS, some patients have additional abnormalities on quantitative MRI in otherwise normal-appearing white and grey matter that suggest an extensive pathological process. Functional outcome for patients with symptomatic CIS lesions is determined by the interplay of inflammation, demyelination, axonal damage, remyelination, and cortical adaptation. Recovery of function may be accelerated by high dose corticosteroids, and although interferon beta delays the development of a second relapse, its long-term effect is unknown. A better understanding of pathological and pathogenetic processes in patients with a CIS will facilitate the development of disease-modifying treatments for patients with MS before they become disabled. Continued clinical and laboratory investigation of patients with a CIS should be encouraged.

Mihai, C. and B. Jubelt (2005). "Post-infectious encephalomyelitis." Curr Neurol Neurosci Rep 5(6): 440-5.

            The term post-infectious encephalomyelitis (PIEM) is frequently used interchangeably with acute disseminated encephalomyelitis (ADEM), although technically PIEM occurs after a known infection whereas with ADEM there is no antecedent infection. PIEM represents one of the primary demyelinating disorders of the central nervous system, along with multiple sclerosis and Devic's disease. There is no specific diagnostic test for any of these conditions and at onset it may be difficult to differentiate between ADEM and the first attack of multiple sclerosis. However, there are clinical and magnetic resonance imaging features that allow differentiation between PIEM/ADEM and a relapsing disease such as multiple sclerosis. Some patients improve spontaneously; most improve with methylprednisolone. If that fails, plasma exchange or intravenous immunoglobulin may be effective.

Mezzapesa, D. M., M. Rovaris, et al. (2005). "Glatiramer acetate in multiple sclerosis." Expert Rev Neurother 5(4): 451-8.

            Glatiramer acetate (Copaxone) is a disease-modifying agent approved by several health authorities worldwide for the treatment of relapsing-remitting multiple sclerosis. Although its primary target is the inflammatory component of the disease, there are emerging pieces of evidence suggesting that glatiramer acetate might also have a neuroprotective effect. In this review, the results of glatiramer acetate clinical trials and other relevant studies as well as the place of glatiramer acetate among other approved disease-modifying treatments for relapsing-remitting multiple sclerosis are discussed critically.

Meyers, J. H., C. A. Sabatos, et al. (2005). "The TIM gene family regulates autoimmune and allergic diseases." Trends Mol Med 11(8): 362-9.

            The recently identified TIM gene family encodes cell-surface receptors that are involved in the regulation of Th1- and Th2-cell-mediated immunity. Tim-3 protein is specifically expressed on Th1 cells and negatively regulates Th1 responses, whereas Tim-2 is preferentially expressed in Th2 cells. Tim-1, previously identified as the hepatitis A virus receptor, co-stimulates T-cell expansion and cytokine production. Tim-4, which is preferentially expressed on mature dendritic cells, is the ligand for Tim-1. In mouse models of asthma and multiple sclerosis, affecting the function of Tim molecules altered disease phenotype. Because TIM molecules are differentially expressed on effector Th1 and Th2 cells, further understanding of the mechanisms by which they regulate Th1- and Th2-effector functions will probably provide opportunities for the therapeutic modulation of immune-mediated diseases.

Menge, T., H. P. Hartung, et al. (2005). "Statins--a cure-all for the brain?" Nat Rev Neurosci 6(4): 325-31.

            'Statins' are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors - oral cholesterol-lowering drugs that are used to treat hypercholesterolaemia. It is widely accepted that statins have anti-inflammatory effects that are independent of their ability to lower cholesterol. Animal studies and observational clinical studies have indicated that statins might also be effective in treating certain neurological diseases - in particular, multiple sclerosis, Alzheimer's disease and ischaemic stroke. At present, however, results from ongoing prospective, randomized clinical trials are not available.

Menge, T., B. Hemmer, et al. (2005). "Acute disseminated encephalomyelitis: an update." Arch Neurol 62(11): 1673-80.

            Acute disseminated encephalomyelitis (ADEM) is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or a vaccination. Children are predominantly affected. A plethora of viral and bacterial pathogens and a number of vaccinations have been associated with ADEM. Experimental animal studies indicate that both primary and secondary autoimmune responses contribute to central nervous system inflammation and subsequent demyelination. The clinical diagnosis of ADEM is strongly suggested by a close temporal relationship between an infectious incident or an immunization and the onset of leukoencephalopathic neurological symptoms. Paraclinical tests may support the diagnosis. Particularly helpful are acute signs of newly developed extensive, multifocal, subcortical white matter abnormalities on magnetic resonance images of the brain. The cerebrospinal fluid may disclose a mild lymphocytic pleocytosis and elevated albumin levels. Oligoclonal bands are not always present in ADEM and, if so, may be transient. The major differential diagnosis of ADEM is multiple sclerosis. Treatment options for ADEM consist of anti-inflammatory and immunosuppressive agents. In general, the disease is self-limiting and the prognostic outcome favorable. In the absence of widely accepted clinical or paraclinical diagnostic guidelines, a number of recently conducted observational case series have substantially broadened our understanding about the clinical phenotype, diagnosis, and prognosis of ADEM.

McFarland, H. F. and S. C. Reingold (2005). "The future of multiple sclerosis therapies: redesigning multiple sclerosis clinical trials in a new therapeutic era." Mult Scler 11(6): 669-76.

            Due to past success in testing and gaining regulatory approval for a variety of therapies in multiple sclerosis (MS), the conduct of future clinical trials has become increasingly problematic. An international workshop has met to discuss the issues facing the MS clinical trial community and to examine possible new strategies for the design of trials. Particular focus has been placed on trials that either avoid the use of a placebo because of ethical considerations or on designs that allow new therapies to be studied more rapidly or with fewer patients than needed in a conventional placebo-controlled trial. The discussions resulting from the workshop should provide a basis for the examination and implementation of innovative clinical trial designs in MS.

McCrery, R. J. and R. A. Appell (2005). "Female neurogenic vesicourethral dysfunction: evaluation and management." Curr Urol Rep 6(5): 348-55.

            This paper outlines the evaluation and management of neurogenic vesicourethral dysfunction (NVUD). The anatomy and neurophysiology involved with lower urinary tract functions are reviewed. Multiple sclerosis, diabetes, lumbar disc prolapse, and Parkinson's disease are specifically addressed. Proper evaluation of patients suspected of having NVUD, which is fundamental to making an accurate diagnosis, is discussed. This is followed by options for initiating individualized management plans that focus on protecting and preserving renal function, in addition to relieving the symptoms of NVUD.

Maurelli, M., R. Bergamaschi, et al. (2005). "Cerebral venous thrombosis and demyelinating diseases: report of a case in a clinically isolated syndrome suggestive of multiple sclerosis onset and review of the literature." Mult Scler 11(2): 242-4.

            Cerebral venous thrombosis (CVT) has been described in several cases of clinically definite multiple sclerosis (MS). In the majority of these, lumbar puncture followed by intravenous corticosteroid treatment was suspected as the cause. We report what is, to our knowledge, the first case of a patient with a multifocal clinically isolated syndrome suggestive of MS onset, who developed multiple CVT after lumbar puncture and during high-dose i.v. corticosteroid treatment We conclude that the sequence 'lumbar puncture followed by corticosteroid treatment' may be a contributory risk factor for the development of CVT when associated with other risk factors.

Matute, C. and F. Perez-Cerda (2005). "Multiple sclerosis: novel perspectives on newly forming lesions." Trends Neurosci 28(4): 173-5.

            The mechanisms underlying lesion formation in multiple sclerosis are unknown. The prevailing view is that macrophages are primary mediators of myelin destruction in the relapsing and remitting forms of this disease. However, recent findings have revealed widespread oligodendrocyte apoptosis in the absence of a clear cellular immune response. These observations unveil a novel aspect of the pathogenesis of multiple sclerosis that is worthy of further exploration.

Mattle, H. P. (2005). "[Multiple sclerosis--update]." Schweiz Rundsch Med Prax 94(30-31): 1167-70.

            Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Its etiology is not known, but it is well established that auto-reactive T-cells and monocytes play an important pathogenetic role. The inflammation causes focal demyelination and loss of axons, neurons and glial cells. Typical symptoms and signs are monocular blurred vision, double vision, sensory symptoms and motor weakness, and eventually also cognitive deficits and a disturbed micturition. In younger patients the neurological deficits tend to be present for a limited time and then to improve and disappear, only to be followed by new and different deficits later on. Each relapse may leave neurological deficits which in a later course tend to progress slowly, uninterrupted by remissions. When older patients present for the first time with MS, they tend to present with primary progressive spasticity. Important ancillary tests and findings to confirm the diagnosis are multiple focal lesions on MR images, oligoclonal bands in the cerebrospinal fluid, and slowed evoked potentials. Relapses are treated with corticosteroids. Immunomodulation with beta-interferons or glatiramer acetate reduce the number and severity of relapses and long-term disability. Very active forms can be treated with immunosuppression using mitoxantrone. Individual manifestations such as urinary tract infections or paroxysmal phenomena should be treated accordingly with medication.

