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  1. Home
  2. Books
  3. Multiple Sclerosis Therapeutics
  • Cited by 10
Publisher:
Cambridge University Press
Online publication date:
December 2011
Print publication year:
2011
Online ISBN:
9781139023986
DOI:
https://doi.org/10.1017/CBO9781139023986
Subjects:
Neurology and Clinical Neuroscience, Medicine
Information

Book description

This book comprehensively reviews the current state of clinical trial methods in multiple sclerosis treatment, providing investigators, sponsors and specialists with current knowledge of outcome measures and study designs for disease and symptom management. The status of the rapidly evolving field of disease-modifying drugs is presented, with emphasis on the most promising therapies currently being tested. Experts discuss disease and symptom management for MS subtypes, including neuromyelitis optica and pediatric MS. In addition, key scientific advances in MS pathology, genetics, immunology and epidemiology are presented. The fourth edition has been extensively revised, featuring more than 50% new material. All chapters have been substantially updated to provide current information on rapidly evolving topics and this volume contains 15 new chapters, reflecting the growth of the field in recent years. This book is an essential reference for practitioners caring for MS patients, investigators planning or conducting clinical trials, and clinical trial sponsors.

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Contents

Page 2 of 3

Contents
  • 21 - The growing need for alternative clinical trial designs for multiple sclerosis
    pp 253-260
  • View abstract

    Summary

    Double inversion recovery (DIR) is an inversion recovery sequence which applies two consecutive inversion pulses leading to a simultaneous attenuation of the cerebrospinal fluid (CSF) and white matter which improves the contrast between gray and white matter. Quantitative magnetic resonance imaging (MRI) techniques are able to detect and to quantify primary and secondary gray matter abnormalities and provide further insights into disease progression and contribution of these changes to clinical outcome measures. Proton MR spectroscopy (1H-MRS) is frequently used for the evaluation of normal appearing brain tissue in multiple sclerosis (MS). Diffusion tensor imaging (DTI) assesses the random movement of water molecules within the brain tissue. Magnetization transfer (MT) imaging is based on a magnetization interaction between free water protons and protons bound to macromolecular structures. T1- and T2-relaxation time (RT) measurements allow the assessment and quantification of white matter and gray matter damage in various neurodegenerative and neuro-inflammatory diseases.
  • 22 - Ethical considerations in multiple sclerosis clinical trials
    pp 261-271
  • View abstract

    Summary

    Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are among the earliest developed functional imaging techniques. SPECT images are acquired after administration of a radioactive compound that emits single photons that can be detected by gamma-cameras. Similar to SPECT, PET imaging also uses radioactive biotracers to monitor physiological processes. However, better localization is achieved in PET imaging. Functional magnetic resonance imaging (fMRI) can be used with several different experimental designs to answer distinct questions about brain function. Multiple sclerosis (MS) disease-related brain changes including the presence of focal lesions and atrophy can complicate functional neuroimaging studies. Functional imaging is utilized to study fatigue, depression, motor system, vision, cognition, and for interpretation of cortical reorganization. Functional imaging plays a much larger role in clinical trials for MS involving remyelination, cell grats, neuroprotective treatments, and in illuminating the mechanisms of progressive disease.
  • 23 - Pharmacogenomics and related discovery-driven approaches in multiple sclerosis
    pp 272-286
  • View abstract

    Summary

    Early evaluations of multiple sclerosis (MS) with diffusion imaging focused on the most basic form of diffusion imaging, diffusion-weighted imaging (DWI), which is relatively easy to perform using only acquisitions in cardinal imaging planes. Diffusion tensor imaging (DTI) is employed to evaluate MS. The simplest non-spherical model of a full three-dimensional diffusion profile is described by a second-rank tensor. Useful mathematical parameters that emerge from the tensor include the geometric axes of the tensor ellipsoid, the mean diffusivity (MD), fractional anisotropy (FA), and the parallel and perpendicular diffusivity. Several investigators have proposed evaluating diffusion imaging data using voxel-wise comparisons (VWC). A new VWC method to address the issues of different smoothing algorithms is tract-based spatial statistics (TBSS). DTI is unique in its ability to identify white matter pathways in the brain. A recent study has demonstrated a high level of sensitivity for detection of disease progression in MS using DTI.
  • 24 - Neutralizing antibodies directed against biologic agents to treat multiple sclerosis
    pp 287-299
  • View abstract

