Multiple Sclerosis: Wiendl H

Anonymous00013, Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. · Department of Neurology and Clinical Research, Unit for MS and Neuroimmunology, University of Würzburg, Würzburg, Germany. · J Neurol. · Pubmed #19005625 No free full text.

Abstract: This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

Hohlfeld R, Wiendl H. · No affiliation provided · Ann Neurol. · Pubmed #11261499 No free full text.

This publication has no abstract.

Meuth SG, Kleinschnitz C, Wiendl H. · Universität Würzburg, Klinik und Poliklinik für Neurologie, Josef-Schneider Str. 11, 97080 Würzburg, Germany. · J Neurol. · Pubmed #19300967 No free full text.

Abstract: Immunotherapy for multiple sclerosis (MS) has developed extremely successfully during the past decade and a number of new strategies were developed for the treatment of the disease. Examples include therapeutic strategies targeting leukocyte differentiation molecules, costimulatory molecules, anti-adhesion molecules, chemotaxis, novel immunomodulators, autologous stem cell transplantation, anti-infectious therapies and strategies for neuroprotection, neurorepair and remyelination. Here we describe examples of monoclonal antibodies, a novel immunosuppressant and interesting neuroprotective strategies.

Kieseier BC, Wiendl H, Leussink VI, Stüve O. · Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany. · J Neurol. · Pubmed #19300955 No free full text.

Abstract: Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults. The mainstays in the immunomodulatory therapy of MS are currently interferon beta and glatiramer acetate, both of which have proven to be clinically and paraclinically effective. Current clinical evidence indicates that treatment should be initiated as early as possible. In this review we summarize available data from clinical studies on clinical efficacy of immunomodulatory drugs for treating patients with multiple sclerosis.

Wiendl H, Hohlfeld R. · Department of Neurology, Julius-Maximilians-University Würzburg, Würzburg, Germany. · Neurology. · Pubmed #19289741 No free full text.

Abstract: In this essay, we draw attention to some recent downsides and surprises of multiple sclerosis (MS) therapeutics. These include experiences with recent head-to-head trials of interferon-beta and glatiramer acetate, dose escalation trials, frustrating efforts with progressive MS trials, failures of smart concepts and designer therapies, and harsh lessons from newly observed adverse reactions.

Meuth SG, Melzer N, Kleinschnitz C, Budde T, Wiendl H. · Klinik für Neurologie, Klinische Forschungsgruppe für Neuroimmunologie, Julius-Maximilians-Universität, Würzburg, Germany. · Nervenarzt. · Pubmed #19011824 No free full text.

Abstract: Multiple sclerosis (MS) has traditionally been regarded as an inflammatory demyelinating disorder of the CNS in which clinical symptoms result from axon conduction block caused by myelin degradation. However, typical accumulation of permanent neurological deficits during the clinical course of MS cannot be explained solely by de- and remyelinating processes. It is considered to be rather due to neuronal degeneration, for which several reasons could be identified depending on the state of the disease. First, neurons and their axons can be damaged by infiltrating lymphocytes and macrophages either directly by cell-to-cell contact or by the release of harmful mediators such as nitric oxide or glutamate. Second, indirect injury to neurons and axons may occur through the loss of trophic support by neighbouring oligodendrocytes due to destruction of both the myelin sheath and the oligodendrocyte itself. Third, redistribution of certain voltage- and ligand-gated ion channels and transporters along naked demyelinated axons restores axonal conduction but also leads to excessive spatially restricted electrical activity of the axonal membrane, intracellular calcium accumulation, impairment of mitochondrial function, and subsequent neuronal degeneration. The neuroprotective potential of pharmacological modulation of these channels and transporters using already approved drugs has been demonstrated in several animal studies, is the subject of current clinical trials and will be the topic of this review.

Sailer M, Fazekas F, Gass A, Kappos L, Radue EW, Rieckmann P, Toyka K, Wiendl H, Bendszus M. · Neurologische Universitätsklinik, Otto-von-Guericke-Universität, Magdeburg. · Rofo. · Pubmed #18937154 No free full text.