Mastronardi, F. G. and M. A. Moscarello (2005). "Molecules affecting myelin stability: a novel hypothesis regarding the pathogenesis of multiple sclerosis." J Neurosci Res 80(3): 301-8.

            In this Mini-Review we present a new hypothesis in support of the neurodegenerative theory as a mechanism for the pathogenesis of multiple sclerosis (MS). The pathogenesis of MS results from changes in two distinct CNS compartments. These are the "myelin" and "nonmyelin" compartments. The myelin compartment is where primary demyelination, amidst attempts at remyelination, is superseded in the CNS by ongoing disease. Recent evidence obtained via magnetic resonance imaging and spectroscopy techniques supports the view that the normal-appearing white matter (NAWM) in the MS brain is altered. Several biochemical changes in NAWM have been determined. These include the cationicity of myelin basic protein (MBP) as a result of the action of peptidyl argininedeiminase (PAD) activity converting arginyl residues to citrulline. The accompanying loss of positive charge makes myelin susceptible to vesiculation and MBP more susceptible to proteolytic activity. An increase of MBP autocatalysis in the MS brain might also contribute to the generation of immunodominant epitopes. Accompanying the destruction of myelin in the myelin compartment is the activation of astrocytes and microglia. These contribute to the inflammatory response and T-cell activation leading to autoimmunity. The complex environment that exists in the demyelinating brain also affects the "nonmyelin" compartment. The inappropriate up-regulation of molecules, including those of the Jagged-1-Notch-1 signal transduction pathway, affects oligodendrocyte precursor cell (OPC) differentiation. Other effectors of oligodendrocyte maturation include stathmin, a microtubule-destabilizing protein, which prevents healing in the demyelinating brain. The hypothesis we present suggests a therapeutic strategy that should 1) target the effectors within the myelin compartment and 2) enable resident OPC maturation in the nonmyelin compartment, allowing for effective repair of myelin loss. The net effect of this new therapeutic strategy is the modification of the disease environment and the stimulation of healing and repair.

Masson, C. (2005). "[Acute transverse myelopathy: inflammatory or ischemic?]." Presse Med 34(12): 869-77.

            The rapid development of paraparesis or tetraparesis combined with a bilateral sensory deficit that has a clearly defined rostral border and bladder dysfunction are the principal features of acute transverse myelopathy. Acute partial transverse myelopathy is far much more frequent: its symptoms are asymmetric, sometimes unilateral, and sensory deficit may predominate. An urgent MRI is required to exclude acute spinal cord compression. Diagnosis of ischemic acute transverse myelopathy includes the following elements: sudden onset, neurologic symptoms compatible with infarction in the anterior spinal artery area (by far the most frequent location for spinal cord infarction), and presence of a specific cause of spinal cord ischemia. In all other cases where it is difficult to distinguish spinal cord infarction from myelitis, analysis of the cerebrospinal fluid is essential. Most cases of inflammatory acute transverse myelopathy can be linked to a defined cause. Multiple sclerosis is a major cause of partial acute transverse myelopathy. MRI lesions are usually small, located in the lateral or posterior part of the spinal cord. Diagnostic elements include multiple lesions of multifocal demyelination on the cerebral MRI, oligoclonal bands in the cerebrospinal fluid, and the absence of clinical or laboratory abnormalities that suggest systemic disease. Neuromyelitis optica, also known as Devic's disease, has often been considered a variant form of multiple sclerosis. Recent immunologic studies confirm the hypothesis that it is a distinct entity. Infectious transverse acute myelitis is often of viral origin. It may result from direct viral stress but more frequently follows immunologically-mediated indirect stress. This acute parainfectious myelitis, like postvaccinal myelitis, may be considered as a spinal single-focus form of acute disseminated encephalomyelitis (ADEM). It is important to distinguish the latter from an initial episode of multiple sclerosis, because their prognosis and treatment differ.

Mascalchi, M., M. Filippi, et al. (2005). "Diffusion-weighted MR of the brain: methodology and clinical application." Radiol Med (Torino) 109(3): 155-97.

            Clinical diffusion magnetic resonance (MR) imaging in humans started in the last decade with the demonstration of the capabilities of this technique of depicting the anatomy of the white matter fibre tracts in the brain. Two main approaches in terms of reconstruction and evaluation of the images obtained with application of diffusion sensitising gradients to an echo planar imaging sequence are possible. The first approach consists of reconstruction of images in which the effect of white matter anisotropy is averaged -- known as the isotropic or diffusion weighted images, which are usually evaluated subjectively for possible areas of increased or decreased signal, reflecting restricted and facilitated diffusion, respectively. The second approach implies reconstruction of image maps of the apparent diffusion coefficient (ADC), in which the T2 weighting of the echo planar diffusion sequence is cancelled out, and their objective, i.e. numerical, evaluation with regions of interest or histogram analysis. This second approach enables a quantitative and reproducible assessment of the diffusion changes not only in areas exhibiting signal abnormality in conventional MR images but also in areas of normal signal. A further level of image post-processing requires the acquisition of images after application of sensitising gradients along at least 6 different spatial orientations and consists of computation of the diffusion tensor and reconstruction of maps of the mean diffusivity (D) and of the white matter anisotropic properties, usually in terms of fractional anisotropy (FA). Diffusion-weighted imaging is complementary to conventional MR imaging in the evaluation of the acute ischaemic stroke. The combination of diffusion and perfusion MR imaging has the potential of providing all the information necessary for the diagnosis and management of the individual patient with acute ischaemic stroke. Diffusion-weighted MR, in particular quantitative evaluation based on the diffusion tensor, has a fundamental role in the assessment of brain maturation and of white matter diseases in the fetus, in the neonate and in the child. Diffusion MR imaging enables a better characterisation of the lesions demonstrated by conventional MR imaging, for instance in the hypoxic-ischaemic encephalopathy, in infections and in the inherited metabolic diseases, and is particularly important for the longitudinal evaluation of these conditions. Diffusion-weighted MR imaging has an established role in the differential diagnosis between brain abscess and cystic tumour and between epidermoid tumour and arachnoid cyst. On the other hand, the results obtained with diffusion MR in the characterisation of type and extension of glioma do not yet allow decision making in the individual patient. Diffusion is one of the most relevant MR techniques to have contributed to a better understanding of the pathophysiological mechanisms of multiple sclerosis (MS). In fact, it improves the specificity of MR in characterising the different pathological substrata underlying the rather uniform lesion appearance on the conventional images and enables detection of damage in the normal-appearing white and grey matter. In MS patients the ADC or D values in the normal-appearing white matter are increased as compared to control values, albeit to a lesser degree than in the lesions demonstrated by T2-weighted images. In addition, the D of the normal appearing grey matter is increased in MS patients and this change correlates with the cognitive deficit of these patients. Histogram analysis in MS patients shows that the peak of the brain D is decreased and right-shifted, reflecting an increase of its value, and the two features correlate with the patient's clinical disability. Ageing is associated to a mild but significant increase of the brain ADC or D which is predominantly due to changes in the white matter. Region of interest and histogram studies have demonstrated that D or ADC are increased in either the areas of leukoaraiosis or the normal-appearing white matter in patients with inherited cerebral autosomal dominant arteriopathy with subcortical infarcts and stroke or sporadic ischaemic leukoencephalopathy. Diffusion changes might be a more sensitive marker for progression of the disease than conventional imaging findings. In neurodegenerative diseases of the central nervous system such as Alzheimer's disease, Huntington's disease, hereditary ataxias and motor neuron disease, quantitative diffusion MR demonstrates the cortical and subcortical grey matter damage, which is reflected in a regional increase of D or ADC, but also reveals the concomitant white matter changes that are associated with an increase in D or ADC and decrease in FA. In all these diseases the diffusion changes are correlated to the clinical deficit and are potentially useful for early diagnosis and longitudinal evaluation, especially in the context of pharmacological trials.

Martinelli Boneschi, F., M. Rovaris, et al. (2005). "Mitoxantrone for multiple sclerosis." Cochrane Database Syst Rev(4): CD002127.

