Bernd C Kieseier

Publications of Bernd C Kieseier

• Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany.

  Authors: Anke Stroet, Claudia Hemmelmann, Michaela Starck, Uwe Zettl, Jan Dörr, Friedmann Paul, Peter Flachenecker, Vinzenz Fleischer, Frauke Zipp, Holger Nückel, Bernd C Kieseier, Andreas Ziegler, Ralf Gold, Andrew Chan

  Therapeutic advances in neurological disorders. 03/2012; 5(2):75-9.

  Background: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed.Methods and results: In a retrospectiveBackground: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed.Methods and results: In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09-0.13%).Conclusions: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments.

• Ex vivo activation of naturally occurring IL-17-producing T cells does not require IL-6.

  Authors: Vsevolod Smolianov, Thomas Dehmel, Bernd C Kieseier, Bernhard Hemmer, Hans Peter Hartung, Harald H Hofstetter

  Cytokine. 02/2012; 58(2):231-7.

  Interleukin (IL-)17 is a potent proinflammatory cytokine for which an important role in the immune response against infections and in autoimmune diseases has been demonstrated. Recently, it has beenInterleukin (IL-)17 is a potent proinflammatory cytokine for which an important role in the immune response against infections and in autoimmune diseases has been demonstrated. Recently, it has been shown that - in addition to mature T cells which are primed in the immune periphery - this cytokine can also be produced by T cells in the thymus, so-called naturally occurring IL-17-producing T cells (nT17 cells). In this study we demonstrate that the generation and activation of nT17 cells in the thymus do not depend on the cytokine IL-6. In addition, nT17 cells are not regulated by IL-2. These properties of nT17 cells significantly differ from induced IL-17-producing T cells primed in the immune periphery (iT17 cells). Given the strong association of IL-17-producing T cells with immune responses against infections and human autoimmune diseases, closer characterization of nT17 cells is warranted.

• Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab.

  Authors: Per Soelberg Sørensen, Antonio Bertolotto, Gilles Edan, Gavin Giovannoni, Ralf Gold, Eva Havrdova, Ludwig Kappos, Bernd C Kieseier, Xavier Montalban, Tomas Olsson

  Multiple sclerosis (Houndmills, Basingstoke, England). 02/2012; 18(2):143-52.

  Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), anNatalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy. Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit-risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.

• Inflammatory demyelinating brain lesions heralding primary CNS lymphoma.

  Authors: Leila Husseini, Andreas Saleh, Guido Reifenberger, Hans-Peter Hartung, Bernd C Kieseier

  The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 01/2012; 39(1):6-10.

  Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and inflammatory demyelination.Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and inflammatory demyelination. We present the case of a previously healthy, immunocompetent woman, aged fifty-nine, who developed a histologically confirmed demyelinating white matter lesion months prior to the manifestation of a PCNSL. Similar cases of "sentinel lesions" preceding a PCNSL have been reported. In a literature review, we compared the diagnostic features that may be useful to differentiate a PCNSL from inflammatory demyelinating disease in older age. We conclude that the occurrence of large, contrast-enhancing cerebral lesions in older patients with a relapsing-remitting disease course and steroid-resistant vision disorders should lead to the consideration of a PCNSL.

• Long-term antiepileptic treatment with histone deacetylase inhibitors may reduce the risk of prostate cancer.

  Authors: Mark Stettner, Günter Krämer, Arne Strauss, Tatjana Kvitkina, Sandra Ohle, Bernd C Kieseier, Paul Thelen

  European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP). 01/2012; 21(1):55-64.