Abstract: PURPOSE: Magnetic resonance imaging (MRI) has become a valuable tool for diagnosing and monitoring multiple sclerosis (MS). The high sensitivity for the detection of hyperintense lesions in T 2-weighted scans contributes substantially to diagnosis. The initial lesion number or lesion volume stands for an increased probability of further accumulation of lesion burden, an earlier conversion to clinically definite MS and progression of disability in the next 5 - 15 years. This diagnostic and prognostic information gained from MRI early in the disease course lead in 2001 to a revision of the diagnostic criteria. MATERIALS AND METHODS: For the first time MRI criteria were defined in addition to the clinical and paraclinical criteria using the clinical terms for dissemination with respect to space and time. In particular, the defined MRI criteria are based on lesion number and location, the appearance of new lesions and lesion enhancement using contrast agent. RESULTS: Reliable detection and description of older and new lesions in the disease course by MRI represents subclinical disease activity which can substitute the clinical confirmation of a relapse leading to an earlier diagnosis. This places importance on the assessment of the subclinical disease activity in sequential MR scans requiring a standardized and reproducible approach to minimize variability despite different MR scanners. CONCLUSION: This review provides an updated proposal for the approach and management of cranial and spinal MR scans in patients with MS. We describe the influence of variables which cannot be standardized (scanner, field strength, manufacturer and software) and outline potential pitfalls of clinical MR imaging in MS resulting from a non-standardized approach. This updated proposal for slice positioning, sequences and documentation is a result of a consensus process targeting systematic and standardized use in clinical MR evaluations of MS.

Kleinschnitz C, Meuth SG, Wiendl H. · Department of Neurology, University of Wurzburg, Wurzburg, Germany. · Int MS J. · Pubmed #18808741 links to  free full text

Abstract: The development programme for novel therapies in multiple sclerosis (MS) has an impressive track record which is unique in the field of neurology, and has led to the approval of several drugs during the past decade. However, therapeutic prosperities face numerous trials that either failed to show efficacy or that had to be halted because of other reasons including adverse events. Moreover, certain treatment strategies are controversial, both for reasons of practicability and for their true clinical benefit. There are serious caveats that highly immunoselective approaches such as monoclonal antibodies can only be applied at the expense of an increased risk of acute or long-term adverse effects. This review focuses on the most important clinical trials on yet unlicensed compounds in relapsing-remitting and secondary-progressive MS which failed, were halted or are associated with significant adverse effects since 2002. Furthermore, we discuss the implications these experiences have for our current view of MS pathogenesis as well as future study design. Examples include agents that target leukocyte differentiation molecules, co-stimulatory molecules, adhesion molecules and chemotaxis, as well as novel immunomodulators and anti-infective therapies.

Zozulya AL, Wiendl H. · University of Würzburg, Department of Neurology, Würzburg, Germany. · Hum Immunol. · Pubmed #18723060 No free full text.

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of putative autoimmune origin. Recent evidence indicates that MS autoimmunity is linked to defects in regulatory T-cell function, which normally regulates immune responses to self-antigens and prevents autoimmune diseases. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have long been regarded as a CD4(+) T-cell-mediated autoimmune disease. Studies addressing the role of CD8(+) T cells, however, have only recently begun to emerge. Pathogenic function was attributed to CD8(+) T cells because of their abundant presence or oligoclonal repertoire within MS lesions. However, CD8(+) T cells appeared to have important regulatory functions, as demonstrated in EAE or human MS studies. We here review the contribution of CD8(+) T cells to inflammation and immune regulation in CNS autoimmunity. The knowledge of distinct CD8(+) T-cell populations exerting destructive versus beneficial functions is summarized. The long-term goal is to delineate the exact phenotypic and functional characteristics of regulatory CD8(+) T-cell populations (natural as well as inducible) in humans. This knowledge may help to further develop concepts of reconstituting or enhancing endogenous mechanisms of immune tolerance in future therapeutic concepts for MS.

Zozulya AL, Wiendl H. · Neurology Department, University of Würzburg, Würzburg, Germany. · Nat Clin Pract Neurol. · Pubmed #18578001 No free full text.

Abstract: The dysregulation of inflammatory responses and of immune self-tolerance is considered to be a key element in the autoreactive immune response in multiple sclerosis (MS). Regulatory T (T(REG)) cells have emerged as crucial players in the pathogenetic scenario of CNS autoimmune inflammation. Targeted deletion of T(REG) cells causes spontaneous autoimmune disease in mice, whereas augmentation of T(REG)-cell function can prevent the development of or alleviate variants of experimental autoimmune encephalomyelitis, the animal model of MS. Recent findings indicate that MS itself is also accompanied by dysfunction or impaired maturation of T(REG) cells. The development and function of T(REG) cells is closely linked to dendritic cells (DCs), which have a central role in the activation and reactivation of encephalitogenic cells in the CNS. DCs and T(REG) cells have an intimate bidirectional relationship, and, in combination with other factors and cell types, certain types of DCs are capable of inducing T(REG) cells. Consequently, T(REG) cells and DCs have been recognized as potential therapeutic targets in MS. This Review compiles the current knowledge on the role and function of various subsets of T(REG) cells in MS and experimental autoimmune encephalomyelitis. We also highlight the role of tolerogenic DCs and their bidirectional interaction with T(REG) cells during CNS autoimmunity.