            BACKGROUND: Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The objective was to assess the efficacy and safety of MX in relapsing-remitting MS (RRMS), progressive relapsing MS (PRMS) and secondary progressive MS (SPMS). SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched April 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2004), MEDLINE (Pub Med) (January 1966 to April 2005), EMBASE (January 1974 to April 2005), and reference lists of articles. We also undertook hand searching and contacting trialists and pharmaceutical companies. SELECTION CRITERIA: The trials were selected if double-blinded, placebo-controlled, randomised, irrespective of eventual additive therapy (such as steroids). DATA COLLECTION AND ANALYSIS: Three reviewers independently selected articles for inclusion, assessed trials' quality and extracted data. MAIN RESULTS: Four trials involving 270 participants were included. MX was found to reduce the progression of disability at 2 years follow-up (proportion of participants with 6-months confirmed progression of disability: Odds Ratios (OR) 0.3, p = 0.05). Similar figures were found regarding the reduction in annualised relapse rate and the proportion of patients free from relapses at 1 and 2 years, as well as the number of patients with active MRI lesions at 6 months/ 1 year only. Side effects reported in the trials were more frequent in treated patients than in controls. Caution must be exercised in drawing conclusions from such data because of the heterogeneous quality and characteristics of the included trials, which are different in terms of treatment schedule and type of enrolled patients. More than half of the included patients came from a single study. Moreover, from the included trials, it was not possible to estimate the long-term efficacy and safety of MX, which may raise concerns about the risk of cardiotoxicity and therapy-related leukemias, which is increasingly reported in the literature. AUTHORS' CONCLUSIONS: MX is moderately effective in reducing the disease progression and the frequency of relapses in patients affected by RR, PR and SP MS in the short-term follow-up (2 years), even if the results are based on trials heterogeneous in terms of drug dosage and inclusion criteria. No major neoplastic or symptomatic cardiotoxicity related to MX have been reported from the trials. However, longer follow-up studies are highly warranted to better explore the efficacy and safety of the drug, mainly as regards the long-term risk of therapy-related leukemias and cardiotoxicity.As a conclusion, MX has a partial efficacy, but, due to its unclear long-term safety profile, it should be used to treat patients with worsening RR and SP MS with evidence of worsening disability.

Martinelli, V. and G. Comi (2005). "Induction versus escalation therapy." Neurol Sci 26 Suppl 4: S193-9.

            Most of the consensus groups in Europe and America support an early decision-making therapeutic approach in patients with a diagnosis of multiple sclerosis (MS), either with interferon-beta or glatiramer acetate, which have been demonstrated to be a reasonable therapeutic strategy because of their benefit. The "treat-early approach" within disease management is based on the assumption, particularly during the early phase of the disease, of the reduction of both relapse rate and of the ongoing inflammatory processes may delay irreversible neurological damages. As soon as the MS diagnosis is certain or even in patients with a first episode suggestive of MS, with negative prognostic factors and a typical presentation, "induction therapy", which is more aggressive on the immune system, seems to have more relevant short- and long-lasting beneficial effects. However, if the disease course is suboptimally controlled, an "escalating strategy", using mitoxantrone, cyclophosphamide, various other immunoactive agents or a combination of different drugs, is suggested. The current challenge in therapeutic strategy is to identify the most effective drug, or combination of drugs, during a specific phase of the disease for each single patient. Anyhow, the decision to adopt a combination therapy in patients with a low response to monotherapy should not be delayed until severe irreversible disability is evident.

Marjanovic, Z., I. Gerber, et al. (2005). "[Therapeutic intensification and autologous stem cell transplantation in autoimmune diseases]." Presse Med 34(4): 311-8.

            THE PATHOPHYSIOLOGY of most autoimmune diseases is often poorly understood. EXPERIMENTAL CONSIDERATIONS and clinical experience suggest that high doses immunoablation followed by stem cell transplantation is a therapeutic option to consider for certain severe autoimmune disorders. THE CONCEPT OF RESTORING NORMAL IMMUNE REACTIVITY must in part br true since current results of 466 transplants (445 autologous, 21 allogeneic) patients suffering from various autoimmune diseases show a beneficial outcome in approximately 2/3 of the patients. TO IMPROVE THE EFFICACY AND SAFETY OF SUCH AN AGGRESSIVE PROCEDURE in patients with potentially affected vital organs by the underlying autoimmune disease, it is especially important to follow international consensus guidelines and to centrally collect clinical data for in depth analysis in the EBMT International Stem Cell Project for Autoimmune Disease in Basel, Switzerland. PHASE III STUDIES ARE RUNNING FOR SYSTEMIC SCLEROSIS (Astis, Autologous Stem cell Transplantation International Rheumatoid Arthritis Trial) started in 2003. A STUDY PROJECT IS PLANNED FOR MULTIPLE SCLEROSIS (Astims, Autologous Stem cell Transplantation International Multiple Sclerosis).

Marchetti, B. and M. P. Abbracchio (2005). "To be or not to be (inflamed)--is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?" Trends Pharmacol Sci 26(10): 517-25.

            A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.

Manzoni, G. C. and P. Torelli (2005). "Epidemiology of typical and atypical craniofacial neuralgias." Neurol Sci 26 Suppl 2: s65-7.

            Trigeminal neuralgia (TN) has a prevalence of 0.1-0.2 per thousand and an incidence ranging from about 4-5/100,000/year up to 20/100,000/year after age 60. The female-to-male ratio is about 3:2. A review of several case series shows that pain is more predominant on the right side, but the difference is not statistically significant. TN is significantly associated with arterial hypertension, Charcot-Marie-Tooth neuropathy, glossopharyngeal neuralgia (GN) and multiple sclerosis. GN has an incidence of 0.7/100,000/year and epidemiological studies have shown it to be less severe than previously thought. Post-herpetic neuralgia has a comparable incidence to idiopathic TN. The epidemiology of the central causes of facial pain is still unclear, but it is known that persistent idiopathic facial pain is a widespread, not easily manageable problem.

Mantzourani, E. D., T. M. Mavromoustakos, et al. (2005). "Structural requirements for binding of myelin basic protein (MBP) peptides to MHC II: effects on immune regulation." Curr Med Chem 12(13): 1521-35.

            Confronting Multiple Sclerosis requires as an underlying step the manipulation of immune response through modification of Myelin Basic Protein peptides. The aim is to design peptidic or nonpeptidic molecules that compete for recognition of self-antigens at the level of antigen presentation. The rational approach is to substitute residues that serve as anchors for the T-Cell Receptor with others that show no binding at all, and those that serve as Major Histocompatibility Complex II anchors with others that present increased binding affinity. The resulting structure, hence, retains normal or increased MHC II binding properties, but fails to activate disease-inducing T-cells. This rational design can only be achieved by identifying the structural requirements for binding of the natural peptide to MHC II, and the anchor residues with their corresponding specific pockets in the binding groove. The peptide-MHC II complex then interacts with the TCR; thus, an additional way to trigger the desired immune response is to alter secondary anchor residues as well as primary ones. In this review, the structural requirements for binding of MBP peptides to MHC II are presented, as are the mechanism and key features for TCR recognition of the peptide-MHC II complex.

Manganas, L. N. and M. Maletic-Savatic (2005). "Stem cell therapy for central nervous system demyelinating disease." Curr Neurol Neurosci Rep 5(3): 225-31.

            Recent advances in cell-based therapies for demyelinating central nervous system diseases have demonstrated the ability to restore damaged neuronal architecture and function. Demyelinated axons in patients with multiple sclerosis can spontaneously remyelinate over time; however, the rate and extent at which remyelination occurs is inadequate for complete recovery. Previous attempts aimed at regenerating myelin-forming cells have been successful but limited by the multifocal nature of the lesions and the inability to produce large numbers of myelin-producing cells in culture. Stem cell-based therapy can overcome these limitations to some extent and may prove useful in the future treatment of demyelinating diseases.

Mancardi, G. L. (2005). "Autologous haematopoietic stem cell transplantation." Neurol Sci 26 Suppl 1: S19.

Malfitano, A. M., G. Matarese, et al. (2005). "From cannabis to endocannabinoids in multiple sclerosis: a paradigm of central nervous system autoimmune diseases." Curr Drug Targets CNS Neurol Disord 4(6): 667-75.

            An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of multiple sclerosis, including spasticity and pain. Endogenous molecules with cannabinoid-like activity, such as the "endocannabinoids", have been shown to mimic the anti-inflammatory properties of cannabinoids through the cannabinoid receptors. Several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis. Indeed, they can down regulate the production of pathogenic T helper 1-associated cytokines enhancing the production of T helper 2-associated protective cytokines. A shift towards T helper 2 has been associated with therapeutic benefit in multiple sclerosis. In addition, cannabinoids exert a neuromodulatory effect on neurotransmitters and hormones involved in the neurodegenerative phase of the disease. In vivo studies using mice with experimental allergic encephalomyelitis, an animal model of multiple sclerosis, suggest that the increase of the circulating levels of endocannabinoids might have a therapeutic effect, and that agonists of endocannabinoids with low psychoactive effects could open new strategies for the treatment of multiple sclerosis.