  Various antiepileptic drugs such as valproic acid, carbamazepine, oxcarbazepine, lamotrigine and levetiracetam are known to exert histone deacetylase inhibitory (HDACi) properties, which can modifyVarious antiepileptic drugs such as valproic acid, carbamazepine, oxcarbazepine, lamotrigine and levetiracetam are known to exert histone deacetylase inhibitory (HDACi) properties, which can modify aberrantly silenced gene expression by an epigenetic mechanism. This study was initiated to examine a potential beneficial effect of these drugs on prostate cancer (PC) development. The prostate-specific antigen (PSA) levels of 106 patients under long-term treatment with antiepileptic drugs and known HDACi properties were examined. PSA represents a hallmark in the early detection of PC, and its levels may predict an invasive disease in subsequent years. For in-vitro experiments, the PC cell line LNCaP was treated with HDACi drugs; subsequently, PSA and further PC markers were assessed. When men over 50 years of age were treated with HDACi drugs they had lower age-corrected PSA levels compared with control groups, according to the following ranking: valproic acid>levetiracetam>carbamazepine/oxcarbazepine>lamotrigine. Furthermore, there was a correlation between PSA reduction and the number of HDACi drugs within the medication, lending credence to the idea that a synergistic effect might be possible. Moreover, in vitro, HDACi drugs decrease PSA on mRNA and protein levels and exhibit further oncoprotective properties.The fact that HDACi drugs exert antiproliferative effects on neoplastic cells in vitro and in vivo, which are paralleled by expression alterations of aberrantly regulated genes, underlines the potential therapeutic value of HDACi drugs. These data suggest that long-term HDACi treatment can positively influence the characteristically slow transformation of tumour precursor cells in the prostate and may thus reduce a patient's risk of developing PC.

• Multiple sclerosis: Combination therapy in MS--still a valid strategy.

  Authors: Bernd C Kieseier, Olaf Stüve

  Nature reviews. Neurology. 12/2011; 7(12):659-60.

• Natalizumab and impedance of the homing of CD34+ hematopoietic progenitors.

  Authors: Christian Saure, Clemens Warnke, Fabian Zohren, Thomas Schroeder, Ingmar Bruns, Ron P Cadeddu, Christian Weigelt, Ute Fischer, Guido Kobbe, Hans-Peter Hartung, Ortwin Adams, Bernd C Kieseier, Rainer Haas

  Archives of neurology. 11/2011; 68(11):1428-31.

  Treatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis. ToTreatment with natalizumab, an antibody blocking the α4-integrin, is associated with increased numbers of circulating CD34+ cells in the peripheral blood of patients with multiple sclerosis. To determine whether natalizumab mobilizes CD34+ cells from or inhibits homing to the bone marrow (BM). Fifty-two patients with relapsing-remitting multiple sclerosis treated with natalizumab were included. Flow cytometric analyses; polymerase chain reaction assays for JC (John Cunningham) virus DNA detection; and adhesion, migration, and apoptosis assays of immunomagnetically enriched peripheral blood and BM CD34+ cells were conducted. A comparison was made with CD34+ cells from granulocyte colony-stimulating factor-mobilized peripheral blood or steady-state BM of age- and sex-matched healthy donors. We found adhesion and migration of peripheral blood-derived CD34+ cells to be reduced. In BM aspirates from natalizumab-treated patients, the cellularity, the proportion, and the adhesive capacity of CD34+ cells were normal. The JC virus was undetectable. Natalizumab mediates an increase in circulating CD34+ cells by interfering with homing to the BM. Thus, CD34+ cells appear unlikely to represent a source mobilizing JC virus out of the BM in patients treated with natalizumab.

• Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential.

  Authors: Rebecca Noack, Svenja Frede, Philipp Albrecht, Nadine Henke, Annika Pfeiffer, Katrin Knoll, Thomas Dehmel, Gerd Meyer Zu Hörste, Mark Stettner, Bernd C Kieseier, Holger Summer, Stefan Golz, Andrzej Kochanski, Martina Wiedau-Pazos, Susanne Arnold, Jan Lewerenz, Axel Methner

  Human molecular genetics. 09/2011; 21(1):150-62.

