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`Pharmacology 2
`and Therapeutics
`Principles to Practice
`
`Page 2 of 26
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`Page 2 of 26
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`

`

`ASSOCIATE EDITORS
`
`LaurenceJ. Egan, MD, FRCPI
`Professor, National University of Ireland, Galway; Department of
`Pharmacology and Therapeutics, Clinical Science Institute, University
`College Hospital Galway, Newcastle, Galway, Ireland
`Jean-Luc Elghozi, MD, PhD
`Professor of Pharmacology,Faculté de Médecine, Université Paris—
`Descartes; Head,Clinical Pharmacology Unit, Hépital Necker,
`Paris, France
`
`Arshad Jahangir,MD
`Associate Professor of Medicine, Division of Cardiovascular Diseases,
`MayoClinic, Rochester, Minnesota
`
`Garvan C. Kane, MD, PhD
`- Assistant Professor of Medicine, Division of Cardiovascular Diseases,
`Mayo Clinic, Rochester, Minnesota
`
`Lionel] D. Lewis, MA, MB BCh, MD, FRCP (London)
`'
`Professor of Medicine/Pharmacology and Toxicology, Department.
`of Medicine, Dartmouth Medical School and Dartmouth Hitchcock
`Medical Center, Lebanon, New Hampshire
`
`Jason D. Morrow, MD
`Chief, Division of Clinical Pharmacology, F. ‘Tremaine Billings
`Professor of Medicineand Pharmacology, and Director of the
`Research Center for Pharmacology and Drug Toxicology, Vanderbilt
`University Medical enter Nashville, Tennessee
`Leonid V. Zingmiani MD
`Assistant Professor ofMedicine, Department of Medicine, University
`of Jowa, lowa City, lowa
`
`Walter K. Kraft, MD, MS
`Associate Professor of Pharmacology and Experimental Therapeutics
`and Medicine, Director of the Jefferson Clinical Research Unit,
`ThomasJefferson University, Philadelphia, Pennsylvania
`
`
`
`EDITORIAL BOARD*
`
`
`°
`
`Darrell R. Abernethy, MD, PhD
`Professor of Medicine and Pharmacology and Molecular Science,
`Johns Hopkins University School of Medicine, Baltimore; Chief
`Science Officer, United States Pharmacopeia, Rockville, Maryland
`
`Arthur J. Atkinson, Jr, MD
`Adjunct Professor, Department of Molecular Pharmacology and
`Biochemistry, Feinberg School of Medicine, Northwestern University,
`Chicago,Tlinois
`
`Neal L. Benowitz, MD
`Professor of Medicine and Biopharmaceutical Sciences, University of
`California, San Francisco; Chief, Division of Clinical Pharmacology
`andExperimental Therapeutics, San Francisco General Hospital
`Medical Center, San Francisco, California
`=
`
`D. Craig Brater, MD
`Dean and Walter J. Daly Professor, Indiana University School of
`Medicine; Vice President with Responsibility for Life Sciences, Indiana
`University, Indianapolis, Indiana
`Jean Gray, CM, MD, FRCPC, LLD (Hon), DSc (ie;
`FRCP (London)
`Professor Emeritus, Medical Education, Medicine, and Pharmacology, ;
`Dalhousie University, Halifax, Nova Scotia, Canada
`
`*All members of the Editorial Board are former presidents of the American
`Society for Clinical Pharmacology and Therapeutics (ASCP).
`
`Peter K. Honig, MD, MPH
`ExecutiveVice President, Worldwide Regulatory Affairs and Product
`Safety, Merck Research Laboratories, West Point, Pennsylvania
`
`Gregory L. Kearns, PharmD, PhD
`Marion Merrell Dow/Missouri Chair of Pediatric Medical Research,
`Departments of Pediatrics and Pharmacology, University of
`Missouri-Kansas City; Chairman, Department of Medical Research,
`Associate Chairman, Department of Pediatrics, and Chief, Division
`of Pediatric Pharmacology and Medical Toxicology, Children’s Mercy
`Hospitals and Clinics, Kansas City, Missouri
`
`Barbara A. Levey, MD
`Adjunct Professor, Medicine, and Molecular and Medical
`Pharmacology, David Geffen School of Medicine at UCLA; Assistant
`Vice ChancellorforBiomedical Affairs, UCLA,‘Los Angeles, California
`Stephen P. Spielberg, Mp, PhD
`_ Dean and Professorof Pediatrics, Pharmacologyand Toxicology,
`Dartmouth Medical School, Hanover, New Hampshire
`
`Richard Weinshilboum, MD
`Professor of Molecular Pharmacology and Experimental Therapeutics
`and Medicine, Mayo Clinic, Rochester, Minnesota
`
`Raymond L. Woosley, MD, PhD
`CEO,President, and Chairmanofthe Board of Directors, Critical
`Path Institute; Director, Arizona Center for Education and Research
`on Therapeutics, Tucson, Arizona
`
`Page 3 of 26
`
`Page 3 of 26
`
`