Maiese, K., Z. Z. Chong, et al. (2005). "Driving cellular plasticity and survival through the signal transduction pathways of metabotropic glutamate receptors." Curr Neurovasc Res 2(5): 425-46.

            Metabotropic glutamate receptors (mGluRs) share a common molecular morphology with other G protein-linked receptors, but there expression throughout the mammalian nervous system places these receptors as essential mediators not only for the initial development of an organism, but also for the vital determination of a cell's fate during many disorders in the nervous system that include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, Multiple Sclerosis, epilepsy, trauma, and stroke. Given the ubiquitous distribution of these receptors, the mGluR system impacts upon neuronal, vascular, and glial cell function and is activated by a wide variety of stimuli that includes neurotransmitters, peptides, hormones, growth factors, ions, lipids, and light. Employing signal transduction pathways that can modulate both excitatory and inhibitory responses, the mGluR system drives a spectrum of cellular pathways that involve protein kinases, endonucleases, cellular acidity, energy metabolism, mitochondrial membrane potential, caspases, and specific mitogen-activated protein kinases. Ultimately these pathways can converge to regulate genomic DNA degradation, membrane phosphatidylserine (PS) residue exposure, and inflammatory microglial activation. As we continue to push the envelope for our understanding of this complex and critical family of metabotropic receptors, we should be able to reap enormous benefits for both clinical disease as well as our understanding of basic biology in the nervous system.

Magdzik, W. and A. Zielinski (2005). "[Vaccination against hepatitis B and the risk of multiple sclerosis]." Przegl Epidemiol 59(1): 11-9.

            A paper on sclerosis multiplex as sequellae of vaccination against hepatitis B with recombinant vaccine was published in the journal of "Neurology" in September 2004. Problem was evaluated in United Kingdom on the ground of General Practice Research Database (GPRD). In 1996 similar problem was evaluated with negative results in several studies. Just now in opinions of many institutions as well as many persons vaccination against hepatitis B with recombinant vaccine should be continued in similar way as it was performed to this time.

Maclean, C. H., A. M. Issa, et al. (2005). "Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases." Evid Rep Technol Assess (Summ)(114): 1-3.

Macciardi, F., F. M. Boneschi, et al. (2005). "Pharmacogenetics of autoimmune diseases: research issues in the case of Multiple Sclerosis and the role of IFN-beta." J Autoimmun 25 Suppl: 1-5.

            Pharmacogenetics of auto-immune diseases is a complex field of application for this relatively new discipline, since we still have a partial knowledge of the biological mechanisms of the disease and of the drugs currently used to treat it. We address a few key issues that emerge when planning a pharmacogenetic investigation in Multiple Sclerosis and that relate to the complexities existing at the biological-genetic level and at the phenotypic characterization. In fact, we think that a clearer characterization of the clinical phenotype representing the end-point of the investigation together with a critical appraisal of the multi-faceted dimension of the genetic component of either the disease and the pharmacogenetic profile of the drug investigated, will help to design more thorough study and to achieve deeper understanding of the practical results. We will primarily focus our research considerations on the role of Interferon Beta (IFN-beta) as a prototypal therapeutic agent in Multiple Sclerosis.

MacAllister, W. S. and L. B. Krupp (2005). "Multiple sclerosis-related fatigue." Phys Med Rehabil Clin N Am 16(2): 483-502.

            Fatigue is a significant factor in the lives of many MS patients and the most commonly reported symptom in many studies. Fatigue is an important symptom to consider because it affects patients' social lives, occupations, and activities of daily living. Efforts to predict fatigue have been mixed, but it appears to be related to overall quality of life and mood. From a pathophysiologic perspective, fatigue in MS is multifactorial and complex,involving dysregulation of the immune system, changes in the nervous system related to the disease process, neuroendocrine and neurotransmitter changes, and other factors such as physical deconditioning, sleep disturbance, pain, and medication side effects. Various attempts to assess fatigue have been made, and many measures are now available for use in clinical practice and research. In clinical practice, these measures help guide treatment considerations. Recent research has provided valuable strategies to ameliorate fatigue in MS, and although many patients continue to experience fatigue despite interventions, many receive substantial relief.Nonpharmacologic approaches-considered the first step in treatment-include exercise programs, cooling, dietary considerations, and energy conservation strategies. For patients who continue to experience significant fatigue, several medications (although not specifically approved for use in the reduction of MS-related fatigue) have proved effective in this regard.The first-line agents include amantadine for mild fatigue and modafinil for more severe cases. Second-line agents include pemoline and antidepressant medications. Other pharmacologic agents have also shown some promise.

Lycklama a Nijeholt, G. J. (2005). "Reduction of brain volume in MS. MRI and pathology findings." J Neurol Sci 233(1-2): 199-202.

            Atrophy is one of the hallmarks in multiple sclerosis (MS), especially in the advanced stage. Modern magnetic resonance (MR) techniques can reliably measure brain volume and changes therein. Depending on the technique used, changes of about 1% may be detected. Clinicoradiological studies show good correlation between atrophy measures, both in brain and spinal cord, and clinical measures. The exact relationship between focal MS lesions and global atrophy has yet to be established. Number of lesions early in the disease seems to predict later atrophy. The exact pathomechanism of atrophy in MS probably may be explained by both demyelination and axonal loss--which may occur independently from each other.

Ludwin, S. K. (2005). "Pathologic classification systems in MS: what is their significance?" Mult Scler 11(1): 106-7.

Lucchinetti, C. F., J. Parisi, et al. (2005). "The pathology of multiple sclerosis." Neurol Clin 23(1): 77-105, vi.

Lucchinetti, C. F. (2005). "Update on the international project on pathologic correlates in MS." Mult Scler 11(1): 99-100.

Lublin, F. D. (2005). "Clinical features and diagnosis of multiple sclerosis." Neurol Clin 23(1): 1-15, v.

Lublin, F. (2005). "History of modern multiple sclerosis therapy." J Neurol 252 Suppl 3: iii3-iii9.

            Although the earliest recorded description of multiple sclerosis (MS) dates back to the 14(th) century, it was not until the latter years of the 20(th) that treatments for this disabling condition were found. However, the "road to success" has not been without hurdles. Trials with both interferon alpha and gamma proved unsuccessful, as did treatment with oral myelin, cladribine, sulfasalazine and inhibitors of tumour necrosis factor. In 1993, interferon beta-1b (IFNbeta-1b) became the first therapy proven to be effective in altering the natural history of relapsing-remitting MS (RRMS). This was followed by successful trials with IFNbeta-1a and glatiramer acetate. In 1998, a European trial showed IFNbeta-1b to be also beneficial in the treatment of secondary progressive MS (SPMS). A similar trial in North America failed to reach its primary endpoint but was effective across secondary endpoints, highlighting how different methodology and patient populations can lead to inconsistent results and, thus, making comparisons across trials difficult. The trend for early intervention in MS with IFNbeta was recently supported by the CHAMPS (Controlled High-risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment of Multiple Sclerosis) studies using once-weekly IFNbeta-1a. Both trials demonstrated delayed conversion to clinically definite MS in patients with a clinically isolated syndrome and magnetic resonance imaging (MRI) findings suggestive of MS. Two directly comparative trials of high- (250 microg IFNbeta-1b or 44 microg IFNbeta-1a) and low-dose (30 microg IFNbeta-1a) IFNbeta (INCOMIN [INdependent COMparison of INterferons] and EVIDENCE [EVidence of Interferon Dose-response: European North American Comparative Efficacy]) support the superior efficacy of the higher dose and/or more frequent administration for treating RRMS. Since MS entered the treatment era in 1993, therapies for RRMS, SPMS and, more recently, progressive- relapsing MS have been developed. There is now a much better understanding of the pathogenesis of the disease, but new and improved therapeutic approaches are still needed.

Lublin, F. (2005). "Multiple sclerosis trial designs for the 21st century: building on recent lessons." J Neurol 252 Suppl 5: v46-53.

            Starting with the first positive pilot study of glatiramer acetate, trial design in multiple sclerosis has advanced considerably over the past two decades, successively building and improving on previous successes in the implementation and analysis of new clinical trials. Most of these trials have been successful and this has led to the regulatory approval and commercial availability of six agents for the treatment of multiple sclerosis. During this period, outcome measures have been validated to determine the efficacy and safety of such agents, notably those useful in reducing the inflammatory aspects of disease. These include measurements of relapse reduction (annualized relapse rate, time to first relapse, proportion of subjects relapse free), disability (change in EDSS score, change in MSFC score) and MRI metrics (measurements of gadolinium-enhancing lesions, T1 and T2 lesion load). Recent trial design has shown that one can answer some clinical questions after one year on study and that these results may be predictive of more robust two-year trial data. The other important recent lesson involves emergence of rare complications of immunomodulatory therapy, namely progressive multifocal leucoencephalopathy with natalizumab that blocks the access of immune cells to the nervous system. In addition to the increased need for enhanced safety assessment, this issue will have an impact both on the study of combination therapies and on the use of combinations in clinical practice.