  Mutations in GDAP1 lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT), indicating that GDAP1 is essential for the viability of cells in theMutations in GDAP1 lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease, CMT), indicating that GDAP1 is essential for the viability of cells in the peripheral nervous system. GDAP1 contains domains characteristic of glutathione-S-transferases (GSTs), is located in the outer mitochondrial membrane and induces fragmentation of mitochondria. We found GDAP1 upregulated in neuronal HT22 cells selected for resistance against oxidative stress. GDAP1 over-expression protected against oxidative stress caused by depletion of the intracellular antioxidant glutathione (GHS) and against effectors of GHS depletion that affect the mitochondrial membrane integrity like truncated BH3-interacting domain death agonist and 12/15-lipoxygenase. Gdap1 knockdown, in contrast, increased the susceptibility of motor neuron-like NSC34 cells against GHS depletion. Over-expression of wild-type GDAP1, but not of GDAP1 with recessively inherited mutations that cause disease and reduce fission activity, increased the total cellular GHS content and the mitochondrial membrane potential up to a level where it apparently limits mitochondrial respiration, leading to reduced mitochondrial Ca(2+) uptake and superoxide production. Fibroblasts from autosomal-recessive CMT4A patients had reduced GDAP1 levels, reduced GHS concentration and a reduced mitochondrial membrane potential. Thus, our results suggest that the potential GST GDAP1 is implicated in the control of the cellular GHS content and mitochondrial activity, suggesting an involvement of oxidative stress in the pathogenesis of CMT4A.

• Levetiracetam exhibits protective properties on rat Schwann cells in vitro.

  Authors: Mark Stettner, Thomas Dehmel, Anne K Mausberg, Angelika Köhne, Christine R Rose, Bernd C Kieseier

  Journal of the peripheral nervous system : JPNS. 09/2011; 16(3):250-60.

  Oxidative stress and inflammation represent pathways causing substantial damage to the peripheral nervous system. Levetiracetam (LEV) is a commonly used antiepileptic drug targeting high-voltageOxidative stress and inflammation represent pathways causing substantial damage to the peripheral nervous system. Levetiracetam (LEV) is a commonly used antiepileptic drug targeting high-voltage activated N-type calcium channels. Recent evidence suggests that LEV may also act as a histone deacetylase inhibitor, suggesting that this drug exhibits both anti-inflammatory and anti-oxidative effects, and as such may represent an interesting candidate for treating inflammatory diseases affecting the peripheral nerve. Therefore, we analysed the influence of LEV ex vivo on purified Schwann cells from neonatal P3 rats as well as on dorsal root ganglia prepared from E15 rat embryos. LEV diminished a lipopolysaccharide (LPS)-induced increase of the pro-inflammatory signature molecules tumour necrosis factor alpha, matrix metalloproteinase 9 (MMP-9), and caspase 6. Furthermore, LEV decreased LPS-induced cell death and protected cells against oxidative stress in a glutamate-based oxidative stress model. MMP-2 activity, usually elevated during myelination and repair, was also found to be up-regulated following LEV, while LEV exhibited no negative effects on myelination. Intracellular sodium or calcium concentrations were unaltered by LEV. Thus, LEV may be a promising, well-tolerated drug that - besides its antiepileptic potential - mediates anti-inflammatory, anti-oxidative, and anti-apoptotic properties that may potentially be useful in treating diseases of the peripheral nerve.

• Transforming multiple sclerosis trials into practical reality.

  Authors: Bernd C Kieseier, Heinz Wiendl

  Lancet neurology. 06/2011; 10(6):493-4.

• Risks and benefits of multiple sclerosis therapies: need for continual assessment?

  Authors: Bernd C Kieseier, Heinz Wiendl, Hans-Peter Hartung, Verena-Isabell Leussink, Olaf Stüve

  Current opinion in neurology. 06/2011; 24(3):238-43.