    Summary

    Lesions that are hyperintense on T1 images after intravenous administration of gadolinium chelate represent focal areas of blood-brain barrier (BBB) disruption, which in multiple sclerosis (MS) are presumed to represent areas of active inflammation. T2 lesion burden early in the disease is the best known magnetic resonance imaging (MRI) predictor of long-term disability and brain atrophy. Several imaging approaches have been proposed to provide additional pathologic specificity with greater ability to monitor tissue integrity both within lesions visible on standard imaging, normal appearing brain tissue (NABT), and gray matter (GM). Phase 1 trials aim to expose a relatively small number of subjects to a new medication for a short period of time, monitoring primarily for safety concerns. MRI-based studies have become standard for Phase 2 (proof-of-concept) trials of disease modification in MS. Primary outcomes for Phase 3 (pivotal) trials remain relapses and disability progression.
  • 25 - Interferon beta to treat multiple sclerosis
    pp 300-314
  • View abstract

    Summary

    The emergence of optical coherence tomography (OCT) technologies has allowed measurements of retinal nerve fiber layer (RNFL) and macular thickness that complement the history and clinical examination in distinguishing forms of acute optic neuropathy and retinal disease. High-resolution Fourier domain OCT has allowed for rapid imaging of the retina as well as three-dimensional imaging and improved volumetric measurements. Ongoing studies of OCT in clinical trials and research examine patterns of axonal degeneration and visual loss over time, and establish the role for OCT and other ocular imaging modalities as structural markers. With the emergence of a variety of OCT techniques, including Fourier Domain OCT, future studies will also help establish the protocols for data analysis to provide meaningful information about changes in structure from baseline. OCT is likely to play an increasing role in multiple sclerosis (MS) trials for measuring both axonal integrity and neuronal preservation.
  • 26 - Glatiramer acetate to treat multiple sclerosis
    pp 315-329
  • View abstract

    Summary

    The process of drug approval in the United States is regulated by the Food and Drug Administration (FDA). The European Union (EU) includes 27 member states, and each member state has its own national regulatory agency responsible for the approval of clinical trial and marketing applications. Clinical studies to support drug development are increasingly becoming more global in nature as trial subjects are recruited from countries throughout the world. The regulatory environment is very dynamic as global health authorities grapple with innovations in science and technology in addition to changes in health policy in their respective countries. Cooperation amongst regulators in regional health authorities has also been advanced through engagement in the International Conference on Harmonization (ICH). The regulations and requirements continue to evolve as further strides are made in the understanding of diseases and the relevant tools, approaches, and therapies for the management of those diseases.
  • 27 - Natalizumab to treat multiple sclerosis
    pp 330-343
  • View abstract

    Summary

    Multiple sclerosis (MS) research in recent years has identified an increasing number of potential therapeutic products that can be evaluated. The ultimate goal of a drug development program is to establish that the drug has a favorable effect upon the patient and has risks that are acceptable in light of the benefit. The Kurtzke Expanded Disability Status Scale (EDSS) is employed as the chief physical disability measure in development programs for many of the currently available therapies. An important aspect of drug development is determining what drug benefits should be claimed in the approved drug labeling. Biomarkers have the potential to be informative on a number of different aspects of biological responses in much shorter time and fewer patients, and contribute to feasible and successful drug development. An important aspect of efficient and informative drug development programs is selection of appropriate end-points for each study in the clinical development program.
  • 28 - Mitoxantrone to treat multiple sclerosis
    pp 344-357
  • View abstract