Lubetzki, C., A. Williams, et al. (2005). "Promoting repair in multiple sclerosis: problems and prospects." Curr Opin Neurol 18(3): 237-44.

            PURPOSE OF REVIEW: Despite recent progress in treating the inflammatory component of multiple sclerosis, current therapies have no clear impact on progression of disability, which closely relates to tissue (myelin and axon) injury. Many scientists now focus their efforts on elucidating the mechanisms that lead to tissue injury, and on developing new strategies for tissue repair. We review recent breakthroughs in this field and discuss their putative applications to therapy. RECENT FINDINGS: Several hypotheses have been raised to explain the failure of remyelination, including depletion of remyelinating cells, quiescence of oligodendrocyte precursor cells and axonal inhibitory signals. Success in remyelination therapy may be achieved either by enhancing endogenous repair or by grafting exogenous remyelinating cells. Several neurotrophic factors have been shown to enhance endogenous remyelination, and many immature cells have been shown to induce efficient exogenous remyelination in animal models. Although effective remyelination probably represents the best way to prevent neurodegeneration, several alternative neuroprotective strategies are emerging. Statins, cyclins and immunophilin ligands are orally available immunomodulatory agents that may protect neurones. Other promising possibilities include the modulation of excitotoxicity, nitric oxide synthesis, or cationic channels. SUMMARY: Despite the increasing number of putative therapeutic targets, no treatment to achieve remyelination or neuroprotection has yielded positive clinical results in humans. Forging a link between basic biology and treatment of patients will require us to overcome several challenges, including assessment of efficacy of repair, improving tolerance to and delivery of neurotrophic factors, and better defining the indications for and limitations of transplantation.

Lovett-Racke, A. E., P. D. Cravens, et al. (2005). "Therapeutic potential of small interfering RNA for central nervous system diseases." Arch Neurol 62(12): 1810-3.

Liu, L., M. K. Callahan, et al. (2005). "Chemokine receptor CXCR3: an unexpected enigma." Curr Top Dev Biol 68: 149-81.

            CXCR3, the receptor for CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC, is preferentially expressed on activated Th1 T cells and has been predicted to play an important role in their trafficking. However, this simplistic view of the function of CXCR3 and its ligands has not been borne out by studies of disease models, including experimental autoimmune encephalomyelitis (EAE), using varied methods of receptor blockade, as well as knockout or transgenic mice. This review focuses on the current understanding of the enigmatic role of CXCR3 and its ligands in CNS inflammatory/autoimmune disorders. The conflicting results among varied models of CNS inflammation suggest complex and multiple roles for CXCR3 and its ligands in the pathogenesis of CNS inflammatory/autoimmune diseases. Thus, further study is needed to determine how CXCL10 neutralizing agents or CXCR3 receptor antagonists might be applied to treating human disease.

Liu, L., D. Meier, et al. (2005). "Multiple sclerosis medical image analysis and information management." J Neuroimaging 15(4 Suppl): 103S-117S.

            Magnetic resonance imaging (MRI) has become a central tool for patient management, as well as research, in multiple sclerosis (MS). Measurements of disease burden and activity derived from MRI through quantitative image analysis techniques are increasingly being used. There are many complexities and challenges in building computerized processing pipelines to ensure efficiency, reproducibility, and quality control for MRI scans from MS patients. Such paradigms require advanced image processing and analysis technologies, as well as integrated database management systems to ensure the most utility for clinical and research purposes. This article reviews pipelines available for quantitative clinical MRI research in MS, including image segmentation, registration, time-series analysis, performance validation, visualization techniques, and advanced medical imaging software packages. To address the complex demands of the sequential processes, the authors developed a workflow management system that uses a centralized database and distributed computing system for image processing and analysis. The implementation of their system includes a web-form-based Oracle database application for information management and event dispatching, and multiple modules for image processing and analysis. The seamless integration of processing pipelines with the database makes it more efficient for users to navigate complex, multistep analysis protocols, reduces the user's learning curve, reduces the time needed for combining and activating different computing modules, and allows for close monitoring for quality-control purposes. The authors' system can be extended to general applications in clinical trials and to routine processing for image-based clinical research.

Lipton, H. L., A. S. Kumar, et al. (2005). "Theiler's virus persistence in the central nervous system of mice is associated with continuous viral replication and a difference in outcome of infection of infiltrating macrophages versus oligodendrocytes." Virus Res 111(2): 214-23.

            Theiler's murine encephalomyelitis virus (TMEV) infection of mice, in which persistent central nervous system (CNS) infection induces Th1 CD4+ T cell responses to both virus and myelin proteins, provides a relevant experimental animal model for MS. During persistence, >10(9) TMEV genome equivalents per spinal cord are detectable by real-time reverse transcription-polymerase chain reaction (RT-PCR). Because of the short half-life of TMEV (<1 day), continual viral replication is needed to sustain these very high TMEV copy numbers. An essential role for macrophages in TMEV persistence has been documented and, although limited by host anti-viral immune responses, TMEV nonetheless spreads during persistence to infect other cells, particularly oligodendrocytes, in which the infection is productive and lytic. Virus factors influencing persistence of TMEV are expression of the out-of-frame L* protein and use of sialic acid co-receptors.

Linsen, L., V. Somers, et al. (2005). "Immunoregulation of autoimmunity by natural killer T cells." Hum Immunol 66(12): 1193-202.

            Natural killer T (NKT) cells are a conserved subpopulation of lymphocytes that recognize glycolipid antigens in a CD1d context. Upon activation through their semi-invariant T cell receptor, these cells rapidly release large amounts of immunomodulating Th1 and Th2 cytokines. NKT cells have therefore been implicated in immune responses controlling various diseases, including infection, cancer, transplantation, and autoimmunity. Stimulation of the immunoregulatory capacity of NKT cells by the prototypical antigen alpha-galactosylceramide results in amelioration of disease in several animal models. This review will focus on the current knowledge of human NKT cells and their role in autoimmune diseases. The features of these cells and their importance in regulation of autoimmunity suggest that NKT cell-based therapies might be an interesting approach for the treatment of autoimmune diseases.

Linker, R. A., M. Sendtner, et al. (2005). "Mechanisms of axonal degeneration in EAE--lessons from CNTF and MHC I knockout mice." J Neurol Sci 233(1-2): 167-72.

            The major pathological hallmarks of multiple sclerosis (MS) comprise inflammation, demyelination with associated gliosis and axonal damage, which most likely correlates with persisting disability. Axonal damage can occur by several mechanisms. This article focuses on myelin disintegration and direct immune attack on axons by CD8-positive T-cells as two possible scenarios for axonal injury. As protoypic models, we investigated experimental autoimmune encephalomyelitis (EAE) in ciliary neurotrophic factor gene knockout mice (CNTF-/- mice) with severe myelin pathology and EAE in beta-2 microglobulin gene knockout mice (beta2m-/- mice) lacking CD8-positive T-cells. The results from these studies indicate that the trigger attack for axonal injury even in a well-defined experimental design can be multi-faceted. No single factor seems to be absolutely necessary for the initiation of the process, but they rather act in concert and orchestrate tissue destruction, inflammation and regeneration. Some mechanisms of primary or secondary axonal damage may be shared between inflammatory and degenerative diseases of the nervous system, thereby establishing a link which might be of importance for future therapeutic strategies.

Linker, R. A., C. Stadelmann, et al. (2005). "[Recent advances in pathogenesis and therapy of multiple sclerosis]." Fortschr Neurol Psychiatr 73(12): 715-27.

            In this article, recent advances in the research on pathogenesis and therapy of multiple sclerosis (MS) will be summarized. New evidence from clinical studies, imaging, histopathology and experimental models are discussed with a focus on neurodegenerative aspects and evidence from recent therapeutic studies. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. The introduction of interferons and glatiramer acetate into MS therapy often leads to a stabilization of the disease course if administered adequately and early. The pathogenetic insights presented here may open new avenues for innovative immunomodulatory approaches and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

Lim, E. T. and G. Giovannoni (2005). "Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis." Expert Rev Neurother 5(3): 379-90.

            Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-beta, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Lee, S. M., Y. Morcos, et al. (2005). "HTLV-1 induced molecular mimicry in neurological disease." Curr Top Microbiol Immunol 296: 125-36.