  The aim is to describe and discuss the ongoing debate on how to balance an increase in clinical efficacy against a heightened risk of developing serious side-effects, as has surfaced recently withThe aim is to describe and discuss the ongoing debate on how to balance an increase in clinical efficacy against a heightened risk of developing serious side-effects, as has surfaced recently with some novel therapies for relapsing forms of multiple sclerosis. New therapies are emerging that differ with regard to their mechanism of action, their mode of administration, their side-effect profile and the clinical benefits that they offer to patients in comparison with established therapeutic modalities in multiple sclerosis. Treating physicians will need to make choices on the best treatments for their patients on the basis of limited experience. This process requires optimal assessment of risks and benefits. Careful assessment of the risk-benefit profile of the various options may allow treatment choices and perhaps ensure that patients obtain the most benefit from treatment without being exposed to unnecessary risk.

• Cladribine as a therapeutic option in multiple sclerosis.

  Authors: Clemens Warnke, Verena I Leussink, Norbert Goebels, Orhan Aktas, Alexey Boyko, Bernd C Kieseier, Hans-Peter Hartung

  Clinical immunology (Orlando, Fla.). 06/2011; 142(1):68-75.

  There is an unmet need for more potent and convenient drugs in the treatment of patients diagnosed with multiple sclerosis (MS). Among five currently investigated oral drugs with an ongoing orThere is an unmet need for more potent and convenient drugs in the treatment of patients diagnosed with multiple sclerosis (MS). Among five currently investigated oral drugs with an ongoing or completed phase III program, promising efficacy data for oral cladribine have recently been published. However, benefits need to be weighed against potential risks to define the role of this compound within current treatment regimens. Here we review present data on efficacy of oral cladribine and discuss known and anticipated risks of this drug.

• Novel treatment for immune neuropathies on the horizon.

  Authors: Hans-Peter Hartung, Helmar C Lehmann, Bernd C Kieseier, Richard A C Hughes

  Journal of the peripheral nervous system : JPNS. 06/2011; 16(2):75-83.

  Immune neuropathies represent a heterogeneous spectrum of acute and chronic peripheral nerve disorders of autoimmune origin. Despite the current available treatment options, immune neuropathies areImmune neuropathies represent a heterogeneous spectrum of acute and chronic peripheral nerve disorders of autoimmune origin. Despite the current available treatment options, immune neuropathies are still associated with severe neurological deficits and poor clinical prognosis. However, during the last years, significant advances have been made in unraveling some of the underlying pathomechanisms. The exploration of novel therapeutic approaches including monoclonal antibodies and oral immunosuppressants, known from other autoimmune disorders such as multiple sclerosis, suggests new approaches to treatment. Here, we review the available clinical data as well as the scientific rationale and expected benefits and risks for these strategies.

• The mechanism of action of interferon-β in relapsing multiple sclerosis.

  Authors: Bernd C Kieseier

  CNS drugs. 06/2011; 25(6):491-502.

  Multiple sclerosis (MS) is characterized by autoimmune inflammation and subsequent neurodegeneration. It is believed that early in the disease course, proinflammatory T cells that are activated inMultiple sclerosis (MS) is characterized by autoimmune inflammation and subsequent neurodegeneration. It is believed that early in the disease course, proinflammatory T cells that are activated in the periphery by antigen presentation cross the blood-brain barrier (BBB) into the CNS directed by various chemotaxic agents. However, to date, there has been no formal demonstration of a specific precipitating antigen. Once inside the CNS, activated T cells including T helper-1 (T(h)1), T(h)17, γδ and CD8+ types are believed to secrete proinflammatory cytokines. Decreased levels of T(h)2 cells also correlate with relapses and disease progression in MS, since T(h)2-derived cytokines are predominantly anti-inflammatory. In healthy tissue, inflammatory effects are opposed by specific subsets of regulatory T cells (T(regs)) including CD4+, CD25+ and FoxP3+ cells that have the ability to downregulate the activity of proinflammatory T cells, allowing repair and recovery to generally follow inflammatory insult. Given their function, the pathogenesis of MS most likely involves deficits of T(reg) function, which allow autoimmune inflammation and resultant neurodegeneration to proceed relatively unchecked. Interferons (IFNs) are naturally occurring cytokines possessing a wide range of anti-inflammatory properties. Recombinant forms of IFNβ are widely used as first-line treatment in relapsing forms of MS. The mechanism of action of IFNβ is complex, involving effects at multiple levels of cellular function. IFNβ appears to directly increase expression and concentration of anti-inflammatory agents while downregulating the expression of proinflammatory cytokines. IFNβ treatment may reduce the trafficking of inflammatory cells across the BBB and increase nerve growth factor production, leading to a potential increase in neuronal survival and repair. IFNβ can also increase the number of CD56bright natural killer cells in the peripheral blood. These cells are efficient producers of anti-inflammatory mediators, and may have the ability to curb neuron inflammation. The mechanistic effects of IFNβ manifest clinically as reduced MRI lesion activity, reduced brain atrophy, increased time to reach clinically definite MS after the onset of neurological symptoms, decreased relapse rate and reduced risk of sustained disability progression. The mechanism of action of IFNβ in MS is multifactorial and incompletely understood. Ongoing and future studies will increase our understanding of the actions of IFNβ on the immune system and the CNS, which will in turn aid advances in the management of MS.