Stüve O, Bennett JL, Hemmer B, Wiendl H, Racke MK, Bar-Or A, Hu W, Zivadinov R, Weber MS, Zamvil SS, Pacheco MF, Menge T, Hartung HP, Kieseier BC, Frohman EM. · Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, Texas 75216, USA. · Drugs. · Pubmed #18081373 No free full text.

Abstract: Currently, six medications are approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). In contrast, no pharmacological agent has proved to be effective in patients with secondary-progressive MS without relapses, or in patients with primary-progressive MS. One of the principal issues concerning an optimal pharmacotherapy for relapsing forms of MS is the optimal time of treatment initiation. There is now an almost universal consensus among MS experts that many patients will benefit from early therapy. However, several formidable challenges exist in identifying individuals who will benefit versus those who will do well without intervention. How do we define early MS and what clinical and paraclinical markers may be useful in defining the timing and nature of therapy? Do patients with a benign form of MS require therapy or are they exposed unnecessarily to adverse effects of our currently available medications? How do we identify disease progression and treatment failures? This review discusses these issues and outlines the evidence for application of 'early' treatment in patients with relapsing forms of MS.

Kleinschnitz C, Meuth SG, Stüve O, Kieseier B, Wiendl H. · Department of Neurology, Bayerische Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. · J Neurol. · Pubmed #18004638 No free full text.

Abstract: Six pharmacological agents are currently approved for the treatment of multiple sclerosis (MS).However, all established substances are only partially effective in reducing disease progression or relapse rates. In addition, they have potentially serious side effects. Thus, significant efforts are being made to develop new agents or to optimize current therapies. The latter includes modifications of dose, route of administration or the time point of treatment initiation. In this review, we provide an update on the most important clinical phase II/III trials on approved and novel immunotherapeutic strategies in MS reported during the last two years. Pharmacotherapies include agents that target chemoattraction, cell migration, chemotherapies, and antigen-based therapies.

Kleinschnitz C, Meuth SG, Kieseier BC, Wiendl H. · Neurologische Klinik und Poliklinik, Universitätsklinikum, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany. · Nervenarzt. · Pubmed #17551708 No free full text.

Abstract: Multiple sclerosis (MS) is a chronic disabling disease with significant implications for patients and society. The individual disease course is difficult to predict due to the heterogeneity of clinical presentation and of radiologic and pathologic findings. Although its etiology still remains unknown, the last decade has brought considerable understanding of the underlying pathophysiology of MS. In addition to its acceptance as a prototypic inflammatory autoimmune disorder, recent data reveal the importance of primary and secondary neurodegenerative mechanisms such as oligodendrocyte death, axonal loss, and ion channel dysfunction. The deepened understanding of its immunopathogenesis and the limited effectiveness of currently approved disease-modifying therapies have led to a tremendous number of trials investigating potential new drugs. Emerging treatments take into account the different immunopathological mechanisms and strategies, to protect against axonal damage and promote remyelination. This review provides a compilation of novel immunotherapeutic strategies and recently uncovered aspects of known immunotherapeutic agents. The pathogenetic rationale of these novel drugs for the treatment of MS and accompanying preclinical and clinical data are highlighted.

Kieseier BC, Wiendl H. · Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany. · CNS Drugs. · Pubmed #17521228 No free full text.

Abstract: Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the CNS. It is the most common cause of neurological disability in young adults and exhibits considerable clinical, radiological and pathological heterogeneity. Increased understanding of the immunopathological processes underlying this disease, advances in biotechnology and the development of powerful magnetic resonance imaging (MRI) technologies, together with improvements in clinical trial design, have led to a variety of valuable therapeutic approaches to MS. Therapy for MS has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing remitting and secondary progressive forms; however, most of the clinically relevant therapeutic approaches are not yet available as oral formulations. A substantial number of preliminary and pivotal reports have provided promising results for oral therapies, and various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. It is hoped that these trials will advance the development of oral therapies for MS.

Kieseier BC, Wiendl H, Hemmer B, Hartung HP. · Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany. · Curr Opin Neurol. · Pubmed #17495622 No free full text.