`

`Principles to Practice
`
`Pharmacology
`and Therapeutics
`
`, Samuel M.V. Hamilton Professor-of Medicine
`
`Scott A. WaldmarsMD, PhD, FCP
`' Past President, American Society for Clinical Pharmacology 3andThendneuttes
`Professor of Pharmacology and Experimental Therapeuticsain widdicind
`Chair, Department of Pharmacology and Experimental Therapeutics
`, Director, Division of Clinical Pharmacology, Department of Medicine
`| Director, Gastrointestinal Malignancies Program, Kimmel Cancer Center
`- Director, NIH Training Programin “Clinical Pharmacology”
`_ Thomas Jefferson University-
`ra
`eel, Philadelphia, Pennsylvania
`
`i
`
`bee
`Ps
`
`
`Andre Terzic, MD, PhD.
`Past President, American Society for Clinical Pharmacology and Therapeutics
`Marriott Family Professor of Cardiovascular Research
`_ Professor of Medicine and Pharmacology, Medical Genetics
`Director, Marriott Heart Disease Research Program
`- Director, NIH Training Program in “Cardiovasology”:
`‘Mayo Clinic Associate Director for Research
`, Co-Director, Mayo Clinic Center for Individualized Medicine.
`! Mayo Clinic
`| Rochester, Minnesota
`
`
`
`Page 4 of 26
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`Page 4 of 26
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`

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`PHARMACOLOGY AND THERAPEUTICS; PRINCIPLES TO PRACTICE
`Copyright © 2009 by Saunders, an imprintof Elsevier Inc.
`
`ISBN: 978-1-4160-3291-5
`Expert Consult: 978-1-4160-3291-5
`Expert Consult Premium: 978-1-4160-6098-7
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`Library of Congress Cataloging-in-Publication Data
`Pharmacology and therapeutics : principles to practice / [edited by] Scott A. Waldman, Andre Terzic—1si ed.
`5 CI.
`.
`'
`ISBN 978-1-4160-3291-5
`.
`[I Waldman, ScottA.
`1, Pharmacology.
`2. Chemotherapy.
`II. Terzic, Andre,
`[DNLM: 1. Pharmacology, Clinical—methods.
`2, Drug Therapy. QV 38 P53603 2008]
`RM300.P5193 2008
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`615’.1—dce22
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`2007044208
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`* Acquisitions Editor: Druanne Martin
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`