    Summary

    This chapter focuses on the various study designs used to estimate long-term treatment effects of disease-modifying therapies (DMTs) in multiple sclerosis (MS). It also discusses their strengths and weaknesses and the methodological challenges. Results suggest that sustained early treatment in MS patients can delay progression to significant disability and the studies support the concept that early treatment with DMTs has long-lasting effects. Long-term follow-up of patients have significant limitations, including loss of randomization and blinding, incomplete ascertainment, and the absence of an appropriate comparator. Long-term non-randomized observational trials (NROTs) include a wide range of study designs, such as prospective and retrospective cohort studies, case-control studies, and cross-sectional studies, with the common feature that any intervention studied is determined by clinical practice and not by the protocol. Several epidemiological and statistical methods are available to deal with confounding, in both design and analytical phases of NROTs.
  • 29 - Cladribine to treat multiple sclerosis
    pp 358-369
  • View abstract

    Summary

    A mainstay of current multiple sclerosis (MS) clinical trial conduct is the comparison of randomized groups of patients using experimental therapy and a placebo. If placebo must be used, it may be possible to limit the number of subjects exposed to placebo by unbalanced randomization, in which fewer subjects are randomized onto placebo than onto experimental therapy. It could, in theory, be possible to replace a placebo arm with a treatment arm in which patients are exposed to a considerably lower dose of active therapy that is not expected to be maximally effective, but is expected to show some benefit. Creating a virtual placebo cohort using extant data from natural history and placebo-controlled studies could reduce the need for, or even replace, placebo groups in future studies. Clinical trials in MS have traditionally been designed with a frequentist approach to statistical inference. An alternative statistical inference approach uses Bayesian procedures.
  • 30 - Fingolimod to treat multiple sclerosis
    pp 370-386
  • View abstract

    Summary

    The imperative to develop more effective medication for multiple sclerosis (MS) persists. In view of the availability of several partially effective immunomodulatory drugs for the treatment of MS, the National MS society (NMSS) convened an international task force to deliberate the continued use of placebo-controlled trials. Clearly, patients should not be deprived of the opportunity to participate in a placebo-controlled trial if they do not wish to use approved therapies. The ethical issues and practical limitations governing placebo controlled trials remain complex. Clinical trialists clearly have a mandate to include ethical considerations in all aspects of the design, implementation, and conduct of clinical trials. The continued use of placebo controlled randomized clinical trials in an era of partially effective therapy remains controversial. Both the utility and ethical conduction of placebo-controlled trials in MS are likely to continue to evolve as the MS therapeutic armamentarium grows increasingly refined.
  • 31 - Dimethyl fumarate to treat multiple sclerosis
    pp 387-392
  • View abstract

    Summary

    This chapter lists the factors that differentiate pharmacogenomics from conventional biomarker research on a strategic, operational, and technical level. The "-omics" technologies and conventional methods are mutually complementary approaches in the search for biomarkers. The genetic component of multiple sclerosis (MS) risk has been the focus of study for a long time, and beyond the classic association with the MHC locus, seven genome-wide association studies (GWAS) reported in recent years have helped identify other candidate genes, such as the IL-7 and IL-2 receptors. Compared with DNA- and RNA-based analyses, proteomics and metabolomics are less advanced techniques. The requirements for establishing a comprehensive and integrated matrix of genotype/phenotype interaction are: development of technologies for proteomics and metabolomics to the same level as genotyping and trancriptomics, development of bioinformatic tools, and development of longitudinally studied cohorts characterized using standardized, high-quality clinical and paraclinical methods.
  • 32 - Alemtuzumab to treat multiple sclerosis
    pp 393-398
  • View abstract

    Summary

    In vitro, two different classes of antibodies are recognized according to the assay used to identify them: binding antibodies (BAbs) and neutralizing antibodies (NAbs). There is emerging agreement that NAbs are correlated with reduced therapeutic efficacy of IFNβ. None of the pivotal trials in relapsing-remitting multiple sclerosis (MS) showed an effect of NAbs on disease progression. Among the therapeutic monoclonal antibodies natalizumab, alemtuzumab, and daclizumab are humanized monoclonal antibodies, whereas rituximab is a mouse-human chimeric antibody. NAbs are associated with reduction of the therapeutic effect of IFNβ, and patients with persistent high titers of NAbs should be switched to an alternative therapy. Patients with low or intermediate titers should have their IFN bioactivity measured with an in vivo mRNA MxA induction test. Patients with repeated abrogation of the mRNA MxA response to IFN injections should be switched to another therapy.
  • 33 - Daclizumab to treat multiple sclerosis
    pp 399-404
  • View abstract