            As a model for molecular mimicry, we study patients infected with human T-lymphotropic virus type 1 (HTLV-1) who develop a neurological disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease with important biological similarities to multiple sclerosis (MS) (Khan et al. 2001; Levin et al. 1998, 2002a; Levin and Jacobson 1997). The study of HAM/TSP, a disease associated with a known environmental agent (HTLV-1), allows for the direct comparison of the infecting agent with host antigens. Neurological disease in HAM/TSP patients is associated with immune responses to HTLV-1-tax (a regulatory and immunodominant protein) and human histocompatibility leukocyte antigen (HLA) DRB1*0101 (Bangham 2000; Jacobson et al. 1990; Jeffery et al. 1999; Lal 1996). Recently, we showed that HAM/TSP patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), a neuron-specific autoantigen (Levin et al. 2002a). Monoclonal antibodies to tax cross-reacted with hnRNP A1, indicating molecular mimicry between the two proteins. Infusion of cross-reactive antibodies with an ex vivo system completely inhibited neuronal firing indicative of their pathogenic nature (Kalume et al. 2004; Levin et al. 2002a). These data demonstrate a clear link between chronic viral infection and autoimmune disease of the central nervous system (CNS) in humans and, we believe, in turn will give insight into the pathogenesis of MS.

Leary, S. M., B. Porter, et al. (2005). "Multiple sclerosis: diagnosis and the management of acute relapses." Postgrad Med J 81(955): 302-8.

            Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that may result in a wide range of neurological symptoms and accumulating disability. Its course is unpredictable resulting in a changing pattern of clinical need. Diagnostic criteria for multiple sclerosis require objective evidence for dissemination in space and time. The diagnostic and management process should follow good practice guidelines with the person at the centre of the process. Appropriate support and information should be available from the time of diagnosis. Continuing education is key in enabling the person to actively participate in their management. In the event of an acute relapse the person should have direct access to the most appropriate local service. Provided medical causes have been excluded, corticosteroid treatment to hasten the recovery from the relapse should be considered. Management of an acute relapse should be comprehensive addressing any medical, functional, or psychosocial sequelae.

Leary, S. M. and A. J. Thompson (2005). "Primary progressive multiple sclerosis : current and future treatment options." CNS Drugs 19(5): 369-76.

            Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used. Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-beta-1a and interferon-beta-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.

Lazzeri, E. and P. Romagnani (2005). "CXCR3-binding chemokines: novel multifunctional therapeutic targets." Curr Drug Targets Immune Endocr Metabol Disord 5(1): 109-18.

            The goal to attenuate inflammation without inducing generalized immunosuppression has focused the attention on chemokines, a family of chemotactic peptides that regulate the leukocyte traffick into tissues. However, the development of drugs that block ckemokine activity may be hampered by the observation that some chemokines display pleiotropic biologic functions. For example, the chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC exhibit the ability to recruit different leukocytes subsets, the capacity to induce the proliferation of vascular pericytes as well as powerful anti-tumor effects, which are mediated by a common receptor, named CXCR3. Because of their pleiotropic biologic effects, these chemokines have been proposed as possible therapeutic targets in cancer, allograft rejection, glomerulonephritis, diabetes, multiple sclerosis, and autoimmune disorders of the thyroid. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including angiostatic effects, although its specific receptor has remained unknown for a long time. Recently, we provided evidence that the different functions of CXCL9, CXCL10, and CXCL11 on distinct cell types can be at least partly explained by the interaction of these chemokines with two distinct receptors. Indeed, in addition to the classic form of CXCR3 receptor, which we have renamed as CXCR3-A, a novel CXCR3 receptor variant (CXCR3-B) was identified, that not only mediates the angiostatic activity of CXCR3 ligands, but also acts as functional receptor for CXCL4. In this review, we focus on the accumulating evidence demonstrating the pivotal role of CXCR3-binding chemokines in several human diseases. Studies based on CXCR3 targeting have shown its importance in different pathologic conditions and orally active small molecules capable of inhibiting this receptor are now being developed in order to be tested for their activity in humans.

Lassmann, H. (2005). "Stem cell and progenitor cell transplantation in multiple sclerosis: the discrepancy between neurobiological attraction and clinical feasibility." J Neurol Sci 233(1-2): 83-6.

            Recent developments in our understanding of stem- and progenitor cell differentiation raises hopes that brain damage in chronic neurological diseases may become repaired by systemic or focal transplantation of such cells. In this review the potential of such an approach is discussed, but it is also highlighted that many aspects regarding its feasibility or safety are currently unresolved. Furthermore, recent findings on the pathogenesis of multiple sclerosis lesions indicate that major problems in this disease rather are related to axonal pathology and neurodegeneration rather than to the absence of oligodendrocyte progenitor cells within the lesions. In light of this complex situation, it is concluded that clinical trials of stem- or progenitor cell transplantation in multiple sclerosis are currently premature.

Lassmann, H. (2005). "Multiple sclerosis pathology: evolution of pathogenetic concepts." Brain Pathol 15(3): 217-22.

            This historical review describes the evolution of pathogenetic concepts of multiple sclerosis (MS) from the viewpoint of pathology. MS research is based on studies of descriptive neuropathology, performed during the 19th and early-20th century, which defined the basic nature of the inflammatory demyelinating lesions. Advances in basic immunology and neurobiology, performed during the second half of the 20th century, paved the way for the understanding of the molecular mechanims involved in inflammation and well as tissue destruction in this disease. However, recent clinical and neuroradiological studies on the evolution of the disease and its brain lesions as well as ongoing attempts to define the genetic basis of the disease indicate that our current pathogenetic concepts may be too simple and that essential aspects of MS pathology have to be redefined.

Lassmann, H. (2005). "Heterogeneity of multiple sclerosis: implications for therapy targeting regeneration." Ernst Schering Res Found Workshop(53): 11-22.

Langgartner, M., I. Langgartner, et al. (2005). "The patient's journey: multiple sclerosis." Bmj 330(7496): 885-8.

Lan, R. Y., A. A. Ansari, et al. (2005). "Regulatory T cells: development, function and role in autoimmunity." Autoimmun Rev 4(6): 351-63.

            The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4(+) T cells. Much focus has been placed on thymically derived CD4(+)CD25(+) regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4(+) lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus.

Lamprecht, P. (2005). "TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases." Autoimmun Rev 4(1): 28-34.

            The introduction of TNF-alpha inhibitors in the treatment of rheumatoid arthritis and several other diseases meant a major progress in the management and to the understanding of these chronic inflammatory diseases. In this article, the evidence of the role of TNF-alpha and for TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases is reviewed. TNF-alpha is expressed in inflammatory lesions. TNF-alpha acts as a proinflammatory cytokine in most disease processes analyzed so far, but it might have anti-inflammatory properties under certain conditions as well, e.g. with respect to B-cell regulation in systemic lupus erythematosus. It is not clear to what extent such aspects will be important in the treatment of connective tissue diseases and systemic vasculitides with TNF-alpha inhibitors. So far, most case reports and case series have suggested favourable results with TNF-alpha inhibitor therapy in systemic lupus erythematosus, dermato- and polymyositis, giant cell arteritis, Churg-Strauss syndrome, Wegener's granulomatosis and microscopic polyangiitis. Results of randomized, placebo-controlled trials are awaited for several connective tissue diseases and systemic vasculitides. One randomized, placebo-controlled trial has found no efficacy of infliximab treatment in primary Sjogren's syndrome recently.

Kwiatkowski, D. J. and B. D. Manning (2005). "Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways." Hum Mol Genet 14 Spec No. 2: R251-8.

            Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is characterized by benign tumors (hamartomas and hamartias) involving multiple organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review recent advances in our understanding of the growth and signaling functions of the TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 complex has been positioned in an ancestrally conserved signaling pathway that regulates cell growth. TSC1/TSC2 receives inputs from at least three major signaling pathways in the form of kinase-mediated phosphorylation events that regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP towards Rheb, which is a major regulator of the mammalian target of rapamycin (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas.

Kutzelnigg, A. and H. Lassmann (2005). "Cortical lesions and brain atrophy in MS." J Neurol Sci 233(1-2): 55-9.

            Multiple sclerosis is generally considered a disease of the white matter. However, this is only one pathological aspect of the disease as demyelination is prominent in the grey matter of deep cerebral nuclei and the cerebral cortex. In this review, we discuss the possibility that disease involvement of grey matter structures may significantly contribute to clinical disability in multiple sclerosis patients.

Kurzepa, J., H. Bartosik-Psujek, et al. (2005). "[Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis]." Neurol Neurochir Pol 39(1): 63-7.

            Multiple sclerosis (MS) is an autoimmune disease whose features include a massive lymphocyte recruitment into the central nervous system and segmental demyelinization of the white matter. One of the MS development factors is an increase of matrix metalloproteinases (MMPs) activity with a coincidental decrease of tissue inhibitors of MMPs (TIMPs) activity. Investigations of serum, cerebrospinal fluid and brain tissue of patients showed an increase of MMP-1, -2, -3, -7, -9 and MMP-12 activity. MMPs disrupt the blood-brain barrier (BBB), increase lymphocyte migration into the central nervous system and are involved in degradation of myelin proteins. MMPs induce the appearance of an active form of tumor necrosis factor alpha, a strong proinflammatory cytokine. The drugs used in MS treatment decrease MMPs expression. Multiple actions of MMPs prove their involvement in the pathogenesis and treatment of MS.