Abstract: PURPOSE OF REVIEW: This review focuses on advances in current and novel treatment approaches in multiple sclerosis. RECENT FINDINGS: New therapeutic approaches in multiple sclerosis are emerging. Orally available treatment strategies are more acceptable for patients and may improve adherence to therapy. An oral formulation of glatiramer acetate failed to demonstrate efficacy in a clinical trial, but other promising compounds are on the horizon, such as FTY720. Advances are currently being made in use of therapeutic monoclonal antibodies that specifically target key molecules involved in the immunopathogenesis of multiple sclerosis. Natalizumab directed against the adhesion molecule very late antigen-4 represents the first specific antibody to be added to our therapeutic armamentarium for multiple sclerosis. Further evidence that immunomodulation should be initiated as early as possible has been reported. SUMMARY: Treatment of multiple sclerosis has changed dramatically over the past decade. Enhanced understanding of the immunopathological processes that underlie the disease, advances in biotechnology and development of powerful magnetic resonance imaging technologies, together with improvements in clinical trial design have led to a variety of valuable therapeutic approaches, which are currently being studied in detail.

Kleinschnitz C, Meuth SG, Kieseier BC, Wiendl H. · Department of Neurology, Bayerische Julius-Maximilians-Universität Würzburg, Würzburg, Germany. · Endocr Metab Immune Disord Drug Targets. · Pubmed #17346203 No free full text.

Abstract: Multiple sclerosis (MS) is a chronic disabling disease with significant implications for patients and society. The individual disease course is difficult to predict due to the heterogeneity of clinical presentation as well as radiological and pathological findings. Although its etiology still remains unknown, the last decade has generated considerable success in understanding the underlying pathophysiology of MS. In addition to its view as a prototypic inflammatory autoimmune disorder, recent data support the importance of primary and secondary neurodegenerative mechanisms such as oligodendrocyte death, axonal loss and ion channel dysfunction. The deepened understanding of the immunopathogenesis as well as the limited effectiveness of the currently approved disease modifying therapies have led to a tremendous number of trials investigating potentially new drug targets. Emerging treatments take into account the different immunopathological mechanisms as well as strategies to protect against axonal damage or to promote remyelination. This review provides a compilation of novel immunotherapeutic strategies or new aspects of known immunotherapeutic agents which have evolved recently. The pathogenetic rationale of these novel drug targets for the treatment of MS as well as accompanying preclinical and clinical data are highlighted.

Kieseier BC, Wiendl H. · Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Duesseldorf, Germany. · Lancet Neurol. · Pubmed #16361006 No free full text.

This publication has no abstract.

Menge T, Hemmer B, Nessler S, Wiendl H, Neuhaus O, Hartung HP, Kieseier BC, Stüve O. · Department of Neurology, University of San Francisco, San Francisco, Calif, USA. · Arch Neurol. · Pubmed #16286539 links to  free full text

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

Trebst C, Wiendl H, Stangel M. · Neurologische Klinik, Medizinische Hochschule Hannover. · Nervenarzt. · Pubmed #16160810 No free full text.

Abstract: The pathogenesis and development of lesions in multiple sclerosis (MS) are still unexplained and are the subject of some controversy. On the basis of histopathological analysis of a small set of MS cases, a recently published study postulates primary oligodendroglial damage as the initiator of MS lesions, with infiltration of leukocytes into the central nervous system (CNS) as a secondary phenomenon. In this paper we outline the current controversial discussion and different concepts of lesion development in MS. We conclude that demyelination can result from different pathogenic mechanisms, with either primary autoimmune inflammation or primary oligodendroglial damage and a secondary inflammatory reaction. Lesions can be divided into four subtypes (patterns I-IV) on the basis of histopathological characteristics, which supports the idea that MS lesions develop in different ways. These new aspects may have major implications for treatment. However, except in a few specific forms, most MS patients cannot currently be assigned to one of these lesion subtypes by means of clinical and paraclinical parameters. Without this, individual treatments tailored to the pathogenesis will not be possible.

Schreiner B, Kieseier BC, Hartung HP, Hohlfeld R, Wiendl H. · Neurologische Klinik und Poliklinik der Julius-Maximilians-Universität Würzburg. · Nervenarzt. · Pubmed #15812675 No free full text.