    Summary

    This chapter summarizes interferon (IFN) biological effects, its possible mechanisms of action, and the key studies in clinically isolated syndromes (CIS), relapsing remitting multiple sclerosis (RRMS), and progressive MS. Measures of specific IFNβ-induced products, such as oligoadenylate synthetase (OAS), β-2 microglobulin, or neopterin, have been useful in pharmacodynamic studies to determine the magnitude and duration of the IFNβ-response, since serum levels of IFNβ are undetectable following injections. A consistent finding of follow-up studies from the three pivotal IFNβ RRMS trials and two CIS trials is that early treatment is beneficial compared with delayed treatment. IFNβ is partially effective in clinical trial groups. Since approval 18 years ago of the first IFNβ product for RRMS, treatment effects of β at all stages of MS have become fairly clear. The development of β for MS has illustrated many of the challenges in developing treatments for MS.
  • Chapter 35 - Teriflunomide to treat multiple sclerosis
    pp 410-417
  • View abstract

    Summary

    Glatiramer acetate (GA) seems to affect immune cells in an antigenic specific way, and could be considered as an example of a therapeutic vaccination, as opposed to the prophylactic vaccinations commonly used for infectious diseases. The first human use of GA was in three patients with acute disseminated encephalomyelitis and four in the terminal stages of multiple sclerosis (MS). Cross-sectional analysis of data from the extended, open label follow-up of the US trial investigated the consequences of long-term GA treatment on several magnetic resonance imaging (MRI) markers of MS activity and disease burden. As GA has unique mechanisms of action, which differs from those of other MS disease therapies, use in combination with other agents might produce additive or synergistic therapeutic effects and better efficacy. The effects of oral GA were extensively studied in both rodents and primates in acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE) models.
  • 36 - High-dose methylprednisolone to treat multiple sclerosis
    pp 418-435
  • View abstract

    Summary

    The pharmacokinetics of a single I.V dose of natalizumab were studied in a phase 1, dose-escalation study in 28 multiple sclerosis (MS) patients. As part of the clinical trial program to establish the pharmacokinetic/pharmacodynamic and safety profiles of natalizumab, four Phase 1, dose-finding studies were conducted. An additional Phase 2 study was conducted to evaluate the safety and efficacy of natalizumab in combination with glatiramer acetate (GA). One of the recommendations of the therapeutics and technology assessment subcommittee of the AAN about the use of natalizumab was to carefully monitor patients receiving natalizumab to establish its long-term safety i.e. the true risk of progressive multifocal leukoencephalopathy (PML). Large Phase 3 trials of natalizumab alone or in combination with interferon (IFN)β-1a show that natalizumab reduces the progression of disability, and dramatically reduces the frequency of relapses and magnetic resonance imaging (MRI) lesion formation in patients with relapsing MS.
  • 37 - Use of immunosuppressants to treat multiple sclerosis
    pp 436-443
  • View abstract

    Summary

    In the Mitoxantrone in Multiple Sclerosis (MIMS) study, patients were enrolled between 1993 and 1997 at 17 centers in Belgium, Germany, Hungary, and Poland, and randomly assigned to treatment with mitox. Cardiac monitoring, electrocardiography (ECG), and left ventricular ejection fraction (LVEF) assessed by echocardiography or radionuclide scan, was performed before treatment. The comparative study of mitox efficacy profile in relapsing-remitting multiple sclerosis (RRMS) and secondary-progressive multiple sclerosis (SPMS) evaluated the clinical and neuroradiological response to mitox. Substantial tolerability data are available from oncology studies in which mitox was generally used in combination with cyclophosphamide, luorouracil, mitomycin, methotrexate, and radiotherapy for leukemia, non-Hodgkin's lymphoma and solid tumors, and from MS studies in which mitox was used as monotherapy. The available data from studies in patients with MS suggest that mitox may have a role to play in the management of aggressive disease, as an induction therapy.
  • 38 - Intravenous immunoglobulin to treat multiple sclerosis
    pp 444-453
  • View abstract

