A patient with a benign course of neuromyelitis optica (Devic's syndrome) over 12 years: MRI follow up and histological findings.
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Adult↗
Biomedical subjects
B C Kieseier
Publications and source records attributed to B C Kieseier.
[Revision of McDonald's new diagnostic criteria for multiple sclerosis].
In 2001, an international panel suggested new diagnostic criteria for multiple sclerosis (MS). These criteria integrate clinical, imaging (MRI), and paraclinical results in order to facilitate diagnosis. Since then, these so-called McDonald criteria have been broadly accepted and widely propagated. In the meantime a number of publications have dealt with the sensitivity and specificity for MS diagnosis and with implementing these new criteria in clinical practice. Based on these empirical values and newer data on MS, an international expert group recently proposed a revision of the criteria. Substantial changes affect (1) MRI criteria for the dissemination of lesions over time, (2) the role of spinal cord lesions in the MRI and (3) diagnosis of primary progressive MS. In this article we present recent experiences with the McDonald and revised criteria.
Adult↗
[Statins for treatment of CNS diseases. Status report from research and clinical practice].
3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, "statins," are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.
Biomedical Research↗
[Acute disseminated encephalomyelitis. Pathogenesis, diagnosis, treatment, and prognosis].
Acute disseminated encephalomyelitis (ADEM) is typically a monophasic, demyelinating disease of the CNS that predominantly affects children. Typically, its clinical symptoms follow an infection or vaccination. In this regard, numerous viral and bacterial pathogens as well as several vaccinations have been associated with ADEM. Studies from animal models suggest that primary and secondary autoimmune responses may contribute to CNS inflammation and demyelination in ADEM. The diagnosis of ADEM is strongly suggested by a close temporal relationship between a viral infection or immunization and the onset of neurologic symptoms, and it is supported by extensive, multifocal, subcortical white-matter disease on brain magnetic resonance imaging. While mild lymphocytic pleocytosis and elevated proteins are detectable in the CSF in ADEM, oligoclonal bands are not always present. Treatment of this disorder consists of anti-inflammatory and immunosuppressive therapies, and the prognosis is generally considered favorable.
Animals↗
[Blocking adhesion molecules with natalizumab in multiple sclerosis].
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.
Antibodies, Monoclonal↗
The pentapeptide QYNAD does not inhibit neuronal network activity.
BACKGROUND: Controversial data was published about the sodium channel-blocking effect of the endogenous pentapeptide QYNAD, which is elevated in patients with multiple sclerosis and Guillain-Barré-syndrome. In some experiments with single cells and nerve preparations QYNAD inhibited sodium currents to the same extent as the known sodium channel blocker lidocaine whereas in other laboratory testing QYNAD failed to show any effect at all. METHODS: Micro-electrode arrays with cultured neuronal networks are highly suitable to determine neuroactive activity of applied substances. The impact on electrophysiological parameter changes was compared between QYNAD and the established sodium channel blockers lidocaine and tetrodotoxin (TTX). RESULTS: QYNAD did not alter network activity whereas the sodium channel blockers lidocaine (IC50 14.9 micorM) and tetrodotoxin (IC50 1.1 nM) reversibly decreased network activity in similar concentrations as in patch-clamp experiments. This decrease of spontaneous electrophysiological activity was achieved by prolonging the interburst-interval. CONCLUSION: Although QYNAD might have mild effects on single-cell sodium currents, there is no significant effect on neuronal network function. These results raise concerns about QYNAD exhibiting a relevant impact on functional disability of the central nervous system in patients.
Animals↗
[Jean-Martin Charcot in German neurology].
Jean-Martin Charcot (1825-1893), well known as the founder of modern neurology, was the most celebrated neurologist in the nineteenth century. His international success stemmed not only from mastery descriptions of various neurological disorders but also from his many contacts with scientists all over the world. The aim of this article is to review Charcot's ambivalent relationship to German neuropsychiatry of the time and to examine the German reception of his personality and work. Wilhelm Erb, Ludwig Hirt, Ernst von Leyden, Max Nonne, Adolph Strümpell, and other German physicians cultivated -to varying degrees - professional contacts with Charcot and, based on the fascination of his personality and significance of his work, were long and intensively influenced by the Salpêtrière school. The extent of their admiration became apparent in 1882 by the award of an honorary doctorate to Charcot by the University of Würzburg. Along with increasingly severe criticism of Charcot's research on hysteria and hypnosis, most German neuropsychiatrists became estranged, without neglecting his importance to the development of neurology in Germany.
