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Multiple Sclerosis Reviews: 2002

(251 References)

(2002). "Proposed diagnostic criteria and nosology of acute transverse myelitis." Neurology 59(4): 499-505.

            Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. A set of uniform diagnostic criteria and nosology for ATM is proposed to avoid the confusion that inevitably results when investigators use differing criteria. This will ensure a common language of classification, reduce diagnostic confusion, and lay the groundwork necessary for multicenter clinical trials. In addition, a framework is suggested for evaluation of individuals presenting with signs and symptoms of ATM. Best treatment often depends on a timely and accurate diagnosis. Because acute transverse myelopathies are relatively rare, delayed and incomplete work-ups often occur. Rapid and precise diagnosis will ensure not only that compressive lesions are detected and treated but also that idiopathic ATM is distinguished from ATM secondary to a known underlying disease. Identification of etiologies may suggest medical treatment, whereas no clearly established medical treatment currently exists for idiopathic ATM. Establishment of a diagnostic algorithm will likely lead to improved care, although it is recognized that the entire evaluation may not be performed for each patient.

(2002). "MS, Parkinson's disease and physiotherapy." Drug Ther Bull 40(5): 38-40.

            In the UK, around 10-12 in every 10,000 people have multiple sclerosis, typical features of which include weakness, ataxia, spasticity and sensory loss. By comparison, around 16-18 in every 10,000 have Parkinson's disease, a condition typified by rigidity, bradykinesia, tremor and postural instability. Both conditions can limit function with, for example, nearly 25% of patients with multiple sclerosis and about 10% of those with Parkinson's disease being dependent on a wheelchair. Physiotherapy is widely used as part of a multidisciplinary approach to the management of multiple sclerosis, while 7-38% of people with Parkinson's disease are referred for physiotherapy. Here, we review the evidence for physiotherapy in the management of patients with either condition.

Ajuebor, M. N., M. G. Swain, et al. (2002). "Chemokines as novel therapeutic targets in inflammatory diseases." Biochem Pharmacol 63(7): 1191-6.

            Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.

Alvarez-Cermeno, J. C., C. Cid, et al. (2002). "[The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis]." Rev Neurol 35(10): 994-7.

            In vitro studies have shown that the cerebrospinal fluid of patients with multiple sclerosis transports compounds which may affect the function or viability of central nervous system cell function. The presence of nerve ion channel blockers and other molecules, as yet unidentified, which may cause the death of nerve cells or oligodendrocytes has been shown, although their relevance and clinical correlation is still not clear. If their usefulness is proved, these methods may be useful in the search for inhibitors of the noxious effects of the substances mentioned.

Arnold, D. L. and P. M. Matthews (2002). "MRI in the diagnosis and management of multiple sclerosis." Neurology 58(8 Suppl 4): S23-31.

            MRI techniques, including conventional T(2)-weighted and gadolinium (Gd)-enhanced T(1)-weighted images, have provided important insights into the pathophysiology of MS. Although the correlation of MRI measures with clinical disability and outcome continues to be investigated, MRI measures are routinely used both in clinical practice and in MS research. In addition to its use as a diagnostic tool, MRI is used as a surrogate marker to monitor disease progression and response to therapy. A variety of MRI measures are used in drug development studies and have aided our understanding of the potential benefits and possible mechanisms of action of drug therapies. Advances in MRI techniques may further elucidate the pathology of MS, thus providing opportunities for new treatment strategies.

Arzimanoglou, A., E. Hirsch, et al. (2002). "Epilepsy and neuroprotection: an illustrated review." Epileptic Disord 4(3): 173-82.

            Multiple types of insults, such as status epilepticus, hypoxia and trauma, may alter the central nervous system. Strategies to protect the brain against insults remain a very difficult and challenging problem. Damage to the central nervous system can be modulated via excessive excitatory and reduced inhibitory neurotransmission. In addition, increased sodium and calcium loading through impaired voltage-sensitive channels, as well as alterations in the acid-base balance can contribute to both excitotoxic and apoptotic cell death. Epilepsy treatment has always been related to neuroprotection, since it aims to reduce the duration or totally suppress seizures. Although the debate on the capacity of simple seizures to induce neuronal injury is still ongoing, no doubt persists on the disastrous effects of prolonged episodes of status. The next step would be to prevent epilepsy. Several animal models have been used to study the various aspects of the epileptogenic process. In humans, one of the most compelling examples of a series of epileptogenic events is temporal lobe epilepsy (TLE). Temporal lobe epilepsy is often attributed to prolonged febrile convulsions in childhood resulting in mesial temporal sclerosis. However, the relationship between TLE, seizures in childhood and hippocampal sclerosis may not be apparent as initially believed. Furthermore, it is well recognized that in a number of patients there is a delay from a specific insult to the onset of seizures. This "latent period" could be an opportunity for effective intervention, provided that the underlying mechanisms are understood and that appropriate means for a beneficial modification of the disease process become available. The present review discusses the various steps of temporal lobe epilepsy and provides illustrations of the various mechanisms implicated in neuronal death. Data from animal models is also presented and illustrated with video sequences. Finally, on the basis of what is known on mechanisms of action of available antiepileptic drugs, some suggestions are put forward. Basic science and research are guided by clinical queries and from ongoing dialogue. The present illustrated review deals with only a small part of the important amount of work related to epilepsy and neuroprotection. As such it is necessarily schematic or even simplistic. The review is designed to inform clinicians about the basic issues related to the subject, thus allowing them to follow the ongoing debate and participate with pertinent questions. (Published with video sequences).

Bach, J. F. (2002). "[Current concepts of autoimmunity]." Rev Neurol (Paris) 158(10 Pt 1): 881-6.

            Autoimmunity is physiological: in every normal individual autoreactive T cells and B cells which produce natural autoantibodies, exist. Auto-immunity becomes pathological, giving rise to an autoimmune disease, when the number of autoreactive cells, and particularly the avidity of their receptors for autoantigens increase. Triggering of the disease depends both on the increase in immunogenicity of the target cell, which may be secondary to a viral infection, and the individual's own capability to recognize the antoantigens (HLA genes, T cell repertoire). More rarely, the disease is caused by an infectious agent leading to a crossed reaction with an autoantigen (Guillain-Barre syndrome). Nevertheless, all these elements are not sufficient to provoke a chronic disease such as multiple sclerosis or myasthenia gravis. The passage to chronicity is usually secondary to a defect in immunoregulation. Several categories of regulatory T cells have been found: Th2 cells, CD25+ cells, Trl cells, NKT cells. It is still difficult to asses the responsibility of the defect of one of these populations in a given disease, or to single out the cytokines implicated, although an essential role is often given to interleukin 10 and/or TGFB. Even if the pathogenic autoimmune reaction is triggered by the autoantigens of the target cell, there is apparently not a unique autoantigen target. The specificity of the reaction spreads progressively from one antigen, which may vary among subjects, to the entire target cell. It is based on these notions that new immunotherapeutic approaches for autoimmune diseases are being developed (soluble autoantigens, or one of their modified peptides: (APL), cytokine, anti-CD3 antibody).

Bagert, B., P. Camplair, et al. (2002). "Cognitive dysfunction in multiple sclerosis: natural history, pathophysiology and management." CNS Drugs 16(7): 445-55.

            Cognitive dysfunction is a major cause of disability in patients with multiple sclerosis (MS). The prevalence of cognitive dysfunction is estimated at 45 to 65%. Natural history studies suggest that once cognitive dysfunction develops in a patient with MS, it is not likely to remit. Unlike physical disability in MS, cognitive disability correlates weakly with T2 lesion burden on brain magnetic resonance imaging (MRI). More robust correlations exist with magnetisation transfer imaging and MRI measures of brain atrophy. Patients with MS who have cognitive impairment most commonly display deficits in the cognitive domains of memory, learning, attention and information processing. In diagnosing cognitive dysfunction in a patient with MS, it is important first to recognise and treat the common comorbidities of fatigue and depression. The first step in the treatment of cognitive dysfunction is to delay disease progression, and there are currently five such disease-modifying agents approved for the treatment of MS (two preparations of interferon-beta-1a, interferon-beta-1b, glatiramer acetate and mitoxantrone). Nonpharmacological measures, such as cognitive rehabilitation, occupational therapy and psychotherapy, are the mainstays of symptomatic treatment. Pharmacological symptomatic therapy centres on the treatment of comorbid fatigue and depression. There are currently no effective pharmacological agents approved as symptomatic therapy of cognitive dysfunction in MS.