    Summary

    This chapter reviews the mechanism of action of cladribine, summarizes data from clinical trials in patients with multiple sclerosis (MS), and provides guidance on the management of these patients in clinical practice. The study of parenteral cladribine showed encouraging results, which lead to the development of an oral tablet formulation. Cladribine is rapidly absorbed with Cmax within 30- 50 minutes after oral administration. CLARITY, a 96-week, placebo-controlled Phase 3 study of cladribine tablets as an annual short-course oral monotherapy in RRMS, was recently completed and the principal results published. Benefit of doses of cladribine over placebo was demonstrated for a variety of clinical and imaging end-points. The most common adverse events in the patients were lymphopenia, headache, nasopharyngitis, and upper respiratory tract infections (URTI). The outcomes observed during the CLARITY study were associated with a reduced consumption of health care resources and a decreased need for medical and societal support.
  • 39 - Plasma exchange treatment for CNS inflammatory demyelinating disease
    pp 454-464
  • View abstract

    Summary

    Fingolimod was first synthesized in the early 1990s as part of an extensive program of chemical derivatization of myriocin, with the goal of creating a novel immunosuppressant that would be more potent and less toxic in vivo. Fingolimod's mechanism of action in multiple sclerosis (MS) is not known with certainty. Fingolimod was initially developed to prevent allograt rejection after demonstration that it was effective in a variety of animal transplantation models, including kidney, heart, pancreatic islet cells and skin. Fingolimod was approved by the Food and Drug Administration (FDA) to reduce relapses and disability progression in relapsing forms of MS. Fingolimod's generally good safety profile and tolerability, including oral route of administration, make fingolimod an attractive treatment option for patients with relapsing forms of MS. Better delineation of the mechanisms leading to both the beneficial and adverse effects of fingolimod is necessary to develop more effective and better-tolerated compounds.
  • 40 - Statins in multiple sclerosis
    pp 465-471
  • View abstract

    Summary

    Dimethyl fumarate (DMF) is an oral therapy in development for multiple sclerosis (MS). Fumaric acids were first studied in MS in a Phase 1, open-label, baseline-controlled trial using the combination fumaric acid ester preparation Fumaderm. Based upon the encouraging Phase 1 results, Fumapharm partnered with Biogen Idec to conduct a Phase 2 trial of DMF in relapsing-remitting multiple sclerosis (RRMS). The use of DMF in autoimmune diseases arose from a personal view of the immune system, whereby autoimmunity is caused by disruption in the Krebs's cycle. The Phase 2 trial found that 720 mg/d of BG00012 reduced active inflammation. The Phase 3 trials provide pivotal and definitive evidence regarding the safety and efficacy of BG00012 in MS. Ongoing laboratory studies and advanced imaging studies in the Phase 3 trials are evaluating the neuroprotective effects of BG00012. Fumaric acids such as BG00012 are an exciting new class of potential MS treatment.
  • 41 - T-cell-based therapies for multiple sclerosis
    pp 472-482
  • View abstract

    Summary

    Initial use of alemtuzumab in multiple sclerosis (MS) was in patients with secondary progressive disease. Just as the efficacy experience of alemtuzumab generated some novel concepts of MS biology, such as the possibility of neuroprotective autoimmunity, so too has exploration of its adverse effects. The most significant adverse effect of alemtuzumab is secondary autoimmunity. A straightforward conclusion from the experience of using alemtuzumab, both open-label and within trials, is that it has the potential to be one of the most efficacious treatments of MS to date. A key lesson from the history of alemtuzumab treatment of MS has been that the disease is only vulnerable to such anti-inflammatory treatments early in its course, before the conditions that predispose to neurodegeneration, and secondary progression, have been set up. The finding of disability improvement after alemtuzumab suggests a new treatment paradigm in MS. There is no signal that alemtuzumab causes neoplasia.
  • 42 - B-cell-based therapies for multiple sclerosis
    pp 483-497
  • View abstract