France↗
[Multiple sclerosis: potential therapeutic options and update of ongoing studies].
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.
Adjuvants, Immunologic↗
[Acute and chronic inflammatory neuropathies--therapy].
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Adrenal Cortex Hormones↗
[Acute and chronic inflammatory neuropathies--diagnosis].
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Diagnosis, Differential↗
[Chronic inflammatory demyelinating polyneuropathy].
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated disease of the peripheral nervous system with a prevalence of 1-2/100,000. Clinical and experimental findings suggest a role of immune pathomechanisms;however, the target antigens are still unknown. Beside classic CIDP with symmetrical proximal and distal paresis, subgroups of CIDP with pure motor or sensory deficits have been described. Diagnostic criteria include evidence of demyelination in electrophysiological examination and biopsy as well as elevated protein content in the CSF. Magnetic resonance imaging of plexuses and roots extends the diagnostic armamentarium and may be helpful in differential diagnosis. The utility of immunosuppressant/immunomodulatory therapies has been demonstrated in several studies.
Autoantigens↗
[Cholesterol-reducing medications-a new therapeutic option for multiple sclerosis? Statins as immunomodulators].
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.
Adjuvants, Immunologic↗
[Mitoxanthrone in the therapy of multiple sclerosis].
The recent publication of the MIMS study (Mitoxantrone in multiple sclerosis), approval by local health authorities, and the recommendation by the MS Therapy Consensus Group (MSTCG) support the use of mitoxantrone in patients with active multiple sclerosis. This review provides an outline of relevant preclinical and clinical studies, discusses relevant side effects of the compound, and compares its use with other therapeutic approaches to this crippling disorder.
Animals↗
Statins as immunomodulators: comparison with interferon-beta 1b in MS.
BACKGROUND: Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate the potential role of statins as immunomodulators in MS, the authors studied their immunologic effects in vitro and compared them to interferon (IFN)beta-1b. METHODS: Peripheral blood mononuclear cells (PBMC) obtained from untreated or IFN beta-1-treated patients with relapsing-remitting MS or from healthy donors (HD) and T cells were stimulated with concanavalin A, phytohemagglutinin, or antibody to CD3 in the presence of lovastatin, simvastatin, mevastatin, IFN beta-1b, or statins plus IFN beta-1b. The authors analyzed proliferative activity of T cells and B cells, cytokine production and release, activity of matrix metalloproteinases (MMP), and surface expression of activation markers, adhesion molecules, and chemokine receptors on both T and B cells. RESULTS: All three statins inhibited proliferation of stimulated PBMC in a dose-dependent manner, with simvastatin being the most potent, followed by lovastatin and mevastatin. IFN beta-1b showed a similar effect; statins and IFN beta-1b together added their inhibitory potentials. Furthermore, statins reduced the expression of activation-induced adhesion molecules on T cells, modified the T helper 1/T helper 2 cytokine balance, reduced MMP-9, and downregulated chemokine receptors on both B and T cells. Besides strong anti-inflammatory properties, statins also exhibited some proinflammatory effects. CONCLUSIONS: Statins are effective immunomodulators in vitro that merit evaluation as treatment for MS.
Adjuvants, Immunologic↗
TACE mRNA expression in peripheral mononudear cells precedes new lesions on MRI in multiple sclerosis.
Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of multiple sclerosis (MS). It has to be released from its cell membrane-bound precursor by proteolytic cleavage. This is mainly performed by a member of the ADAM (a disintegrin and metalloproteinase) family of enzymes, TNF-alpha-converting enzyme (TACE, ADAM 17). In a longitudinal study on 11 relapsing-remitting MS patients, we qualitatively determined mRNA expression of TNF-alpha and TACE in peripheral blood mononuclear cells (PBMCs) without ex vivo stimulation. mRNA expression was related to disease activity as assessed by monthly gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI). Patients found positive for TACE mRNA in PBMCs showed a significantly higher mean number of new Gd-enhancing lesions per scan one month following PBMC sampling.