Baranzini, S. E. and S. L. Hauser (2002). "Large-scale gene-expression studies and the challenge of multiple sclerosis." Genome Biol 3(10): reviews1027.

            In multiple sclerosis, a complex neurodegenerative disorder, a combination of genetic and environmental factors results in inflammation and myelin damage. Recent transcription-profiling studies have found distinct gene-expression patterns in diseased tissue; such large-scale studies at different stages of the disease are contributing to understanding multiple sclerosis and developing effective therapy.

Baranzini, S. E., J. R. Oksenberg, et al. (2002). "New insights into the genetics of multiple sclerosis." J Rehabil Res Dev 39(2): 201-9.

            Tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develop in genetically susceptible individuals after exposure to a causal agent that is yet undefined. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, posttranscriptional regulatory mechanisms, and significant environmental influences. Equally significant is that genetic heterogeneity also likely exists, meaning that specific genes influence susceptibility and pathogenesis in some affecteds but not in others. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen significant progress in the developments of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and to define the pathological basis of demyelination. These developments have set the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. The identification and characterization of the genes are likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.

Barkhof, F. (2002). "The clinico-radiological paradox in multiple sclerosis revisited." Curr Opin Neurol 15(3): 239-45.

            The use of magnetic resonance imaging as a surrogate outcome measure in clinical trials, or even as a prognosticator in the assessment of the natural evolution, assumes a close relationship between extent and rate of development of magnetic resonance imaging abnormalities with the clinical status and rate of development of disability. While it may seem obvious that patients who develop new lesions are worse off than those without new lesions, the association between clinical findings and radiological extent of involvement is generally poor. In this review, various confounders are discussed, including inappropriate clinical rating, lack of histopathological specificity (especially for axonal loss), neglect of spinal cord involvement, underestimation of damage to the normal appearing brain tissue (both white and gray matter), and masking effects of cortical adaptation. It is concluded that much progression has been made in magnetic resonance techniques so that the clinico-radiological dissociation has indeed proved to be a paradox. Thus, the relevance of normal appearing brain tissue damage, residual brain volume, spinal cord damage and cerebral plasticity had to be reiterated. The increased awareness of the subtle interplay between these dimensions should be kept in mind when magnetic resonance is used as a surrogate outcome measure. This corroborates with conventional wisdom that one should not rely on a single magnetic resonance measure, but take full advantage of the fact that magnetic resonance is able to provide multidimensional information.

Barkhof, F. and P. Scheltens (2002). "Imaging of white matter lesions." Cerebrovasc Dis 13 Suppl 2: 21-30.

            Magnetic resonance imaging (MRI) is very sensitive for the detection of white matter lesions (WML), which occur even in normal ageing. Intrinsic WML should be separated from physiological changes in the ageing brain, such as periventricular caps and bands, and from dilated Virchow-Robin spaces. Genuine WML are best seen with T2-weighted sequences such as long TR dual-echo spin-echo or FLAIR (fluid-attenuated inversion recovery); the latter has the advantage of easily separating WML from CSF-like lesions. Abnormal T2 signal in MRI is not specific, and can accompany any change in tissue composition. In the work-up of WML in small vessel disease, magnetic resonance angiography can be used to rule out (concomitant) large vessel disease, and diffusion-weighted MRI to identify new ischaemic lesions (amidst pre-existing old WML). The differential diagnosis of WML includes hereditary leukodystrophies and acquired disorders. The leukodystrophies that can present in adult age include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenomyeloneuropathy, mitochondrial disorders, vanishing white matter, and cerebrotendinous xanthomatosis. These metabolic disorders typically present with symmetrical abnormalities that can be very diffuse, often with involvement of brainstem and cerebellum. Only the mitochondrial disorders tend to be more asymmetric and frequently involve the grey matter preferentially. Among the acquired white matter disorders, hypoxic-ischaemic causes are by far the most prevalent and without further clinical clues there is no need to even consider the next most common disorder, i.e. multiple sclerosis (MS). Among the nonischaemic disorders, MS is far more common than vasculitis, infection, intoxication and trauma. While vasculitis can mimic small vessel disease, MS has distinctive features with preferential involvement of the subcortical U-fibres, the corpus callosum, temporal lobes and the brainstem/cerebellum. Spinal cord lesions are very common in MS, but do not occur in normal ageing nor in small vessel disease.

Bartosik-Psujek, H. and Z. Stelmasiak (2002). "[Axonal damage in multiple sclerosis]." Neurol Neurochir Pol 36(3): 505-12.

            Traditionally, it was believed in MS, that axonal loss occurred in chronic lesions. However, new findings suggest that axonal transection can begin very early in the course of multiple sclerosis and axonal damage was found in active and chronic active MS lesions, particularly in areas of acute inflammation and demyelination. The mechanisms of axonal loss are uncertain, but may involve axonal degeneration secondary to demyelination, the action of inflammatory mediators and immune attack directed at axonal components. Axonal destruction and it's progression, is the major cause of irreversible damage in the CNS and the increase of disability in MS patients. Currently, new diagnostic methods (MRI, MR spectroscopy, magnetic transfer, histopathological and biochemical study) allow better to know the mechanisms of neuronal damage.

Bashir, K. and J. N. Whitaker (2002). "Current immunotherapy for demyelinating diseases." Arch Neurol 59(5): 726-31.

Baxter, A. G. and M. J. Smyth (2002). "The role of NK cells in autoimmune disease." Autoimmunity 35(1): 1-14.

            NK cells are a subset of mononuclear cells which have long been suspected of playing an immunoregulatory role in the prevention of autoimmune diseases. Here, we briefly discuss the characteristics of NK cells--particularly what is known of their functional capabilities--and summarise the major findings from studies of NK cells in human and animals susceptible to three major autoimmune diseases: multiple sclerosis, systemic lupus erythematosus and type 1 (autoimmune) diabetes mellitus. In each case, we present the evidence for an association between disease and deficiencies in NK cells. The prospect of clinical interventions that stimulate NK cell activity are discussed and the current status described.

Bitsch, A. and W. Bruck (2002). "Differentiation of multiple sclerosis subtypes: implications for treatment." CNS Drugs 16(6): 405-18.

            There has been tremendous progress in the immunomodulatory treatment of multiple sclerosis (MS) during recent years. With the introduction of interferon-beta, glatiramer acetate and mitoxantrone (recently registered for MS in the US), there are at least three therapeutic strategies that have proven effective in large phase III studies. However, not all patients with MS respond well to treatment with these drugs. This may largely be a consequence of disease heterogeneity. From a clinical perspective, patients with different disease courses show different treatment responses. Patients with relapsing-remitting MS are more likely to respond to immunomodulatory therapy than those with a progressive disease course. Studies of patients with secondary progressive MS have yielded inconsistent results and, so far, there has been no positive phase III study of immunomodulatory therapy in patients with primary progressive MS. Pathological evidence indicates that subtyping based on clinical findings alone does not reflect actual disease heterogeneity. In a large series of biopsy and autopsy specimens, at least four subtypes could be identified with respect to oligodendrocyte/myelin pathology and immunopathology. As long as the only method of identifying subtypes of disease is histopathology, differential therapy will remain a future goal. Thus, there is an urgent need for in vivo markers of immunopathogenesis in an individual patient that would allow treatment to be specifically directed towards a given pathological focus. However, at least from a theoretical point of view, some therapeutic approaches appear very attractive. Plasmapheresis and/or intravenous immunoglobulins could most plausibly be the best approach for the immunopathological subtype of MS, which is characterised by antibody and complement deposition next to demyelinated axons, in order to remove antibodies. The subtype of MS that is associated with heavy macrophage activation, T cell infiltration and expression of inflammatory mediator molecules, including tumour necrosis factor-alpha, may be most likely to respond to immunomodulation with interferon-beta or glatiramer acetate. There are other subtypes of MS in which viral infection or oligodendrocyte degeneration, rather than autoimmunity, appear to play a role. It is possible that these could benefit from antiviral therapy, oligodendrocyte protection or oligodendrocyte transplantation, although therapies based on these latter approaches have yet to be developed.