    Summary

    In the first of two studies reported by Rose and coworkers, patients with relapsing-remitting multiple sclerosis (RRMS) or secondary-progressive multiple sclerosis (SPMS) were initiated on daclizumab with the same dose. A positive effect on relapses was observed. Safety data coming from daclizumab's regulatory-approved indication in renal transplantation suggest that the drug is overall safe and well tolerated. However, safety data from other of-label indications, such as uveitis, seem to confirm safety concerns regarding a mild increase in infection rate as well as skin reactions. Daclizumab is a novel and promising therapy for MS patients now being tested as monotherapy in a large Phase 3 trial using an active comparator arm. Daclizumab's mechanism of action is not fully understood, but an increase in regulatory immune cells has been related to clinical response and is now thought to play a more important role than direct anti-inflammatory effects derived from IL-2 blockade.
  • 43 - Sex hormones and other pregnancy-related factors with therapeutic potential in multiple sclerosis
    pp 498-507
  • View abstract

    Summary

    Laquinimod is rapidly absorbed following oral administration with bioavailability of 82%-95%. Two Phase 2 clinical trials were conducted with laquinimod. Both demonstrated a reduction in the frequency of gadolinium (Gd)-enhancing lesions and relapses in patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Laquinimod was well tolerated in both Phase 2 trials with few side effects. There was no difference in the overall number of adverse events (AEs) or serious adverse events (SAEs) between the placebo and laquinimod groups. Laquinimod effectively ameliorates both acute and chronic experimental autoimmune encephalomyelitis (EAE) decreasing both demyleination and axonal loss. Laquinimod may have protective effects on axonal integrity beyond that associated with decreased inflammation. Laquinimod has no immuno suppressive effects in animal models or in human studies, and does not decrease the ability of animals to mount a cellular or humeral immune response. The safety profile of laquinimod appears quite favorable.
  • 44 - Hematopoietic stem cell transplantation to treat multiple sclerosis
    pp 508-519
  • View abstract

    Summary

    Terilunomide is being investigated in a comprehensive program of clinical trials in patients with multiple sclerosis (MS) with relapses and in patients with a clinically isolated syndrome (CIS). This program evaluates the efficacy and safety of terilunomide on a range of clinical and magnetic resonance imaging (MRI) end-points when administered either as monotherapy or as an adjunctive therapy to ongoing treatment with conventional disease-modifying therapies (DMTs). Clinical data indicates that terilunomide is generally well tolerated with an acceptable safety profile, with no significant safety concerns identified to date. Safety data from the open-label extension phase of the study are consistent with the safety profile of terilunomide observed in the double-blind treatment phase, without the emergence of any new safety concerns. Based on currently available data on monotherapy and adjunctive therapy, terilunomide appears to have a favorable benefit/risk ratio in relapsing MS, and as such, represents a promising new first-line treatment.
  • 45 - Mesenchymal stem cell transplantation to treat multiple sclerosis
    pp 520-534
  • View abstract

    Summary

    Treatment of multiple sclerosis (MS) with pulses of high dose methylprednisolone (HDMP) is currently the treatment of choice for MS relapses in many parts of the world. The use of corticosteroids as a treatment for MS was first reported in 1951. There is emerging evidence regarding the benefits of HDMP administered in pulses on the course of MS, either alone or in combination with other disease modifying therapy. HDMP was found to improve Expanded Disability Status Scale (EDSS) better than placebo, with improvements primarily in pyramidal, cerebellar, and sensory systems. In general, corticosteroid toxicity is reduced with short-term pulsed administration of HDMP. Altogether, numerous clinical and magnetic resonance imaging (MRI) studies suggest that HDMP not only has transient beneficial effects on clinical relapses and established areas of inflammation and demyelination, but may also have a prolonged, dose-dependent benefit involving early events in MS lesion formation, lesion propagation, and lesion recovery.
  • 46 - Neuroprotection in multiple sclerosis
    pp 535-546
  • View abstract