ADAM Proteins↗
Expression and distribution of transcription factor NF-kappaB and inhibitor IkappaB in the inflamed peripheral nervous system.
The NF-kappaB family of transcription factors is critically involved in the immune response. The activity of these proteins is under strict control of an inhibitory molecule called IkappaB. The present study investigated the expression and distribution pattern of NF-kappaB and IkappaB in sural nerve biopsies obtained from patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and various non-inflammatory neuropathies. In inflammatory demyelinating as well as non-inflammatory neuropathies, NF-kappaB was primarily expressed by macrophages, as determined by immunohistochemistry. IkappaB, however, could be localized to macrophages as well as T cells in inflammatory demyelinating neuropathies, whereas in non-inflammatory controls Schwann cells were found to be the primary cell type expressing this inhibitor. Quantitation of immunoreactivity revealed a statistically significant increase of NF-kappaB expression in inflammatory demyelinating cases compared to controls. Our results suggest an important function of the NF-kappaB pool in the genesis of inflammatory demyelination in the peripheral nervous system.
Guillain-Barre Syndrome↗
Schwann cell-specific regulation of IL-1 and IL-1Ra during EAN: possible relevance for immune regulation at paranodal regions.
We reported Schwann cell (SC)-specific autoregulation of IL-1 in vitro [J. Neuroimmunol. 74 (1997a)]. Whether SC resume this autoregulatory potential in vivo and what significance it may have for processes leading to inflammation and demyelination of the peripheral nerve remain obscure. Therefore, we examine SC-specific autoregulation of IL-1alpha, IL-1beta and their natural antagonist IL-1 receptor antagonist (IL-1Ra) during experimental autoimmune neuritis (EAN), a model for the human Guillain-Barre syndrome. Autoregulation of IL-1 by SC was analyzed in both, actively induced and adoptively transferred, EAN. Sciatic nerves were sampled before the onset of clinical signs, 2 to 11 days post immunization (dpi), with P2 peptide, and during clinically manifest disease, 11 to 15 dpi. In adoptively transferred EAN, sciatic nerves were analyzed at preclinical stage, 2 to 4 days post P2 peptide-specific cell transfer (dpt) and during clinical manifested phase, 5 to 10 dpt. In both models, IL-1alpha and IL-1beta were expressed by SC, during preclinical EAN. IL-1Ra was not detectable in SC at preclinical stage. Further development and progression to clinically manifest disease was accompanied by SC-specific expression of IL-1Ra. Although present in other cells in the nerve, IL-1alpha and IL-1beta were hardly detectable in SC during clinical EAN. IL-1Ra immunoreactivity highly co-localized with myelin associated glycoprotein (MAG), one of the markers for paranodal regions, sites essential for proper impulse transmission. Paranodes are also primary sites where activated macrophages make contact with SC, prior to infiltration.SC-specific autoregulation of IL-1 and IL-1Ra is suggestive of its relevance for immune regulation at paranodes during EAN.
Animals↗
The role of macrophages in immune-mediated damage to the peripheral nervous system.
Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating polyneuropathies, including the demyelinating form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. Macrophages serve a multitude of functions throughout the entire pathogenetic process of autoimmune neuropathy. Resident endoneurial macrophages are likely to act as local antigen-presenting cells by their capability to express major histocompatibility complex antigens and costimulatory B7-molecules, and may thus be critical in triggering the autoimmune process. Hematogenous infiltrating macrophages then find their way into the peripheral nerve together with T-cells by the concerted action of adhesion molecules, matrix metalloproteases and chemotactic signals. Within the nerve, macrophages regulate inflammation by secreting several pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-alpha. Autoantibodies are likely to guide macrophages towards their myelin or primarily axonal targets, which then attack in a complement-dependent and receptor-mediated manner. In addition, non-specific tissue damage occurs through the secretion of toxic mediators and cytokines. Later, macrophages contribute to the termination of inflammation by promoting T-cell apoptosis and expressing anti-inflammatory cytokines including TGF-beta1 and IL-10. During recovery, they are tightly involved in allowing Schwann cell proliferation, remyelination and axonal regeneration to proceed. Macrophages, thus, play dual roles in autoimmune neuropathy, being detrimental in attacking nervous tissue but also salutary, when aiding in the termination of the inflammatory process and the promotion of recovery.
Animals↗