Boiko, A. N. and E. I. Gusev (2002). "[Beta-interferons in multiple sclerosis: comparative trials and potential individual selection in different types of the disease course]." Zh Nevrol Psikhiatr Im S S Korsakova Suppl: 65-71.

            Beta-interferons (beta-IFN) are effective treatment of relapsing-remitting multiple sclerosis (MS). Recent comparative studies showed significantly higher efficacy of high doses of beta-IFN used every other day. In secondary progressive MS data of beta-IFN trials are not so promising. This may be due to mechanisms of action of this medicine: it can effectively block neurodegeneration associated with inflammation, while in secondary progressive MS other mechanisms of degeneration may be present. Own original studies showed, that the level of MMP9 in serum can be used as an informative biological marker of beta-IFN activity in MS, this treatment could be more effective in DR2(15)-positive individuals and the presence of severe brain atrophy at baseline MRI can be used as a predictor of less effective results of treatment with beta-IFN. Future studies must define the methods, which may be used for selecting the subgroup of MS patients with the best response to beta-IFN. Data of pharmacogenetic and pharmacoeconomic studies must be helpful.

Boiko, A. N., T. D. Zhuchenko, et al. (2002). "[Mechanisms of glatiramer acetate action in demyelinating diseases: antigen-specific, organ-specific or process-specific treatment]." Zh Nevrol Psikhiatr Im S S Korsakova Suppl: 52-8.

            Use of the "disease modifying" medicines is a significant success in multiple sclerosis (MS) treatment. These ways of MS treatment were scientificantly based and proved in large well-designed randomized studies, while direct mechanisms of their action is still under investigation. This review is discussing the mechanisms of action of glutiramer acetate (GA)--one of these medicines, modifying MS course. Its positive clinical effects in relapsing-remitting MS were shown in large clinical studies, confirmed by MRI and supported by extension trials. Immunomodulative effects of GA in MS and its experimental model (EAE) may be associated with induction of GA-specific cells clone, which have several positive for MS features, for example producing anti-inflammatory Th2-cytokines. Other characteristics of these cell clones should be studied further.

Brazil, D. P., J. Park, et al. (2002). "PKB binding proteins. Getting in on the Akt." Cell 111(3): 293-303.

            Protein kinase B (PKB) has emerged as the focal point for many signal transduction pathways, regulating multiple cellular processes such as glucose metabolism, transcription, apoptosis, cell proliferation, angiogenesis, and cell motility. In addition to acting as a kinase toward many substrates involved in these processes, PKB forms complexes with other proteins that are not substrates, but rather act as modulators of PKB activity and function. In this review, we discuss the implications of these data in understanding the multitude of functions predicted for PKB in cells.

Brinar, V. V. (2002). "The differential diagnosis of multiple sclerosis." Clin Neurol Neurosurg 104(3): 211-20.

Brochet, B. and V. Dousset (2002). "[Magnetic resonance imaging in multiple sclerosis]." Rev Neurol (Paris) 158(10 Pt 1): 1025-32.

Brod, S. A. (2002). "Ingested type I interferon: state of the art as treatment for autoimmunity." Exp Biol Med (Maywood) 227(11): 981-8.

            We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in three phase I (type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and one phase II clinical trials in multiple sclerosis. In a phase I open-label trial in type 1 diabetes, ingested IFN-alpha preserved residual beta-cell function in recent onset patients. In a second phase I trial, treatment of rheumatoid arthritis with ingested IFN-alpha reduced the secretion of interleukin (IL)-1, a pro-inflammatory cytokine. In a third phase I trial in multiple sclerosis, there was a significant decrease in peripheral blood mononuclear cell IL-2 and IFN-gamma production after ingesting IFN-alpha. In a phase II randomized, placebo-controlled, double-blind trial in multiple sclerosis, 10,000 IU ingested IFN-alpha significantly decreased gadolinium enhancements compared with the placebo group at month 5. Tumor necrosis factor-alpha and IFN-gamma cytokine secretion in the 10,000 IU group at month 5 showed a significant decrease that corresponded with the effect of ingested IFN-alpha on decreasing gadolinium enhancements. Ingested IFN-alpha was not toxic in any of these clinical trials. These studies suggest that ingested IFN-alpha may have a potential role in the treatment of autoimmunity.

Bruck, W., C. Lucchinetti, et al. (2002). "The pathology of primary progressive multiple sclerosis." Mult Scler 8(2): 93-7.

            The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the pathological characteristics of the MS lesions and summarize the current findings of the pathology of primary progressive MS with respect to inflammation, oligodendrocyte myelin pathology, axon destruction and immunopathology of the lesions.

Burks, J. S., B. G. Arnason, et al. (2002). "Issues and practices in multiple sclerosis." Neurorehabil Neural Repair 16(4): 307-20.

            The objective of this roundtable discussion of experts in the field of multiple sclerosis (MS) was to summarize the current understanding of MS and its therapeutic options. The experts discussed subjects ranging from the etiology of MS to the current standards for patient care. Specific topics included the subtypes of MS, with a focus on the benign subtype, brain atrophy, the role of magnetic resonance imaging or "neuroimaging studies," disease-modifying therapies, biological markers as indicators of drug efficacy, and combination therapies. In addition, the experts speculated as to what will be available in the near future for the improved diagnosis and management of MS. This review summarizes the main points of this discussion and is intended to serve as a reference for neurologists involved in the care of patients with MS.

Butterfield, D. A., A. Castegna, et al. (2002). "Vitamin E and neurodegenerative disorders associated with oxidative stress." Nutr Neurosci 5(4): 229-39.

            Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.

Calabresi, P. A. (2002). "Considerations in the treatment of relapsing-remitting multiple sclerosis." Neurology 58(8 Suppl 4): S10-22.

            Disease-modifying drugs are available in the United States for the treatment of relapsing-remitting multiple sclerosis (RRMS), including interferon (IFN) beta-1a, IFNbeta-1b, and glatiramer acetate. Another formulation of IFNbeta-1a is available in Europe, Canada, and other countries. Mitoxantrone is also indicated for the treatment of worsening forms of RRMS and secondary progressive (SP) MS. In addition to reductions in annual relapse rates and other measures of clinical disability, the disease-modifying drugs appear to reduce MRI measures of disease activity. Available data suggest that the efficacy of disease-modifying therapy is sustained for at least for 4 to 6 years. Results of clinical drug trials have been used as a rationale to support treatment of early MS with a disease-modifying drug. Other medical therapies are used in the management of RRMS, including treatments to help manage MS-related symptoms such as spasticity and bladder dysfunction, and corticosteroids to hasten recovery from acute relapses. In some situations, interventions are used to minimize side effects of disease-modifying drug therapy. Several currently marketed treatments, including IV immunoglobulin, methotrexate, and azathioprine, are being evaluated as treatments for RRMS in combination with the approved therapies. Investigational compounds, including oral formulations of glatiramer acetate and interferon, are in various stages of development.

Carra, A. and M. Drake (2002). "[Neuropsychiatric and cognitive aspectos of multiple sclerosis]." Vertex 13(49): 217-25.

            Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that can affect cognitive and emotional functioning. About 50% of MS patients present some degree of neuropsychological impairment. Due to its onset in young adulthood (a period of life in which the individual is professionally and socially very active) the presence of cognitive impairment may greatly alter the patient's daily living activities and future life plans. Memory, attention, executive function and information processing speed are the most commonly reported impaired aspects of cognition. Depression, euphoria, and pathological laughing and crying are frequent psychiatric findings. In this paper we describe the distinctive features of cognitive and psychopathological impairments and their relationship to certain disease variables such as illness duration, lesion sites, physical impairment and clinical course. We also deal with aspects of the neuropsychological and psychiatric assessment, emphasizing its importance when psychological counseling or an eventual cognitive training are needed.

Carson, M. J. (2002). "Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis." Glia 40(2): 218-31.