`
`Eo
`
`Part |
`1
`Principles,
`~ PHARMACOTHERAPEUTIC CONTINUUM:
`ENGINEERING THE FUTURE CF INDIVIDUALIZED
`MEDICINE,
`3
`_ Scott A. Waldman and Andre Terzic
`SECTION 1 Pharmacotherapeutic
`Continuum,
`7
`
`1 DRUG DISCOVERY,
`Patrick Vallance
`
`7
`
`15
`
`2 DRUG DEVELOPMENT,
`Steven Ryder and Ethan Weiner
`3 REGULATIONS AND PHARMACOVIGILANCE,
`Robert G. Sharrar, Linda S. Hostelley, and Filia Mussen
`4 EVIDENCE-BASED DRUG UTILIZATION,| 41
`Christine Laine
`.
`
`29
`
`SECTION 2. Molecular Pharmacology,
`5 DRUG-RECEPTOR INTERACTIONS,
`51
`Scott A. Waldman
`
`°
`
`51
`
`6 SIGNAL TRANSDUCTION,
`Philip B. Wedegaertner
`
`67
`
`7 CELL CYCLE PHARMACOLOGY,
`ANTIPROLIFERATION, AND APOPTOSIS, 83
`Saran A. Holstein and Raymond J, Hohl!
`
`SECTION 3 Systems Pharmacology,
`
`91
`
`8 NEUROTRANSMITTERS,
`Eduardo &. Benarroch
`
`91°
`
`9 AUTONOMIC PHARMACOLOGY,
`Anastasios Lymperopoulos and Walter J. Koch
`
`115
`
`10 FLUID AND ELECTROLYTE HOMEOSTASIS,
`Bruce C. Kone
`
`141
`
`11
`
`Be
`
`INFLAMMATION AND
`IMMUNOMODULATION,
`Laurence J. Egan
`
`157
`
`173
`12 PHARMACOBIOLOGY OF INFECTIONS,
`Dionissios Neofytos, Claudine El-Beyrouty, and Joseph A. DeSimane, Jr.
`
`SECTION 4 Clinical Pharmacology,
`
`193
`
`13 PHARMACOKINETICS,
`Arthur J. Atkinson, jr.
`
`.193
`.
`
`14 PHARMACODYNAMICS,
`Richard L. Lalonde
`
`203
`
`15 PHARMACOGENETICS AND
`PHARMACOGENOMICS,
`219
`Richard Weinshilboum
`
`Page 6 of 26
`
`16 HETEROGENEITY OF DRUG RESPONSES AND
`INDIVIDUALIZATION OF THERAPY,
`225
`Julia Kirchheiner and Matthias Schwab
`
`:
`
`239
`17 PEDIATRIC PHARMACOLOGY,
`Kathleen A. Neville, Michael J. Blake, Michael D. Reed, and
`Gregory L. Kearns
`
`18 SEX DIFFERENCES IN PHARMACOLOGY,
`Jean Gray
`
`19 PHARMACOLOGY ACROSS THE AGING
`
`257
`CONTINUUM,
`Naomi Gronich and Darrell R. Abernethy
`
`251 —
`
`20 ADVERSE DRUG REACTIONS AND
`INTERACTIONS,
`265
`Shiew-Mei Huang, Lawrence J. Lesko, and Robert Temple
`
`21 THERAPEUTIC DRUG MONITORING,
`Michael C. Milone and Leslie M. Shaw
`
`275
`
`Part
`
`Practice,
`289
`SECTION 5 Cardiovascular Therapeutics
`
`291
`
`291
`22 HYPERTENSION,
`Jean-Luc Elghozi, Michel Azizi, and Pierre-Frangois Plouin
`
`303
`23 DYSLIPIDEMIAS,
`Matthew 5. Murphy and Timothy O’Brien
`
`24 CORONARY ARTERY DISEASE,
`Arshad Jahangir and Vigar Maria
`
`.
`
`321
`
`367
`25 RHYTHM DISORDERS,
`Dawood Darbar and Dan M. Roden
`
`389
`
`26 HEART FAILURE,
`Arthur M. Feldman
`- SECTION 6 Pulmonary Therapeutics, 401
`27 PULMONARY ARTERIAL HYPERTENSION,
`Azad Raiesdana and Joseph Loscaizo
`
`401
`
`28 ASTHMA AND CHRONIC OBSTRUCTIVE
`PULMONARY DISEASE,
`417 .
`Walter K. Kraft and Frank T. Leone
`
`SECTION 7 Renal Therapeutics,
`‘29 RENAL INSUFFICIENCY,
`435
`Kumar Sharma
`
`435
`
`445
`30 VOIDING DYSFUNCTION,
`; Alan J. Wein, Rajiv Saini, and David R, Staskin
`SECTION 8 Gastroenterologic Therapeutics,
`31 ACID REFLUX AND-ULCER DISEASE,
`457
`Alex Mejia and Walter K, Kraft
`
`457
`
`xvii
`
`Page 6 of 26
`
`