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

Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Götschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freimüller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Brück W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, Jügelt E, Koehler J, Kölmel W, König N, Lowitzsch K, Manegold U, Melms A, Mertin J, Oschmann P, Petereit HF, Pette M, Pöhlau D, Pohl D, Poser S, Sailer M, Schmidt S, Schock G, Schulz M, Schwarz S, Seidel D, Sommer N, Stangel M, Stark E, Steinbrecher A, Tumani H, Voltz R, Weber F, Weinrich W, Weissert R, Wiendl H, Wiethölter H, Wildemann U, Zettl UK, Zipp F, Zschenderlein R, Izquierdo G, Kirjazovas A, Packauskas L, Miller D, Koncan Vracko B, Millers A, Orologas A, Panellus M, Sindic CJ, Bratic M, Svraka A, Vella NR, Stelmasiak Z, Selmaj K, Bartosik-Psujik H, Mitosek-Szewczyk K, Belniak E, Mochecka A, Bayas A, Chan A, Flachenecker P, Gold R, Kallmann B, Leussink V, Mäurer M, Ruprecht K, Stoll G, Weilbach FX, Anonymous00046. · Dept. of Neurology, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. · J Neurol. · Pubmed #15592728 No free full text.

Abstract: Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Leyhe T, Laske C, Buchkremer G, Wormstall H, Wiendl H. · Klinik für Psychiatrie und Psychotherapie der Universität Tübingen. · Nervenarzt. · Pubmed #15578150 No free full text.

Abstract: Cognitive impairment is meanwhile accepted as a well-known symptomatology affecting up to 60% of the patients even in the early disease course of multiple sclerosis (MS). After a longer duration the development of dementia is not unusual. However, cognitive dysfunction as the primary or only manifestation of MS is thought to be rare. We report on four elderly patients referred to the memory clinic of our psychiatric university hospital because of beginning dementia. All of them were found to have evidence of a chronic inflammatory CNS process compatible with the diagnosis of MS. At the beginning of their symptomatology all patients were older than 60 years . Just in one case, progressive gait disturbances beginning after cognitive decline contributed to restriction in the activities of daily living. Data of 239 cases of the literature were reviewed and revealed motor disturbances as the main initial symptom and often a primary progressive course with unfavourable prognosis in late onset MS. Until now dementia as the primary symptomatology has not been described in patients older than 60 years. Possibly MS as a differential diagnosis in dementia as well as cognitive impairment as an initial symptom of MS is under-recognized.

Wiendl H, Lehmann HC, Hohlfeld R, Hartung HP, Kieseier BC. · Abteilung für Allgemeine Neurologie und Hertie-Institut für Klinische Hirnforschung, Neurologische Klinik der Eberhard-Karls-Universität Tübingen. · Nervenarzt. · Pubmed #15257377 No free full text.

Abstract: The therapeutic options for the treatment of multiple sclerosis (MS) have experienced enormous progress over recent years. Despite these encouraging developments, available therapies are only partially effective, and the ultimate goal of curing MS is still far from being attained. The improved understanding of the cellular and molecular mechanisms of MS (immune) pathogenesis together with recent shifts in paradigms led to a variety of new therapeutic targets and approaches. In addition to modulation of the inflammatory process, therapeutic approaches focussing on active neuroprotection, remyelinization, and regeneration have become increasingly important. Based on current concepts of the MS pathogenesis, this article summarizes new therapeutic approaches. Substances and strategies currently tested in clinical trials are reviewed.

Neuhaus O, Wiendl H, Kieseier BC, Archelos JJ, Hartung HP. · Neurologische Universitätsklinik, Heinrich-Heine-Universität Düsseldorf. · Nervenarzt. · Pubmed #12904873 No free full text.

Abstract: Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is crucial for cholesterol biosynthesis, and are widely used as lipid-lowering agents. These drugs greatly reduce atherosclerosis and cardiovascular morbidity, which in the past was mainly attributed to their cholesterol-lowering properties. However, recent evidence suggests that statins are also potent immunomodulators. They exerted beneficial effects on animal models of experimental autoimmune encephalomyelitis and thus have therapeutic potential for multiple sclerosis. Their exact mechanism of action is still unclear. HMG-CoA-dependent effects and a direct effect on immune receptors are conceivable and are reviewed here.

Wiendl H, Kieseier BC. · Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany. · Expert Opin Investig Drugs. · Pubmed #12665424 No free full text.

Abstract: Multiple sclerosis (MS) is the prototype inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults exhibiting considerable clinical, radiological and pathological heterogeneity. Novel insights in the immunopathological processes, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design led to a variety of evaluable therapeutic approaches. Therapy has changed dramatically over the past decade, yielding significant progress for the treatment of relapsing-remitting and secondary progressive MS. A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of MS patients. This review summarises recent progress with currently available disease-modifying therapies and - on the basis of present immunopathogenetic concepts - outlines ongoing studies as well as future treatment strategies.