            Multiple sclerosis is a chronic demyelinating inflammatory disease of the central nervous system (CNS). As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions, allows the CNS to tailor microglial function for specific physiological needs. However, the great plasticity of microglial responses can also predispose these cells to amplify disproportionately the irrelevant or dysfunctional signals provided by either the CNS or immune systems. The consequences of such an event could be the conversion of self-limiting inflammatory responses into chronic neurodegeneration and may explain in part the heterogeneous nature of multiple sclerosis.

Cerami, A., M. Brines, et al. (2002). "Neuroprotective properties of epoetin alfa." Nephrol Dial Transplant 17 Suppl 1: 8-12.

            Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Chang, T. T., V. K. Kuchroo, et al. (2002). "Role of the B7-CD28/CTLA-4 pathway in autoimmune disease." Curr Dir Autoimmun 5: 113-30.

Chen, G. and D. V. Goeddel (2002). "TNF-R1 signaling: a beautiful pathway." Science 296(5573): 1634-5.

            Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The interaction of TNF with TNF receptor-1 (TNF-R1) activates several signal transduction pathways. A common feature of each pathway is the TNF-induced formation of a multiprotein signaling complex at the cell membrane. Over the past decade, many of the components and mechanisms of these signaling pathways have been elucidated. We provide an overview of current knowledge of TNF signaling and introduce an STKE Connections Map that depicts a canonical view of this process.

Chidiac, C. and E. Braun (2002). "[Atherosclerosis, multiple sclerosis, and Alzheimer's disease: what role for Herpesviridae?]." Pathol Biol (Paris) 50(7): 463-8.

            Herpesviridae are ubiquitous, and are commonly involved in well identified diseases as genital herpes, chickenpox and herpes zoster, infectious mononucleosis, exanthem subitum... They are responsible for latent and chronic infections after primary infection. Atherosclerosis, multiple sclerosis, Alzheimer's disease are diseases which are very different, and for which pathogenesis remains unknown. Several authors have hypothesized that Herpesviridae could play a role in such diseases. The present paper reviews arguments not only in favour but also against such hypothesis. Any formal conclusion is impossible, and more extensive studies are warranted.

Chofflon, M. and A. F. Ben-Amor (2002). "Long-term benefits of early and high doses of interferon beta-1a treatment in relapsing-remitting multiple sclerosis." Clin Neurol Neurosurg 104(3): 244-8.

Chroni, E., C. Paschalis, et al. (2002). "Multiple sclerosis in the course of systemic sclerosis." Ann Rheum Dis 61(2): 188.

Cifelli, A. and P. M. Matthews (2002). "Cerebral plasticity in multiple sclerosis: insights from fMRI." Mult Scler 8(3): 193-9.

            Functional magnetic resonance imaging (fMRI) allows noninvasive localization of cerebral activation with relatively high spatial and temporal resolution. The considerable potential for the elucidation of the mechanisms of brain function has made it a useful tool to investigate the neural substrate of motor, sensory and cognitive functions. Understanding derived from these basic cognitive neuroscience investigations is beginning to be applied to clinically relevant problems. In this article, applications to multiple sclerosis (MS) are reviewed, which address the challenging notion that adaptive cerebral plasticity may have an important influence on the relationship between MS pathology and its clinical expression.

Clark, J. E., A. Brennan, et al. (2002). "Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study." Front Biosci 7: c83-96.

            As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.

Cohen, Y. and A. Nagler (2002). "Treatment of refractory autoimmune diseases with lymphoablation and hematopoietic stem cell support." Isr Med Assoc J 4(11 Suppl): 865-7.

Coleman, M. P. and V. H. Perry (2002). "Axon pathology in neurological disease: a neglected therapeutic target." Trends Neurosci 25(10): 532-7.

            In the C57BL/Wld(S) mouse, a dominant mutation dramatically delays Wallerian degeneration in injury and disease, possibly by influencing multi-ubiquitination. Studies on this mouse show that axons and synapses degenerate by active and regulated mechanisms that are akin to apoptosis. Axon loss contributes to neurological symptoms in disorders as diverse as multiple sclerosis, stroke, traumatic brain and spinal cord injury, peripheral neuropathies and chronic neurodegenerative diseases, but it has been largely neglected in neuroprotective strategies. Defects in axonal transport, myelination or oxygenation could trigger such mechanisms of active axon degeneration. Understanding how these diverse insults might initiate an axon-degeneration process could lead to new therapeutic interventions.

Comi, G. and L. Moiola (2002). "Glatiramer acetate." Neurologia 17(5): 244-58.

            Glatiramer acetate (GA) is a mixture of synthetic polypeptides composed of four aminoacids. GA is very effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Various mechanisms of action of GA have been proposed, but the most important is probably the induction of antigen-specific suppressor T cells. Class one clinical trials have demonstrated that GA reduces the relapse rate and the accumulation of disability in relapsing-remitting (RR) MS. The positive effects on disease activity and disease progression are explained by the reduction of the number and volume of the active lesions as showed by Magnetic resonance imaging (MRI) studies. Moreover new MRI techniques suggest that GA may also have some neuroprotective effects. The drug is usually well tolerated with modest side effects. In vitro and in vivo animal studies have shown that GA is devoid of teratogenic or mutagenic effects. GA is a good alternative to interferon beta for treatment of RR-MS.

Compston, A. and A. Coles (2002). "Multiple sclerosis." Lancet 359(9313): 1221-31.

            Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.

Compston, A. and S. Sawcer (2002). "Genetic analysis of multiple sclerosis." Curr Neurol Neurosci Rep 2(3): 259-66.

            The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.

Confavreux, C. and S. Vukusic (2002). "Natural history of multiple sclerosis: implications for counselling and therapy." Curr Opin Neurol 15(3): 257-66.

            Recent advances in our knowledge of the natural history of multiple sclerosis deal with the influence of pregnancy and vaccination, the predictive value of magnetic resonance imaging-based criteria in terms of activity and severity of the disease, and the weighting of the interplay between relapses and clinical progression. These advances have implications for counselling of patients and adjusting the classification of the disease course. Thus multiple sclerosis should be considered to be as much neurodegenerative as inflammatory and disease-modifying therapeutic strategies should be reconsidered by focusing on protection and repair of the nervous system.

Cook, S. D. (2002). "Multiple sclerosis." Adv Neurol 90: 135-44.

Cooper, G. S., F. W. Miller, et al. (2002). "Occupational exposures and autoimmune diseases." Int Immunopharmacol 2(2-3): 303-13.

            Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.

Corbaton Anchuelo, A., M. Mesa Del Castillo Paya, et al. (2002). "[Multiple sclerosis and ulcerative colitis: 'incidental concurrence or related diseases?]." Med Clin (Barc) 118(10): 397-8.

Correale, J. and M. de los Milagros Bassani Molinas (2002). "Oligoclonal bands and antibody responses in multiple sclerosis." J Neurol 249(4): 375-89.

            Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System with multifocal areas of demyelination. Although its etiology and pathogenesis remain controversial, several lines of evidence indicate that MS is mediated by a misdirected immune response against one or several myelin proteins. The involvement of diverse leukocyte subsets and their products in MS is still the subject of considerable debate. The emphasis on T cells has derived mainly from the detection of activated T cells in MS plaques and analogies with animal models of MS. Because of these observations cell-mediated immunity has dominated the research field of MS to this day. However, in recent years the role of B cells, plasma cells and immunoglobulins in MS have been re-examined, and current findings indicate that humoral immunity also plays a major role in disease pathogenesis. B cells and their products could exert several potential effects during the course of MS. Firstly, autoantibodies against specific myelin antigens could mediate damage to myelin membranes. Secondly, some studies suggest that natural autoantibodies could enhance remyelination. Thirdly, antibodies directed against myelin components can participate in anti-idiotypic networks, which may regulate the course of MS. Increased intrathecal immunoglobulin synthesis reflected by raised IgG indices and an oligoclonal pattern is the most common abnormality detected in MS patients. The introduction of more sensitive procedures for protein detection has allowed demonstrating oligoclonal bands (OCBs) in up to 95 % of patients with clinically definite MS. Although the presence of OCBs in CSF of MS patients is now well established as a sensitive laboratory test to support the clinical diagnosis, OCBs may be present in other disorders, including those not directly related to infection or abnormal immune response. Nevertheless, the pathogenesis of OCBs in MS is still obscure, and despite extensive research their antigenic target(s) have yet to be established. Therefore, a critical task is to identify the specificity of such target(s), thus providing significant clues about MS etiology. For this purpose, novel molecular immunologic strategies have been recently developed to offer alternative approaches to identify putative antigens recognized by antibodies present in MS patients. The elucidation of the mechanisms and target(s) responsible for the onset of MS has obvious implications for the further development of specific therapies.