`

`xviii Contents
`
`475
`32 MOTILITY DISORDERS,
`Michael Camilleri and Viola Andresen
`33 INFLAMMATORY BOWEL DISEASES,
`Laurence J. Egan and Christian Maaser
`
`487
`
`505
`34 HEPATIC CIRRHOSIS,
`victor J. Navarro, Simona Rossi, and Steven K. Herrine
`35 NFECTIOUS HEPATITIS, 527 —
`Steven K. Herrine, Simona Rossi, and Victor J. Navarro
`
`SECTION 9 Endocrinologic Therapeutics, 549
`36 OBESITY AND NUTRITION,
`549
`Robert — Kushner
`
`557
`37 DIABETES MELLITUS,
`- Fobert A. Rizza and Adrian Vella
`38 DISORDERS OF THE THYROID, 571
`Felen L. Baron and Peter A. Singer
`
`39 DISORDERS OF CALCIUM METABOLISM AND
`EONE MINERALIZATION,
`587
`Bart L. Clarke and Sundeep Khosla
`
`40 DISORDERS OF THE HYPOTHALAMIC-PITUITARY
`AXIS,
`611
`Run Yu and Glenn DB. Braunstein
`
`41 ADRENAL DISORDERS,
`Lisa Hamaker and Serge Jabbour
`
`623
`
`631
`42 REPRODUCTIVE HEALTH,
`Dale W. Stovall and Jerome F. Strauss,
`lil
`
`SECTPON 10 Neuropharmacologic
`Therapeutics,
`641
`
`43 ALZHEIMER’S DISEASE AND DEMENTIAS,
`Wael N. Haidar and Ronald C. Petersen
`
`.
`
`641
`
`44 PARKINSON'S DISEASE,
`Ludy Shih and Daniel Tarsy
`
`651
`
`— 45 SEIZURE DISORDERS,
`Scott Mintzer
`685
`46 MULTIPLE SCLEROSIS,
`Benjamin M. Greenberg, John N. Ratchford, and Peter A, Calabresi
`
`663
`
`703
`47 DYSAUTONOMIAS,
`” Kyoko Sata, André Diedrich, and David Robertson
`
`48 HEADACHE,
`Alfredo Bianchi
`
`719
`
`743
`49 STROKE,
`Rocney Bell, Kiwon Lee, Carissa Pineda, and David Brock
`
`SECTION 11. Psychopharmacologic
`Therapeutics,
`753
`
`50 OBSESSIVE-COMPULSIVE DISORDERS,
`Darin D. Dougherty and Michael A. Jenike
`
`753
`
`51 ATTENTION-DEFICIT/HYPERACTIVITY
`DISORDER,
`759
`David A. Mrazek and Kathryn M. Schak
`
`769
`52 ANXIETY,
`Chi-Jn Pae and Ashwin A. Patkar
`
`Page 7 of 26
`
`53 DEPRESSION AND BIPOLAR DISORDERS,
`Wade Berrettini
`
`787
`
`797
`54 PSYCHOSIS AND SCHIZOPHRENIA,
`Steven J. Siegel, Mary E, Dankert, and Jennifer M. Phillips
`
`817
`55 DRUG ADDICTION,
`Doo-Sup Chai, Victor M. Karpyak, Mark A, Frye,
`Danial K. Hall-Flavin, and David A. Mrazek
`56 NICOTINE DEPENDENCE,
`837
`Neal L, Benowitz
`
`57 INSOMNIA (NARCOLEPSY)-RELATED
`DISORDERS,
`849
`Teofilo Lee-Chiong and james F. Pagel
`SECTION 12. Ophthalmologic Therapeutics,
`58 DRUGS IN OPHTHALMOLOGY,
`857
`Douglas J. Rhee and William S. Tasman:
`
`857
`
`- SECTION 13 Anesthesia,
`
`863
`
`59 LOCAL ANESTHESIA,
`John E. Tetztaff
`
`863
`
`60 GENERAL ANESTHESIA AND SEDATION,
`Joseph F. Foss and Marco A, Maurtua
`61 TREATMENT OF PAIN, 883
`Kishor Gandhi, James W. Heitz, and Eugene R, Viscusi
`SECTION 14 Hematologic Therapeutics,
`62 ANEMIAS AND CYTOPENIAS,
`895
`Nandi J. Reddy and Lionel D, Lewis
`63 DISORDERS OF HEMOSTASIS AND
`THROMBOSIS,
`909
`Erev E, Tubb and Steven &. McKenzie
`
`873
`
`895
`
`SECTION 15 Oncologic Therapeutics,
`
`921
`
`| 921
`G4 LUNG CANCER,
`Sarah A. Holstein and Raymond J. Hoh!
`
`933
`65 BREAST CANCER,
`Vivek Roy and Edith A. Perez
`
`66 HEMATOLOGIC MALIGNANCIES,
`Jasmine Nabi and Raymond J. Honl
`
`945
`
`951
`67 PROSTATE CANCER,
`Sarah A, Holstein and Raymond J. Hohl
`68 COLON CANCER,
`959
`Muhammad Wasif Saif and Robert 8. Diasio
`
`969
`69 MELANOMA,
`Jasmine Nabi and Raymond J. Hohl
`
`SECTION 16 Dermatologic Therapeutics,
`
`973
`
`973
`7O ACNE,
`Joseph Genebriera and Mark Davis
`
`~
`
`71
`
`983
`PSORIASIS,
`Mark R. Pittelkow and Joseph Genebriera
`
`72 DERMATITIS,
`Mark Davis
`
`1007
`
`Page 7 of 26
`
`