Kundra, O. (2005). "[The role of evoked potentials in neurological clinical practice]." Ideggyogy Sz 58(11-12): 364-79.

            The author provides an overview on the value of evoked potential (EP) methods (VEP, SEP, BAEP, MEP) in the diagnosis and follow-up of various neurological diseases (multiple sclerosis, cerebrovascular disorders, degenerative diseases, coma, epilepsy, migraine) by reviewing the literature supported by his own clinical experience. While in the past EP was mainly used for establishing the diagnosis, recently, with the expansion of neuroradiology, it has gained a wider use in the assessment of the severity and extent of the pathologic process and especially in longitudinal follow-up. Its role in the diagnostic phase has diminished. In patients with multiple sclerosis the abnormality of the evoked potentials correlate better with the clinical state than with the MRI results. The method is also suitable to monitor the response to therapy. The importance of the EP tests is illustrated by several case demonstrations.

Krishnan, K. R. (2005). "Psychiatric and medical comorbidities of bipolar disorder." Psychosom Med 67(1): 1-8.

            OBJECTIVES: This review summarizes the literature on psychiatric and medical comorbidities in bipolar disorder. The coexistence of other Axis I disorders with bipolar disorder complicates psychiatric diagnosis and treatment. Conversely, symptom overlap in DSM-IV diagnoses hinders definition and recognition of true comorbidity. Psychiatric comorbidity is often associated with earlier onset of bipolar symptoms, more severe course, poorer treatment compliance, and worse outcomes related to suicide and other complications. Medical comorbidity may be exacerbated or caused by pharmacotherapy of bipolar symptoms. METHODS: Articles were obtained by searching MEDLINE from 1970 to present with the following search words: bipolar disorder AND, comorbidity, anxiety disorders, eating disorder, alcohol abuse, substance abuse, ADHD, personality disorders, borderline personality disorder, medical disorders, hypothyroidism, obesity, diabetes mellitus, multiple sclerosis, lithium, valproate, lamotrigine, carbamazepine, atypical antipsychotics. Articles were prioritized for inclusion based on the following considerations: sample size, use of standardized diagnostic criteria and validated methods of assessment, sequencing of disorders, quality of presentation. RESULTS: Although the literature establishes a strong association between bipolar disorder and substance abuse, the direction of causality is uncertain. An association is also seen with anxiety disorders, attention-deficit/hyperactivity disorder, and eating disorders, as well as cyclothymia and other axis II personality disorders. Medical disorders accompany bipolar disorder at rates greater than predicted by chance. However, it is often unclear whether a medical disorder is truly comorbid, a consequence of treatment, or a combination of both. CONCLUSION: To ensure prompt, appropriate intervention while avoiding iatrogenic complications, the clinician must evaluate and monitor patients with bipolar disorder for the presence and the development of comorbid psychiatric and medical conditions. Conversely, physicians should have a high index of suspicion for underlying bipolar disorder when evaluating individuals with other psychiatric diagnoses (not just unipolar depression) that often coexist with bipolar disorder, such as alcohol and substance abuse or anxiety disorders. Anticonvulsants and other mood stabilizers may be especially helpful in treating bipolar disorder with significant comorbidity.

Kriesel, J. D. and W. A. Sibley (2005). "The case for rhinoviruses in the pathogenesis of multiple sclerosis." Mult Scler 11(1): 1-4.

Kraus, T. A. and L. Mayer (2005). "Oral tolerance and inflammatory bowel disease." Curr Opin Gastroenterol 21(6): 692-6.

            PURPOSE OF REVIEW: Oral tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used oral tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of oral tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use oral tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for oral tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding oral tolerance, explore the relation between oral tolerance and inflammatory bowel disease, and comment on the likelihood of successful oral tolerance therapy for inflammatory bowel disease. RECENT FINDINGS: The results of an oral tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced oral tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce oral tolerance is not successful in patients with inflammatory bowel disease. SUMMARY: The fundamental difference in the mechanisms of oral tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before oral tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.

Kranc, K. R., A. M. Taylor, et al. (2005). "Control of autoimmunity by "epitope theft"." Trends Mol Med 11(1): 1-4.

            We all possess T cells with autoaggressive potential. Knowledge of their regulation is crucial for elucidating pathogenetic pathways and designing effective treatments for autoimmune diseases. A novel mechanism of T-cell silencing--in an autoimmune model--has recently been identified and is termed "epitope theft". The "thieves" are naive CD8+ T cells, which apparently "steal" MHC-class-I-antigen complexes from antigen-presenting cells (APCs). The deprived APCs can no longer activate other potentially pathogenic naive CD8+ T cells that are specific for the same epitope. This phenomenon is a previously unrecognized antigen-specific mode of protection against autoimmunity.

Kotter, I., T. Daikeler, et al. (2005). "Autologous stem cell transplantation of treatment-resistant systemic vasculitis--a single center experience and review of the literature." Clin Nephrol 64(6): 485-9.

            AIMS: Autologous peripheral blood stem cell transplantation (autoPBSCT) is increasingly and successfully applied to patients with treatment-resistant autoimmune diseases, mainly multiple sclerosis and systemic sclerosis, but also juvenile idiopathic arthritis and systemic lupus erythematosus. We intended to analyze the effects of autoPBSCT in patients with treatment-resistant systemic vasculitis by analyzing the outcome of 4 patients from our own hospital, and comparing them to cases reported in the literature. METHODS: 4 patients with treatment-resistant vasculitis (Wegener granulomatosis, Churg Strauss syndrome, Takayasu arteritis and relapsing polychondritis) received an autologous PBSCT. Stem cell mobilization was performed with cyclophosphamide (CY) and G-CSF, stem cells were purged by positively selecting CD34+ stem cells over a CliniMacs device, and the conditioning was performed with high dose CY and anti-thymocyte globulin (ATG). RESULTS: AutoPBSCT was well tolerated in all 4 patients. The patient with WG achieved complete remission although cANCA persisted, the other patients are in good partial remissions and respond to maintenance treatments which had been ineffective before PBSCT (CSA, azathioprin). Glucocorticosteroids (GC) could be reduced to a maximum of 10 mg in all patients. Shortly after the procedure, reactivation of viruses from the herpes family occurred in 3 of the patients and had to be treated. In the data base, 25 patients transplanted for severe systemic vasculitis are registered, in the literature, 6 additional vasculitis patients remitting after autoPBSCT are reported. CONCLUSIONS: Autologous PBSCT is feasible and effective in severe, treatment-resistant forms of systemic vasculitis. Data are sparse, further prospective studies are needed. These should also aim at evaluating more optimal regimens for conditioning and purging during PBSCT, as in most of the vasculitis patients reported until now, mostly good partial remissions, but less complete remissions were achieved.

Korsak, J., B. Zaleska, et al. (2005). "[Use of high dose intravenous immunoglobulin in neurologic disease]." Pol Merkur Lekarski 19(109): 98-101.

            Intravenous immunoglobulin has been used generally as a supplement therapy in hypogammaglobulinemia patients. Then it has been shown to be effective in the treatment of patients with thrombocytopenic purpura, and in the last decade, IVIG has been used in the treatment of many autoimmune and systemic inflammatory diseases. In neurologic diseases intravenous immunoglobulin (IVIG) exhibits immunomodulatory properties, depending on the Fc portion of immunoglobulin G. The number of diseases in which IVIG therapy is effective has been demonstrated by controlled clinical trials. The indications for IVIG therapy in neurologic diseases are in four groups: A+ - the basic indication, they have been demonstrated in controlled clinical trials, A - recommended but they have not been proved by clinical trials, B - confirmed by singular trials, C - recommended as a last resort: the indications have not been confirmed any trials. IVIG clinical effect has been shown in trials in patients with GBS, chronic inflammatory demyelinating polyneuropathy, dermatomyositis and multiple sclerosis. An optimal dose and the frequency of IVIG administration depend on the knowledge of the pathophysiology of autoimmune diseases and the mechanism of IVIG action.

Kornhuber, M. E., P. Presek, et al. (2005). "[Differential influence of immune therapy on relapses and progression in multiple sclerosis: interpretation and therapeutic consequences.]." Fortschr Neurol Psychiatr 73(3): 143-9.