Coyle, P. K. and H. P. Hartung (2002). "Use of interferon beta in multiple sclerosis: rationale for early treatment and evidence for dose- and frequency-dependent effects on clinical response." Mult Scler 8(1): 2-9.

            The current approach to the use of interferon (IFN) beta in the treatment of multiple sclerosis (MS) is, in general, conservative. However, recent findings about early events in MS and data on dose-response relationships with IFN beta indicate that such an approach may be suboptimal. Four lines of evidence suggest that delays in the initiation of therapy with IFN beta may be detrimental: 1) axonal damage secondary to inflammation starts very early in the course of MS; 2) pathological events occurring early in MS are predictive of the future course of the disease; 3) inflammatory activity in relapsing MS is not confined to episodes of clinical impairment, but often starts before the first such episode and generally continues during remissions; and 4) the immune-mediated activity that underlies MS may become more difficult to control as the disease progresses. An early treatment strategy is also supported by data from two recently published clinical studies. In addition, preclinical and clinical results suggest that the beneficial effects of IFN may be dose- and frequency-dependent. Taken together, these findings indicate that treatment with IFN beta should be started as early as possible in the course of MS, and suggest that, in order to maximize patent benefit, the highest possible dose of IFN beta should be chosen.

Curatolo, P., M. Verdecchia, et al. (2002). "Tuberous sclerosis complex: a review of neurological aspects." Eur J Paediatr Neurol 6(1): 15-23.

            Tuberous sclerosis complex is characterized by hamartomatous lesions involving skin, brain, kidneys, eyes and heart. Pathologically, tuberous sclerosis is a disorder of cell migration, proliferation and differentiation. Cell lineage and cell migration disorders in the developing cortex of tuberous sclerosis complex patients might produce very different neurological phenotypes including epilepsy, cognitive impairment and autism. Cortical tubers constitute the hallmark of the disease and are pathognomonic of cerebral tuberous sclerosis. Epilepsy is the most common neurological feature, occurring in 96% of patients. Seizures often begin in the first months of life and are frequently severe and intractable. The treatment of seizures has recently benefited from the advent of the new anti-epileptic drugs. Selected drug-resistant patients with tuberous sclerosis complex could be considered for surgical treatment. Clear localization of the most active epileptogenic focus and the zone of the cortical abnormality may lead to tuberectomy and improved seizure control in selective drug-resistant patients. The finding of multiple areas of cerebral involvement should not automatically preclude epilepsy surgery in a child with intractable seizures and a well defined seizure origin.

Czlonkowska, A. and I. Sarzynska-Dlugosz (2002). "[Aims of neurorehabilitation]." Neurol Neurochir Pol 36 Suppl 1: 23-31.

            The aim of this article is to present basic problems of new neuro-rehabilitation, its purposes and methods. This paper shows the newest methods of kinezytherapy and drugs used in improving the rehabilitation process. Authors present interdisciplinary rehabilitation teams dealing with neurologically disabled patients. They also show short programs of rehabilitation in multiple sclerosis and in stroke patients. That diseases are very popular in main population and are one of the main cause of disability in adult people.

DasGupta, R. and C. J. Fowler (2002). "Sexual and urological dysfunction in multiple sclerosis: better understanding and improved therapies." Curr Opin Neurol 15(3): 271-8.

            The fundamental strategy in treating multiple sclerosis patients with unstable bladders involves a combination of suppressing urgency and ensuring effective urinary drainage. Anti-cholinergics remain the first-line treatment, but alternative therapies are undergoing clinical trials. With a range of new pro-erectile oral medications available, interest has grown in treatment of multiple sclerosis-related erectile failure. Female sexual dysfunction is also now gaining some attention, with new classification criteria and methods for assessing and treating these patients.

Davis, R. (2002). "Twenty-eight years of clinical experience with implantable neuroprostheses for various applications." Artif Organs 26(3): 280-3.

            Since 1973, the author has been implanting neural stimulators and later drug pumps to restore or improve motor function and modulate pain, spasticity, and seizures in patients with spinal cord and brain injury, cerebral palsy, stroke, and multiple sclerosis. During these 28 years, many physicians, biomedical engineers, and manufactures have realized worthwhile successes. Many lessons have been learned to improve operative techniques to ensure safety, low infection, and improved results for implant patients. The relationships between manufacturers and physicians have varied. Problems arise with patents, royalties, confidentiality, publishing, and liability insurance. There has been a need to patent ideas and intellectual properties; however, some of the patented concepts have been published previously but missed by the patent author and patent office. This has led to vigorous legal battles, consuming money with time delays, or resulting in surrendering worthwhile projects. There is a need for a responsible, independent appeals board to review these disputed patent claims. Then their findings should be admissible at the Patent Office and if necessary in court.

De Libero, G., A. Donda, et al. (2002). "A new aspect in glycolipid biology: glycosphingolipids as antigens recognized by T lymphocytes." Neurochem Res 27(7-8): 675-85.

            T cells may recognize a large variety of ligands with different chemical structures. Recently, glycosphingolipids have also been shown to stimulate human T lymphocytes. Recognition of glycosphingolipids is restricted by the nonpolymorphic CD1 molecules, expressed by professional antigen-presenting cells and by macrophages infiltrating inflammatory sites. CD1 molecules have a structure resembling that of classical MHC class I molecules, with the terminal extracellular domains characterized by two antiparallel alpha helices placed on two hydrophobic pockets. The glycosphingolipids bound to CD1 insert the lipid tails in the two pockets and position the hydrophilic head on the external part of CD1. The TCR interacts with aminoacids present in the two alpha helices and with residues provided by the carbohydrate moiety of glycosphingolipids and discriminates their structural variations. T cells recognizing self-glycosphingolipids release proinflammatory cytokines and may have a pathogenetic role in autoimmune diseases such as multiple sclerosis.

Delgado, M., C. Abad, et al. (2002). "Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases." J Mol Med 80(1): 16-24.

            Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.

Derksen, R. H. and J. W. Bijlsma (2002). "[The treatment of chronic inflammatory diseases with monoclonal antibodies against tumor necrosis factor: side effects, contraindications and precautions]." Ned Tijdschr Geneeskd 146(25): 1165-8.

            Monoclonal antibodies are increasingly used to modulate immunologically mediated diseases such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, Crohn's disease, multiple sclerosis and systemic vasculitis. Constructs of monoclonal antibodies to tumour necrosis factor (TNF) alpha differ with respect to their structure, effects and immunogenic side effects. Clinical experience with TNF alpha-neutralizing therapy has revealed several other side effects over the past few years. The most important is increased infection rates, especially the activation of (latent) tuberculosis, although other opportunistic infections such as listeriosis, Pneumocystis carinii pneumonia, histoplasmosis, candidiasis and aspergillosis have also been reported. Furthermore, results from clinical studies indicate that TNF alpha-neutralizing therapy should not be given to patients with cardiac failure (NYHA class III or IV) or a history of demyelinating disease. An increased incidence of malignancies has not been observed up to now, but data from the long-term follow-up are not yet available.

DeSousa, E. A., R. H. Albert, et al. (2002). "Cognitive impairments in multiple sclerosis: a review." Am J Alzheimers Dis Other Demen 17(1): 23-9.

            Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Cognitive impairment (CI) may develop at any time during the course of the disease in the presence or absence of neurological disability. On the basis of comprehensive neuropsychological studies, there is now a consensus among investigators that 45 percent to 65 percent of MS patients suffer from some degree and form of cognitive difficulty. Features of CI include bradyphrenia; impaired attention, concentration and abstract reasoning; reduced manual speed and dexterity; deficits in memory retrieval; and language deficits in both the relapsing-remitting and progressive forms of MS. Impairments in all cognitive domains may result from the diffuse spread of microscopic pathology, although a preferential lobar distribution of plaques can present with a predominant deficit in the corresponding cognitive function. Nevertheless, the severity of CI best correlates with total microscopic and macroscopic disease burden of the brain as defined by recently developed magnetic resonance imaging (MRI) sequences. A disruption of connecting intercortical and subcortical pathways is likely to be the main cause of metabolic and functional abnormalities in neurons. However a direct toxic effect of soluble inflammatory products may also compromise neuronal function and survival. Early treatment of MS with interferons and copaxone can prevent or delay the onset of both neurological and cognitive disabilities by reducing the inflammatory activity and damage in the CNS. Until more powerful neuroprotective agents become available, simple neuropsychological screening and cognitive rehabilitation for memory and language impairments will remain important components in the care of MS patients.

Dessa Sadovnick, A. (2002). "The genetics of multiple sclerosis." Clin Neurol Neurosurg 104(3): 199-202.

Deuschl, G. and P. Bain (2002). "Deep brain stimulation for tremor [correction of trauma]: patient selection and evaluation." Mov Disord 17 Suppl 3: S102-11.

            The selection of patients with movement disorders for deep brain stimulation is becoming a common neurological and neurosurgical task. Deep brain stimulation is suitable for different forms of tremor, which can often not be treated with medication. This suitability applies for essential tremor, monosymptomatic tremor at rest, cerebellar or multiple sclerosis tremor, Holmes' tremor, primary writing tremor or tremor in neuropathies. The appropriate selection of patients is critical for the outcome of surgical relief of tremors. Considering the risks of any stereotactic intervention, the following must apply: (1) motor symptoms lead to a relevant disability in activities of daily living, despite optimal medical treatment; (2) biological age of the patient; (3) neurosurgical contraindications; (4) the patient is neither demented nor severely depressed. If these conditions are fulfilled, the individual chances of improvement of the target symptoms need to be checked, based on the following guidelines: (1) the kind of tremor, (2) the natural course of the tremor, (3) the chances for medical treatment in a particular patient, (4) the outcome of surgery in a specific condition, (5) the individual risks for a patient to suffer from complications. The outcome of surgery for tremor depends on the clinical type and distribution. Distal limb tremors are easier to treat than proximal limb tremors. Intention tremor is more difficult to treat than rest or postural tremor. The indication for surgical treatment depends on the analysis of the individual risk-benefit ratio, which also has to take into account the patients' social, professional, and familial background. The patient needs to be well informed about his individual risk-benefit ratio and of alternative treatments, before undergoing stereotactic surgery.

Dhib-Jalbut, S. (2002). "Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis." Neurology 58(8 Suppl 4): S3-9.

            MS is an immunologically mediated disease, as determined by observation of the response to immunotherapy and the existence of an animal model, experimental autoimmune encephalitis. Interferon (IFN) beta-1b, IFN beta-1a, and glatiramer acetate, the therapies used for relapsing or remitting MS, have mechanisms of action that address the immunologic pathophysiology of MS. The IFNs bind to cell surface-specific receptors, initiating a cascade of signaling pathways that end with the secretion of antiviral, antiproliferative, and immunomodulatory gene products. Glatiramer acetate, a synthetic molecule, inhibits the activation of myelin basic protein-reactive T cells and induces a T-cell repertoire characterized by anti-inflammatory effects. Although the two classes of drugs have some overlapping mechanisms of action, the IFNs rapidly block blood-brain barrier leakage and gadolinium (Gd) enhancement within 2 weeks, whereas glatiramer acetate produces less rapid resolution of Gd-enhanced MRI activity. IFN beta has no direct effects in the CNS, but glatiramer acetate-specific T cells are believed to have access to the CNS, where they can exert anti-inflammatory and possibly neuroprotective effects.

Di Majo, L., M. Bisceglia, et al. (2002). "Aphasia as a rare presentation of monosymptomatic demyelinating disease: case report and review of the literature." Neurol Sci 23(2): 79-82.

            We present a case of sudden-onset aphasia due to a single pathological lesion, which at neuroradiological imaging studies was suggestive of glioma, while on biopsy proved be of demyelinating nature. Every cause of demyelinating lesions of the central nervous system was considered in the differential diagnosis, concluding for a primary demyelinating disease. The clinical and radiological differences between multiple sclerosis and acute disseminated encephalomyelitis are discussed. Although aphasia has already been described in demyelinating diseases, we underline its rarity as onset symptom.

Dietrich, J. B. (2002). "The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier." J Neuroimmunol 128(1-2): 58-68.

            The blood-brain barrier (BBB) is formed by high resistance tight junctions within the capillary endothelium perfusing the vertebrate brain. Normal BBB maintains a unique microenvironment within the central nervous system (CNS). In neurodegenerative disorders (for example multiple sclerosis, MS), the BBB becomes impaired. Perivascular cells (astrocytes, macrophages and microglial cells) and brain microvascular endothelial cells (BMEC) produce various inflammatory factors that affect the BBB permeability and the expression of adhesion molecules. Indeed, cytokines can stimulate the expression of several adhesion molecules on brain microvascular endothelial cells. Among these adhesion molecules, the intercellular adhesion molecule-1 (ICAM-1) binds to its leukocyte ligands and allows activated leukocytes entry into the CNS.This review is dealing with the expression and regulation of ICAM-1 in relation with several properties of the BBB. Particularly, the role of ICAM-1 in the control of the leukocyte traffic into the CNS, as well as in cerebral malaria and in CNS infection by viruses, is discussed.

Domanska-Janik, K. (2002). "[Stem cells--potential therapeutic use in neurological diseases]." Neurol Neurochir Pol 36 Suppl 1: 107-17.

            There is a growing interest in medical potential of stem cells which may be used someday to create new tissue. Suggested applications involve a board spectrum ranging from the replacement for cells destroyed by diseases to even organ transplants. As ethical and legal controversy makes uncertain the future of embryonic stem cells research, attention has been recently turned to adult stem cells to discover whether they also can serve to transplantation. In this article we present data indicating that adult stem cells found in areas of the body like blood, skin, lymph and nervous systems, may be more versatile than previously assumed and in certain conditions can broke tissue barriers for differentiation. Thus, in this respect they can behave like their own pluripotent ancestors, although underlying mechanisms for this phenomena are still not clear. Furthermore, the following issues are shortly discussed: What are the characteristics of the different stem cells and where they can be found. What are experimental evidences that stem cells can be used for brain repair. What are the main problems must be solved before their clinical application and the risk-benefit assessment. The possible strategies and targets for stem cell therapies of neurological diseases.

du Haut Champ, A. M. (2002). "[Immunoablation or otherwise followed by hematopoietic cell stem as intensive treatment of severe autoimmune diseases]." Ann Ital Med Int 17(1): 11-20.

            The treatment of severe autoimmune diseases has been recently revitalized by the increasing utilization of clinical interventions aimed at ablating/abrogating autoimmune lymphoid clones followed (but not in certain procedures) by transplantation of allogeneic, but also autologous, hematopoietic stem cells. Two different investigative avenues have paved the way to specific clinical studies. The first originates from the epochal murine experiments of the '70s, and has been greatly expanded in the last decade. A graft-versus-autoimmunity effect could also be demonstrated. In addition, it could also be shown that induced experimental autoimmune diseases such as adjuvant arthritis and autoimmune encephalomyelitis could, surprisingly, be cured following autologous transplantation. The first results in humans were observational and derived from studies including patients with coincidental diseases (severe autoimmune diseases plus leukemia/aplasia) treated with allogeneic hematopoietic stem cell transplants. Although the concept of an allogeneic transplant is indisputably more appealing, very few patients with an isolated severe autoimmune disease have been treated using such a therapeutic approach. Reduced intensity conditioned transplants relying on subsequent graft-versus-autoimmunity effects strengthened by donor lymphocyte infusions are being explored cautiously. On the other hand, autologous transplants are being performed quite extensively. To date, transplanted severe autoimmune diseases include multiple sclerosis, connective tissue diseases (systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis) and many others. It is uncertain if the main mechanism is solely immunoablative, or whether tolerized lymphocytes may also develop during a postulated "window of opportunity" following the transplant.