    Summary

    Cyclophosphamide is employed in autoimmune neuropathies, and vasculidities such as Wegener's granulomatosis and polyarteritis nodosa. Mycophenolate mofetil (Cellcept) is a potent immunosuppressant and has been used increasingly in post-transplant patients because it is considered less toxic than azathioprine and cyclophosphamide. Methotrexate is a general immunosuppressant that acts primarily by inhibition of dihydrofolate reductase. Azathioprine (Imuran) is a purine analog that is metabolized to 6-mercaptopurine and thioinosine acid, which compete with DNA nucleotides, causing immunosuppression. This chapter lists randomized trials of immunosuppressives in multiple sclerosis (MS). In the right patient, cyclophosphamide has been demonstrated effective, while work with methotrexate and mycophenolate mofetil has been less conclusive. Azathioprine also is likely to have a favorable effect on MS, and is relatively safe. Recent novel uses of immunosuppressives in active patients, or new disease populations have broadened the possible uses of these drugs.
  • 47 - Combination therapy in multiple sclerosis
    pp 547-556
  • View abstract

    Summary

    Repeated administration of intravenous immunoglobulin (IVIG) to improve the course of multiple sclerosis (MS) has now been tested in almost all stages of the disease, although to a variable extent and with various study designs. To date, two clinical trials have tested the effects of IVIG on progressive forms of MS. The efficacy of IVIG has been explored in several stages and settings of MS ranging from attempts to ameliorate the acute attack via investigations on the effects of long term immunomodulation to attempts of restoration of fixed deficits. Due to the good tolerability of IVIG, it has been recommended as a possible means to lessen disease activity that may be seen after delivery in some MS patients. The side effects observed at lower dosages of IVIG have been uniformly minor and consisted primarily of headaches, malaise, or a transient rash.
  • 48 - Dalfampridine in multiple sclerosis
    pp 557-561
  • View abstract

    Summary

    Research into therapeutic applications of apheresis is limited by the rarity of many of the diseases for which plasma exchange (PLEX) is indicated. PLEX has now become a widely used treatment in select patients with acute relapses of inflammatory demyelinating disease in a variety of contexts including multiple sclerosis (MS). Natalizumab inhibits central nervous system (CNS) lymphocyte trafficking by blocking alpha4-integrin, and its serological clearance is enhanced by PLEX. Circulating pathologic antibodies directed against myelin oligodendrocyte glycoprotein and myelin basic protein have been implicated in subsets of MS patients. Complications occur in 4.75% to 36% of PLEX procedures. The majority are mild, easily treated, and self-limited and include paresthesias and muscle cramping due to hypocalcemia from citrate anticoagulant, bleeding and hematoma formation from vascular access, urticaria/pruritus and fever from blood products, hypotension, pallor, nausea, and vomiting.
  • 49 - Complementary and alternative treatments in multiple sclerosis
    pp 562-573
  • View abstract

    Summary

    The current understanding regarding the therapeutic potential of statins in central nervous system (CNS) autoimmune diseases evolved from studies in mice with experimental autoimmune encephalomyelitis (EAE). Migration of leukocytes from the blood into the CNS involves multiple steps, including chemo-attraction, cell adhesion, extravasation, and proteolytic degradation of biological membranes. Statin-mediated immunomodulation observed in mice may translate to humans. In vitro, statins inhibit the expression of intracellular adhesion molecule (ICAM)-1 and various chemokine receptors on activated peripheral mononuclear cells from both patients with multiple sclerosis (MS) and controls. Although statins are considered safe and well-tolerated drugs, they have side effects that should be considered. Statins have been shown to target key elements of the immunological cascade associated with glial and neural tissue damage in MS. In a recent placebo-controlled trial in patients with early MS, Statin treatment reduced development of newly occurring CNS inflammatory lesions.

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