            It is well established that relapses can be suppressed by different substances in patients with relapsing-remitting multiple sclerosis (MS). In contrast, patients with progressive forms of MS do hardly respond to immune therapy. Therefore, start of immune therapy after the first relapse has been proposed, especially in order to prevent degeneration and disability. This view is challenged in the present review. Actually no evidence exists in support of a retardation or an attenuation of secondary progression by early immune therapy. Widespread degeneration occurs early and progresses independently from inflammatory plaques. Therefore, autoimmunity per se is no adequate paradigm to explain MS-pathogenesis entirely. A virus/superantigen-dualism is proposed to explain the different parts of MS, instead. It is concluded that evidence-based immune therapy should be adapted to the actual inflammatory activity of the disease. A suitable parameter for this purpose is the interval between 2 relapses.

Korf, B. R. (2005). "The phakomatoses." Clin Dermatol 23(1): 78-84.

            The "phakomatosis" concept was formulated early in the twentieth century by the ophthalmologist van der Hoeve. He included 3 disorders in the group-neurofibromatosis, tuberous sclerosis complex, and von Hippel-Lindau syndrome--on the basis of the occurrence of patchy ophthalmologic manifestations in each disorder. Since the name was coined, much has been learned about the pathogenesis of these 3 disorders. It is clear that 2 of them--neurofibromatosis and tuberous sclerosis--are collective terms for multiple disorders. Each of the conditions is caused by distinct genetic defects, with little commonality in terms of protein function. Yet, in some respects, the disorders share a pathogenetic mechanism, that of the tumor suppressor gene. This review will briefly describe these disorders in light of what has been learned about underlying molecular pathogenesis. In each case, genetic testing is beginning to be available; principles of the use of genetic tests will be described.

Kohm, A. P., D. M. Turley, et al. (2005). "Targeting the TCR: T-cell receptor and peptide-specific tolerance-based strategies for restoring self-tolerance in CNS autoimmune disease." Int Rev Immunol 24(5-6): 361-92.

            A principal theme in autoimmunity is the breakdown of central tolerance resulting in the persistence and eventual activation of autoreactive T cells. Because CD4(+) T cells are key contributors to the underlying pathogenic mechanisms responsible for the onset and progression of most autoimmune diseases, they are a logical target for therapeutic interventions. One technique for restoring self-tolerance is to exploit the endogenous regulatory mechanisms that govern CD4(+) T-cell activation. In this review, we discuss promising techniques with the common goal of inducing antigen (Ag)-specific tolerance. Emphasis is given to the use of non-mitogenic anti-CD3 and peptide-specific tolerance strategies that specifically target the T-cell receptor (TCR) in the absence of costimulatory signals. These approaches produce a TCR signal of insufficient strength to cause CD4(+) T-cell activation and instead induce functional T-cell anergy or deletion while avoiding generalized long-term immunosuppression.

Knutson, K. L. and M. L. Disis (2005). "Tumor antigen-specific T helper cells in cancer immunity and immunotherapy." Cancer Immunol Immunother 54(8): 721-8.

            Historically, cancer-directed immune-based therapies have focused on eliciting a cytotoxic T cell (CTL) response, primarily due to the fact that CTL can directly kill tumors. In addition, many putative tumor antigens are intracellular proteins, and CTL respond to peptides presented in the context of MHC class I which are most often derived from intracellular proteins. Recently, increasing importance is being given to the stimulation of a CD4+ T helper cell (Th) response in cancer immunotherapy. Th cells are central to the development of an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Two predominant Th cell subtypes exist, Th1 and Th2. Th1 cells, characterized by secretion of IFN-gamma and TNF-alpha, are primarily responsible for activating and regulating the development and persistence of CTL. In addition, Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC. Th2 cells favor a predominantly humoral response. Particularly important during Th differentiation is the cytokine environment at the site of antigen deposition or in the local lymph node. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Specifically modulating the Th1 cell response against a tumor antigen may lead to effective immune-based therapies. Th1 cells are already widely implicated in the tissue-specific destruction that occurs during the pathogenesis of autoimmune diseases, such as diabetes mellitus and multiple sclerosis. Th1 cells directly kill tumor cells via release of cytokines that activate death receptors on the tumor cell surface. We now know that cross-priming of the tumor-specific response by potent APC is a major mechanism of the developing endogenous immune response; therefore, even intracellular proteins can be presented in the context of MHC class II. Indeed, recent studies demonstrate the importance of cross-priming in eliciting CTL. Many vaccine strategies aim to stimulate the Th response specific for a tumor antigen. Early clinical trials have shown that focus on the Th effector arm of the immune system can result in significant levels of both antigen-specific Th cells and CTL, the generation of long lasting immunity, and a Th1 phenotype resulting in the development of epitope spreading.

Klegeris, A. and P. L. McGeer (2005). "Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease." Curr Alzheimer Res 2(3): 355-65.

            Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.

Kim, S. U. and J. de Vellis (2005). "Microglia in health and disease." J Neurosci Res 81(3): 302-13.

            Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. It was del Rio Hortega in 1927 who determined that microglia belong a distinct glial cell type apart from astrocytes and oligodendrocytes, and since 1970s there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that microglia are capable of secreting neurotrophic or neuron survival factors upon activation via inflammation or injury. It is thus timely to review current status of knowledge on biology and immunology of microglia, and consider new directions of investigation on microglia in health and disease.

Killestein, J. and C. H. Polman (2005). "Current trials in multiple sclerosis: established evidence and future hopes." Curr Opin Neurol 18(3): 253-60.

            PURPOSE OF REVIEW: The aim of the present report is to briefly review multiple sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights. RECENT FINDINGS: New data have come available that help us understand how currently approved disease modifying drugs can best be used. Nonetheless, their limited effectiveness - especially in progressive forms of multiple sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies. A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis. SUMMARY: Further advances have been made in the treatment of multiple sclerosis patients. On the one hand, we know better how and in whom to use existing medications. On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.

Kieseier, B. C., B. Hemmer, et al. (2005). "Multiple sclerosis--novel insights and new therapeutic strategies." Curr Opin Neurol 18(3): 211-20.

            PURPOSE OF REVIEW: This review focuses on novel aspects of the pathogenesis and advances in the therapy of multiple sclerosis (MS). RECENT FINDINGS: Recent observations suggest that early lesion development in MS may start in some forms with oligodendrocyte death and that inflammation appears as a secondary phenomenon only. The lack of sufficient remyelination in MS may be the result of a disturbed function of basic helix-loop-helix transcription factors. Clinically the identification of patients with a clinically isolated syndrome at high risk to develop clinically definite MS remains difficult; the predictive value of serum antibodies against myelin proteins remains controversial. The role of neutralizing antibodies in interferon therapy is discussed. New therapeutic approaches in MS are emerging. SUMMARY: The existing view on the pathogenesis of MS is still changing. The original assumption that cell-mediated demyelination is the key event in lesion development dictating clinical disability is critically reviewed and alternative pathways have been suggested. Oligodendrocyte death, axonal loss, the role of CD8 T lymphocytes, T regulatory cells, and B lymphocytes have come into the focus of newly evolving concepts in MS pathogenesis. A deepened understanding of the immunopathogenesis of this disease translates into innovative therapeutic approaches, such as blockade of alpha4 integrins by a humanized monoclonal antibody. In various animal models cell-replacement strategies yield promising results; however, turning these findings into an effective therapy in MS patients has a long way to go.

Kidd, P. M. (2005). "Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management." Altern Med Rev 10(4): 268-93.

            Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.

Kesselring, J. and S. Beer (2005). "Symptomatic therapy and neurorehabilitation in multiple sclerosis." Lancet Neurol 4(10): 643-52.

            Multiple sclerosis (MS) is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap. Symptoms that contribute to loss of independence and restrictions in social activities lead to continuing decline in quality of life. Our aim is to give an updated overview on the management of symptoms and rehabilitation measures in MS. Appropriate use of these treatment options might help to reduce long-term consequences of MS in daily life. First, we review treatment of the main symptoms of MS: fatigue, bladder and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. Even though these symptomatic therapies have benefits, their use is limited by possible side-effects. Moreover, many common disabling symptoms, such as weakness, are not amenable to drug treatment. However, neurorehabilitation has been shown to ease the burden of these symptoms by improving self-performance and independence. Second, we discuss comprehensive multidisciplinary rehabilitation and specific treatment options. Even though rehabilitation has no direct influence on disease progression, studies to date have shown that this type of intervention improves personal activities and ability to participate in social activities, thereby improving quality of life. Treatment should be adapted depending on: the individual patient's needs, demands of their surrounding environment, type and degree of disability, and treatment goals. Improvement commonly persists for several months beyond the treatment period, mostly as a result of reconditioning and adaptation and appropriate use of medical and social support at home. These findings suggest that quality of life is determined by disability and handicap more than by functional deficits and disease progression.

Keeley, K. A., M. P. Rivey, et al. (2005). "Natalizumab for the treatment of multiple sclerosis and Crohn's disease." An