Dufour, S. K. (2002). "An unusual case of stabbing eye pain: a case report and review of trigeminal neuralgia." Optometry 73(10): 626-34.

            BACKGROUND: Trigeminal neuralgia is a painful neurological disorder that affects one or more of the divisions of the trigeminal nerve. It is characterized by brief attacks of stabbing pain that can be excruciating. These attacks may be triggered by a light touch, shaving, or even eating. There has been much debate over the exact etiology of trigeminal neuralgia. One of the main theories is vascular compression of the trigeminal nerve as it leaves the brainstem. Another theory suggests that intracranial tumors--particularly those located in the posterior fossa--may be the cause. Trigeminal neuralgia is also associated with multiple sclerosis. CASE REPORT AND REVIEW: A 79-year-old man came to the eye clinic with signs and symptoms consistent with trigeminal neuralgia involving the ophthalmic and maxillary divisions of the nerve. A neurological evaluation confirmed the diagnosis, and proper medical treatment was subsequently implemented to relieve his pain. CONCLUSION: Patients who manifest symptoms consistent with trigeminal neuralgia should be referred for a neurological evaluation, including MRI. With the proper medical and/or surgical treatment, the quality of life of these patients can increase dramatically.

Dumont, F. J. (2002). "IDEC-131. IDEC/Eisai." Curr Opin Investig Drugs 3(5): 725-34.

            IDEC, in collaboration with Eisai, is developing IDEC-131 (E6040), a humanized monoclonal antibody (mAb) against CD154, the ligand for CD40 also called CD40L or gp39, for the potential treatment of several autoimmune diseases. IDEC-131 is based on technology that IDEC licensed from Dartmouth Medical School where researchers demonstrated the biological effects of the anti-CD154 antibody in animal models of autoimmunity. In January 2001, phase II trials in psoriasis and idiopathic thrombocytopenic purpura (ITP) were initiated. By january 2002, a phase II trial in Crohn's disease was also ongoing. A pilot, multicenter, multiple-dose phase I trial in moderate-to-severe psoriasis was initiated in January 2001. This trial was ongoing in January 2002. IDEC, in collaboration with Dartmouth Medical School had also initiated a phase I trial in multiple sclerosis by March 1999. IDEC-131 was also previously being developed for systemic lupus ezythematosus (SLE), although no further development for this indication has been reported since the disclosure of disappointing phase II results in April 2000. Analysts at Morgan Stanley predicted in February 2002, that the product would be launched in 2005, with sales of US $25 million, rising to US $75 million in 2006.

Durelli, L. and G. Isoardo (2002). "High-dose intravenous immunoglobulin treatment of multiple sclerosis." Neurol Sci 23 Suppl 1: S39-48.

            A review of the pathological basis of multiple sclerosis is presented to see whether the many immunological effects if IVIg may exert some benefit and at what level. This is probably due to the wide spectrum of interactions between IVIg and the immune system, which are analyzed in this review. Macrophage Fc receptor saturation and block, anti-idiotypic effect, reduction of endothelial cell activation and superantigen-neutralizing antibodies are probably involved in the action of IVIg in dysimmune demyelinating diseases. Furthermore, IVIg promote remyelination in virus-induced experimental encephalomyelitis. Trials on IVIg in MS demonstrated a reduction of relapse rate (RR) and appearance of gadolinium-enhancing lesions on magnetic resonance imaging. Furthermore IvIg are regarded as a promising treatment to reduce RR in post-partum period. However, studies on secondary-progressive MS failed to demonstrate an IVIg effect on disability and IVIg failed to improve stabilized visual and motor deficits in two large trials.

Dyment, D. A. and G. C. Ebers (2002). "An array of sunshine in multiple sclerosis." N Engl J Med 347(18): 1445-7.

Elhofy, A., K. J. Kennedy, et al. (2002). "Regulation of experimental autoimmune encephalomyelitis by chemokines and chemokine receptors." Immunol Res 25(2): 167-75.

            Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS). Insights into the pathogenesis of this model may help scientists understand the human disease and aid in rational drug discovery. In this review we summarize the role of chemokines and chemokine receptors in disease pathogenesis and suggest a pathway of events that leads to demyelination and subsequent clinical disease manifestation.

Ernerudh, J., G. Berlin, et al. (2002). "The use of cell products for treatment of autoimmune neuroinflammatory diseases." Curr Med Chem 9(16): 1497-505.

            Cell products are live cells that are given to patients in order to replace or modify the function of missing or dysfunctional cells. Progress in technology and in the understanding of pathobiology may lead to the use of cell products in many areas. This review outlines the use of cell products in the treatment of autoimmune diseases, with focus on neuroinflammatory diseases like multiple sclerosis. Treatment of autoimmune diseases should be selective and specific in order to avoid serious side effects. To achieve this, T lymphocyte regulation has been in focus for several immunomodulatory regimens. One area of great interest is the use of T cell vaccination, when autologous attenuated auto-reactive T cells are given to patients in order to initiate a specific immune response to the pathogenic T cell populations. Phopheresis may be an immunomodulatory treatment related to T cell vaccination. Another promising area involves ex-vivo alteration of the cytokine profile of harmful auto-reactive T cells. This can be achieved by genetic manipulation or by certain cytokine stimulations. A subsequent adoptive cell transfer will, by homing mechanisms, lead to at site specific delivery of the cells, which will have a local down-regulatory effect on the inflammatory process. Although unsolved questions regarding doses, timing, optimal preparing conditions and mechanisms still remain, both T cell vaccination and adoptive transfer of ex-vivo manipulated cytokine secreting cells have proven successful for treatment of neuroinflammation in experimental models. T cell vaccination was shown to be feasible in patients with multiple sclerosis, however, otherwise the experience in humans so far is limited.

Esch, T., G. B. Stefano, et al. (2002). "The role of stress in neurodegenerative diseases and mental disorders." Neuroendocrinol Lett 23(3): 199-208.

            OBJECTIVE: Evidence for a connection between stress and selected neurodegenerative diseases as well as mental disorders is analyzed. Does stress cause or exacerbate related pathophysiological disease processes? METHOD: The stress phenomenon is illustrated and the impact of stress on the nervous system, neurodegenerative diseases, and mental disorders is examined. The connection between stress and the hippocampus - and its association with memory functions - is described. In particular, the pathophysiological significance of stress in Alzheimer's disease, multiple sclerosis, anxiety, depression, posttraumatic stress disorder, and schizophrenia is investigated. RESULTS: Stress plays a major role in various (patho)physiological processes associated with neurodegenerative diseases and mental disorders. In principle, stress has the potency to exert either ameliorating or detrimental effects. The specific outcome depends on multiple variables. However, the amount of stress experienced in relation to activated physiological processes that aim at successful coping and positive adjustments (i.e., stress response) most often is overwhelming - and may thus become detrimental in the long-term. Moreover, the hippocampus is sensitive to stress, and its involvement in neurodegeneration - in the course of stress-related disease processes - may account for severe clinical disabilities (e.g., memory loss). DISCUSSION/CONCLUSION: Stress has a major impact upon neurodegenerative diseases and mental disorders. It plays a significant role in susceptibility, progress, and actual outcome. Also, subjective or individual differences have to be taken into account. However, stress - especially 'adequate' acute stress (stress that is not overwhelming) - may even improve performance/biological functions and be beneficial in certain cases.

Fay, B. T. and M. L. Boninger (2002). "The science behind mobility devices for individuals with multiple sclerosis." Med Eng Phys 24(6): 375-83.

            There is a growing body of research related to prescription of mobility devices. This research enables clinicians and clients to make clinical decisions related to mobility based on sound research. Unfortunately, there is little research investigating appropriate prescriptions in degenerative disorders such as multiple sclerosis (MS). In this article we will review the literature on mobility devices in MS and how it can be used to assist with clinical decision-making considering the progressive nature of this condition. In addition, we will review other research not conducted on individuals with MS that is relevant to this population. Finally we will present a call for future research that should help address this critical area.