`

`Contents
`
`xix
`
`SECTION 17 Rheumatologic Therapeutics,
`73 CSTEOARTHRITIS,
`1015
`William. — Harvey and David J. Hunter
`
`74 RHEUMATOID ARTHRITIS,
`Richard M. Keating
`
`1025
`
`1015
`
`85 SEXUALLY TRANSMITTED DISEASES,
`Kristine E. Johnson and Anne M. Rompalo
`
`1201
`
`SECTION 19 Practical Therapeutics,
`
`1213-
`
`86 MEDICAL TOXICOLOGY AND ANTIDOTES,
`Themas P. Moyer
`:
`
`1213
`
`1039 -
`75 COUT,
`Michael P. Keith, William &. Gilliland, and Kathleen Uhl
`
`87 OVER-THE-COUNTER MEDICATIONS,
`Barbara A. Levey
`
`1221
`
`1047
`76 SYSTEMIC LUPUS ERYTHEMATOSUS,
`William R. Gilliland, Michael P. Keith, and Kathleen Uhl!
`
`88 PRESCRIPTION AND ORDER WRITING,
`Carol L. Beck
`:
`
`1225
`
`89 PHARMACY AND THERAPEUTICS COMMITTEES
`AND THE HOSPITAL FORMULARY,
`1233
`:
`Joseph §. Bertino, Jr.
`SECTION 20 Emerging Therapeutics,
`90 COMPLEMENTARY AND ALTERNATIVE
`MEDICINE, NUTRACEUTICALS, AND DIETARY
`SUPPLEMENTS, 1237
`Christine A. Haller
`
`1237
`
`/
`1247
`91 VACCINES,
`Paul ¥. Targonski, Inna G. Ovsyannikova, Pritish K. Tosh,
`Robert M. Jacobson, and Gregory A. Poland
`
`1269
`92 TRANSPLANT MEDICINE,
`Mark Chaballa, Joanne Filicko-O’Hara, Dorothy Holt, Adam M. Frank,
`John-L. Wagner, Dolores Grosse, and Neal Flomenberg
`
`1295
`93 GENE THERAPY,
`Stephen J. Russeli and Kah Whye Peng
`94 REGENERATIVE MEDICINE AND STEM CELL
`THERAPEUTICS,
`1317
`Timothy J. Nelson, Atta Behfar, and Andre Terzic
`
`INDEX,
`
`1333
`
`SECTION 18 Therapy of Infectious
`Diseases,
`1063
`INFLUENZA AND VIRAL RESPIRATORY
`INFECTIONS,
`1063
`Joseph PLynch, lil
`
`77)
`
`.
`
`78 COMMUNITY-ACQUIRED PNEUMONIA,
`Andrew R. Haas and Paul E. Marik
`79 TUBERCULOSIS,
`1089
`Ying Zhang
`
`1081
`
`1109
`80 EACTERIAL MENINGITIS,
`Ciederik van de Beek, Martijn Weisfelt, and Jan de Gans
`
`1121
`81 ENDOCARDITIS,
`Lsa G. Winston, Daniel Deck, and Ann F. Bolger
`
`1141
`82 MALARIA,
`Myaing Nyunt and Christopher V. Plowe
`
`83 PROTOZOAN AND HELMINTHIC
`INFECTIONS,
`1171
`Eric R. Houpt and Orner Chaudhry
`
`84 HIV INFECTIONS AND AIDS,
`Faul 4. Pharn and Charles W. Flexner
`
`1187
`
`Page 8 of 26
`
`Page 8 of 26
`
`