• Alteration of T cell cytokine production in PLPp-139-151-induced EAE in SJL mice by an immunostimulatory CpG oligonucleotide.

  Authors: Vsevolod Smolianov, Thomas Dehmel, Patrick Vollmar, Anne K Mausberg, Bernd C Kieseier, Bernhard Hemmer, Hans P Hartung, Harald H Hofstetter

  Journal of neuroinflammation. 05/2011; 8:59.

  Experimental autoimmune encephalomyelitis (EAE) is--in certain aspects--regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specificExperimental autoimmune encephalomyelitis (EAE) is--in certain aspects--regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specific immunity is induced in a defined way, the initial processes leading to CNS autoimmunity in humans are so far unknown. Despite essential restrictions, which exist regarding the interpretation of EAE data towards MS, EAE might be a useful model to study certain basic aspects of CNS autoimmunity. Studies in MS have demonstrated that established autoimmune pathology can be critically influenced by environmental factors, in particular viral and bacterial infections. To investigate this interaction, EAE as an instrument to study CNS autoimmunity under defined conditions appears to be a suitable experimental tool. For this reason, we here investigated the influence of the Toll-like-receptor (TLR) ligand CpG oligonucleotide (CpG) on already established CNS autoimmunity in murine proteolipid protein (PLP)-induced EAE in SJL mice. CpG were found to co-stimulate PLPp-specific IFN-γ production in the peripheral immune system and in the CNS. However, CpG induced Interleukin (IL)-17 production in the inflamed CNS both alone and in combination with additional PLPp stimulation. These findings might indicate a mechanism by which systemic infections and the microbial stimuli associated with them may influence already existing CNS autoimmune pathology.

• Autoimmune diseases of the peripheral nervous system.

  Authors: Bernd C Kieseier, Helmar C Lehmann, Gerd Meyer Zu Hörste

  Autoimmunity reviews. 05/2011; 11(3):191-5.

  Autoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The applicationAutoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The application of innovative and cutting-edge technologies to the study of immune-mediated disorders of the peripheral nervous system (PNS) have generated a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. These insights may foster the development of specific and highly effective therapies for autoimmune diseases of the peripheral nerve. Of great interest in this context is the application of monoclonal antibodies, such as rituximab or alemtuzumab, which in small observational studies provided promising clinical results. But also other immunomodulatory or immunosuppressive drugs used in other indications currently find their way to PNS autoimmunity. Clearly, prospective controlled clinical trials are warranted before making firm conclusions on the feasibility of these innovative therapeutic approaches for treating immune-mediated disease of the peripheral nerve.

• An interesting case of nuchal rigidity.

  Authors: Christina Boettcher, Clemens Warnke, Stephan Macht, Hans-Peter Hartung, Bernd C Kieseier

  The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 05/2011; 38(3):516-7.

• Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice.