Feinstein, D. L., M. T. Heneka, et al. (2002). "Noradrenergic regulation of inflammatory gene expression in brain." Neurochem Int 41(5): 357-65.

            It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.

Fernandez, O. (2002). "Mechanisms and current treatments of urogenital dysfunction in multiple sclerosis." J Neurol 249(1): 1-8.

            The majority of patients with multiple sclerosis (MS) suffer from lower urinary tract symptoms and sexual dysfunction at some stage of the disease. This has a negative impact on the quality of life of patients as well as causing concern to caregivers and family. Neurologists can now treat most of these symptoms by a number of pharmacological and nonpharmacological methods. This review presents the neuroanatomy, neurophysiology, neuropharmacology and pathophysiology of the urinary bladder and sexual organs, and the biological mechanisms underlying urogenital dysfunction in MS patients. Current treatment options for urinary and sexual dysfunction are reviewed. As most urogenital symptoms of MS can now be treated by conservative means, expert urological or gynaecological consultation should be requested only if more aggressive diagnostic or therapeutic measures are needed.

Fernandez-Munoz, R. and M. Celma-Serrat (2002). "[Virus and demyelination: why suspect that a virus may be involved in the aetiology of multiple sclerosis?]." Rev Neurol 35(10): 964-72.

            INTRODUCTION: Epidemiological data indicate that environmental factors, possibly infections, are associated with the development of multiple sclerosis. Different viruses are known to produce demyelination in natural and experimental animal infections. In humans some virus cause acute or chronic diseases that course with central nervous system demyelination. A series of virus have been claimed to be etiological agents of multiple sclerosis, although a causal role for any of them has so far been demonstrated. METHOD: The mechanisms of viral demyelination are diverse,ranging from direct destruction of infected oligodendrocytes to triggering autoimmune responses without virus multiplication in target cells. The potential indirect mechanisms of viral demyelination and the heterogeneous histopathology shown in multiple sclerosis patients, suggesting an heterogeneus etiology, might explain why not a single virus has been as yet identified as the cause of this disease. CONCLUSIONS: Viral infections that cause demyelination in animals and humans are briefly reviewed, focusing on the potential myelin destruction mechanisms and obstacles to the identifying viruses that might cause multiple sclerosis.

Fernandez-Ruiz, J., I. Lastres-Becker, et al. (2002). "Endocannabinoids and basal ganglia functionality." Prostaglandins Leukot Essent Fatty Acids 66(2-3): 257-67.

            In recent years, our knowledge on the cannabinoid pharmacology has shown a significant rise in terms of both quantity (more compounds and more targets) and quality (more selective compounds). This allows to consider cannabinoids and related compounds as a promising new line of research for therapeutic treatment of a variety of conditions, such as brain injury, chronic pain, glaucoma, asthma, cancer and AIDS-associated effects and other pathologies. Motor disorders are another promising field for the therapeutic application of cannabinoid-related compounds, since the control of movement is one of the more relevant physiological roles of the endocannabinoid transmission in the brain. There are two pathologies, Parkinson's disease and Huntington's chorea, which are particularly interesting from a clinical point of view due to the direct relationship of endocannabinoids and their receptors with neurons that degenerate in those disorders. However, other neurological pathologies, such as Alzheimer's disease or multiple sclerosis, which are not motor disorders in origin, but present a strong alteration in the control of movement, have also been a subject of interesting research for a cannabinoid therapy. This review will summarize our current knowledge on the role of these endogenous substances in the control of movement and, in particular, on the possible therapeutic usefulness of these compounds in the treatment of motor pathologies.

Filippi, M. (2002). "The role of magnetic resonance imaging in the assessment of patients with established multiple sclerosis." Neurol Sci 23(3): 89-90.

Filippi, M., V. Dousset, et al. (2002). "Role of magnetic resonance imaging in the diagnosis and monitoring of multiple sclerosis: consensus report of the White Matter Study Group." J Magn Reson Imaging 15(5): 499-504.

            On June 24-26, 2001, the first meeting of the White Matter Study Group (WMSG) of the International Society for Magnetic Resonance in Medicine (ISMRM) was held in Bordeaux, France. This paper is the report of the consensus reached among the delegates of the meeting on how to use magnetic resonance imaging (MRI) to make an early diagnosis of multiple sclerosis (MS), to measure MS activity accurately and reliably, and to monitor the effect of treatment on disease evolution.

Filippi, M. and R. I. Grossman (2002). "MRI techniques to monitor MS evolution: the present and the future." Neurology 58(8): 1147-53.

            Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS. Measures commonly derived from cMRI include T2 lesions, T1-enhanced lesions, atrophy, and possibly T1-hypointense lesions, which have been extensively investigated in many clinical trials. Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials. This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that 1) metrics derived from magnetization transfer MRI, diffusion-weighted MRI, and proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology; 2) targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials; and 3) reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials.

Filippi, M., M. A. Rocca, et al. (2002). "Clinical trials and clinical practice in multiple sclerosis: conventional and emerging magnetic resonance imaging technologies." Curr Neurol Neurosci Rep 2(3): 267-76.

            Conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and as a paraclinical tool to monitor disease activity and evolution in natural history studies and clinical trials. However, the correlation between cMRI and clinical findings is far from strict, and such a discrepancy is even more evident when moving from the setting of large-scale studies to the management of individual patients. Among the reasons for this "clinical-MRI paradox" is the limited specificity of cMRI to the heterogeneous pathologic substrates of MS and its inability to quantify the extent of damage in the normal-appearing tissues. Modern quantitative MR techniques have the potential to overcome some of the limitations of cMRI. Although the application of modern MR techniques is changing dramatically our understanding of how MS causes irreversible disability, their use for clinical trial monitoring and clinical practice is still very limited. Whereas there is increasing perception that modern quantitative MR techniques should be more extensively employed in clinical trials to advance the understanding of MS and derive innovative information, their use in clinical practice should still be regarded as premature.

Filippi, M., C. Tortorella, et al. (2002). "Magnetic resonance imaging of multiple sclerosis." J Neuroimaging 12(4): 289-301.

            Although conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and monitoring disease activity and evolution, the correlation between cMRI and clinical findings is far from strict. Among the reasons for this "clinical-MRI paradox," a major role has been attributed to the limited specificity of cMRI to the heterogeneous pathological substrates of MS and to its inability to quantify the extent of damage in the normal-appearing tissue. Modern quantitative MRI techniques have the potential to overcome some of the limitations of cMRI. Metrics derived from magnetization transfer and diffusion-weighted MRI enable one to quantify the extent of structural changes occurring within and outside macroscopic MS lesions with increased pathological specificity over cMRI. Magnetic resonance spectroscopy can add information on the biochemical nature of such changes, with the potential to improve significantly our ability to monitor inflammatory demyelination and axonal injury. Finally, functional MRI might provide new insights into the role of cortical adaptive changes in limiting the clinical consequences of white-matter structural damage. This review outlines the major contributions given by MRI-based techniques to the diagnostic work-up of MS patients, to the understanding of the pathobiology of the disease, and to the assessment of the effects of new experimental treatments.

Fiske, J., J. Griffiths, et al. (2002). "Multiple sclerosis and oral care." Dent Update 29(6): 273-83.

            Multiple sclerosis is a complex neurological condition affecting sensory and motor nerve transmission. Its progression and symptoms are unpredictable and vary from person to person as well as over time. Common early symptoms include visual disturbances, facial pain or trigeminal neuralgia and paraesthesia or numbness of feet, legs, hands and arms. These, plus symptoms of spasticity, spasms, tremor, fatigue, depression and progressive disability, impact on the individual's ability to maintain oral health, cope with dental treatment and access dental services. Also, many of the medications used in the symptomatic management of the condition have the potential to cause dry mouth and associated oral disease. There is no cure for multiple sclerosis, and treatment focuses on prevention of disability and maintenance of quality of life. Increasingly a multi-disciplinary team approach is used where the individual, if appropriate his/her carer, and the specialist nurse are key figures. The dental team plays an essential role in ensuring that oral health impacts positively on general health.

Foxman, B. (2002). "Epidemiology of urinary tract infections: incidence, morbidity, and economi