`

`
`
`
`
`MULTIPLE SCLEROSIS
`
`Benjamin M. Greenberg, John N. Ratchford, and Peter A. Calabresi
`
`OVERVIEW 685
`INTRODUCTION 685
`Epidemiology 685
`Genetics
`685
`Clinical Features
`Diagnosis 686
`PATHOPHYSIGLOGY 687
`THERAPEUTICS AND CLINICAL
`PHARMACGLOGY 689
`Goals of Therapy 689
`Therapeutics by Class
`
`689
`
`685
`
`689
`Immunomodulators
`691
`Immunosuppressanis
`692
`Therapeutic Approach
`Treatment with DMT: Patient
`692
`Selection and Initiation
`First-Line Treatment for RRMS
`Treatments Helpful in SPMS
`Treatments Helpful in PPMS
`Definition of Treatment Failure
`Management of Breakthrough
`Disease Activity
`695
`
`:
`693
`694
`695
`695
`
`Management of Acute
`Relapses
`695 .
`_ Treatments Helpful for Common
`MS-Related Symptoms
`696
`Treatment Considerations Related
`to Pregnancy
`697
`Treating the Pediatric MS
`Patient
`697
`Emerging Targets and
`Therapeutics
`698
`
`OVERVIEW
`
`Multiple sclerosis (MS) is a complex disease of the central nervous
`system (CNS) with the potential to cause significant physical and emo-
`tional disability. Approximately 350,000 Americansare currently diag-
`aosed with MS, and the direct and indirect costs associated with the
`disease are about $14 billion per year.’ MS is the most common non-
`traumatic cause of neurologic disability in early to middle adulthood.
`There is an inherentvariability from patient to patient with regard to
`disease course and severity. Some patients experience frequent exacer-
`dations with escalating disability while others havea relatively benign
`course. Most commonly the disease begins with episodic relapses that
`are separated by periods of remission. In the later stages of the disease,
`many patients will develop slowly progressive neurologic disability.
`Most evidence points to an immune-mediated pathophysiology involv-
`ing B and T lymphocytes, macrophages, and microglia. According to
`this hypothesis, an autoimmuneresponse against CNS myelinis initi-
`ated, leading to demyelination and axonal injury. To date, the most
`effective therapies have been immunosuppressant and immunomodu-
`latory drugs. While none of the approaches can be described as cura-
`tive, the presently approved drugs have led to significant reductions in
`relapse rates and disability.
`.
`.
`
`INTRODUCTION |
`Epidemiology
`The typical age of onset for MS is between 20 and 40. The disease is
`unusual before adolescence, but onset has been described as young as
`age 2 and as old as age 74. The ratio of affected women to men is
`between 1.7:1 and 2.5:1, althoughthe ratio is more even at olderages
`of onset. Several important epidemiologic observations have been
`made ahout the geographic distribution of MS. In both the northern
`and southern hemispheres, the prevalence of the disease increases with
`increasing distance from the equator. Thereis also a difference in risk
`tor different ethnic groups, independent of latitude. For example,
`England and Japan are at the samelatitude, but the prevalence of MS
`’ differs significantly in the two countries (85 per 100,000 for England
`versus 1.4 per 100,000 in Japan). Caucasians tend to have the highest
`risk, while lowerrisk is seen in people of African or Asian descent. The
`highest prevalence is seen in the northern United States, southern
`Canada, northern Europe, and southern Australia.: The southern
`United States and southern Europe have a moderate prevalence. The
`
`.
`
`lowest prevalence is seen in Japan, China, Latin America, and equato-
`rial Africa. Migration studies have also added te our understanding of
`the relationship between geography and risk of MS, Children born to