  Authors: João Carlos Correia de Sa, Laura Airas, Emmanuel Bartholome, Nikolaos Grigoriadis, Heinrich Mattle, Celia Oreja-Guevara, Jonathan O'Riordan, Finn Sellebjerg, Bruno Stankoff, Karl Vass, Agata Walczak, Heinz Wiendl, Bernd C Kieseier

  Therapeutic advances in neurological disorders. 05/2011; 4(3):139-68.

  As more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities andAs more investigations into factors affecting the quality of life of patients with multiple sclerosis (MS) are undertaken, it is becoming increasingly apparent that certain comorbidities and associated symptoms commonly found in these patients differ in incidence, pathophysiology and other factors compared with the general population. Many of these MS-related symptoms are frequently ignored in assessments of disease status and are often not considered to be associated with the disease. Research into how such comorbidities and symptoms can be diagnosed and treated within the MS population is lacking. This information gap adds further complexity to disease management and represents an unmet need in MS, particularly as early recognition and treatment of these conditions can improve patient outcomes. In this manuscript, we sought to review the literature on the comorbidities and symptoms of MS and to summarize the evidence for treatments that have been or may be used to alleviate them.

• A critical appraisal of treatment decisions in multiple sclerosis--old versus new.

  Authors: Bernd C Kieseier, Olaf Stüve

  Nature reviews. Neurology. 04/2011; 7(5):255-62.

  Interferon β and glatiramer acetate have been available for the treatment of multiple sclerosis (MS) for over a decade and their efficacy and safety are well established. These agents have detectableInterferon β and glatiramer acetate have been available for the treatment of multiple sclerosis (MS) for over a decade and their efficacy and safety are well established. These agents have detectable effects on the immune system, but have not been associated with a breakdown of immune surveillance. Novel MS therapies have been approved, or are awaiting approval, that differ from established immunotherapies with regard to their mechanisms of action, modes of administration, adverse-effect profiles and, possibly, the clinical and paraclinical benefits that they may provide for patients. Neurologists will soon be required to make complex treatment decisions with their patients on the basis of very limited clinical data and evidence. Under these circumstances, optimal assessment of risks and benefits will be challenging. In this Review, the anticipated benefits of novel therapies, including reduction in disease activity, possible prevention of disability, and improvement in quality of life, are outlined. In addition, the current acceptance of potential risks--including serious or even life-threatening adverse effects, the likelihood of which may rise with increased cumulative exposure to a particular agent--by patients with MS will be reviewed.

• The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration.

  Authors: Gerd Meyer zu Horste, Timo A Miesbach, Johanna I Muller, Robert Fledrich, Ruth M Stassart, Bernd C Kieseier, Michael P Coleman, Michael W Sereda

  Neurobiology of disease. 04/2011; 42(1):1-8.

  Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and a duplication of the peripheral myelin protein of 22 kDa (PMP22) gene causes the most frequent subform CMT1A. ClinicalCharcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and a duplication of the peripheral myelin protein of 22 kDa (PMP22) gene causes the most frequent subform CMT1A. Clinical impairments are determined by the amount of axonal loss. Axons of the spontaneous mouse mutant Wallerian degeneration slow (Wlds) show markedly reduced degeneration following various types of injuries. Protection is conferred by a chimeric Wlds gene encoding an N-terminal part of ubiquitination factor Ube4b and full length nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1). Nmnat1 enzyme generates nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide. Here, in a Pmp22 transgenic animal model of Charcot-Marie-Tooth disease type 1A (CMT rat), the Wlds transgene reduced axonal loss and clinical impairments without altering demyelination. Furthermore, nicotinamide - substrate precursor of the Nmnat1 enzyme - transiently delayed posttraumatic axonal degeneration in an in vivo model of acute peripheral nerve injury, but to a lower extent than Wlds. In contrast, 8 weeks of nicotinamide treatment did not influence axonal loss or clinical manifestations in the CMT rat. Therefore, nicotinamide can partially substitute for the protective Wlds effect in acute traumatic, but not in chronic secondary axonal injury. Future studies are needed to develop axon protective therapy in CMT1A which may be combined with therapeutic strategies aimed at downregulation of toxic PMP22 overexpression.