`parents who migrated from a low- to a high-risk area had an increase
`in their risk of developing MS, and vice versa.’ By analyzing the ages
`. of migrants, it was suggested that one’s environmentalrisk was deter-
`mined by aboutage 15.’ This has led to hypotheses that the risk of MS
`is partly determined byviral exposures during childhood. Recent data
`suggest that the incidence of MS may be increasing, especially in
`women, although issues regarding ascertaininent and diagnosis make
`these studies challenging.
`
`Genetics
`
`In addition to environmental factors, penetics influences the risk of
`developing MS. Family clusters are known to occur. Twin studies have
`found that the monozygotic twin of an MS patient has about a 30%
`chance of developing MS. Dizygatic twins have a risk that is similar to
`that of any sibling of an MS patient, about 2% to 5%. The risk in
`. children of MSpatients is slightly lower than for siblings. Second- and
`third-degree relatives of an MS patient also carry some elevated risk,
`Genetic studies have found the strongest association with the major
`histocompatibility complex (MHC), particularly the HLA-DRB1 locus.
`More recently, two additional genes were identified in genome-wide
`scans,’ the interleukin-2 receptor alpha gene and the interleukin-7
`receptor alphagene. Thefactthatall three genes are part of the immune
`system serves as an important confirmation of the autoimmunenature
`of this disease.
`:
`
`Clinical Features
`
`MShasclassically been separated into four different subtypes: relaps-
`ing-remitting, secondary progressive, primary progressive, and pro-
`gressive relapsing MS (Fig. 46-1). Relapsing-remitting MS (RRMS) is
`the most commonclinical subtype, representing about 85%ofpatients
`at diagnosis. It is marked by intermittent exacerbations that maypartly
`or completely resolve over weeks to months. These relapses are sepa-
`rated by periods of clinical stability. However, patients may continue
`to experience symptoms from priorrelapses that healed incompletely.
`After a variable period of time, a majority of RRMSpatients will enter -
`a secondary progressive phase of the disease (SPMS). SPMSpatients
`experience a slowly progressive worsening of disability that may or may
`not have superimposed relapses. About 10% to 15%of patients will
`
`. 685
`
`Page 9 of 26
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`Page 9 of 26
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`

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`Section 10 Neuropharmacologic Therapeutics
`
`have a primary progressive course (PPMS), marked by slowly progres-
`sive worsening from the outset without relapses. A small number of
`patients are labeled as having progressive relapsing MS, These patients
`begin with a progressive course but develop one or more relapses.
`Patients who have had a single demyelinating event, but do not yet
`meet criteria for MS, are referred to as having a clinically isolated
`syndrome.
`MScan present with a large number of symptomspossibly referable
`to the CNS. The symptoms may be transient and often difficult to
`describe. Classic MS symptoms include unilateral blurred vision with
`b-ow pain on lateral eye movement, weakness, numbness, paresthesias,
`pain,
`imbalance, double vision, bladder and bowel dysfunction,
`impaired coordination,fatigue, depression, cognitive impairment, heat
`intolerance, and sexual dysfunction. On exam, commonsigns include
`y.sual
`impairment, brainstem dysfunction, nystagmus, dysarthria,
`spasticity, hyperreflexia, weakness, sensory loss, and ataxia. Several
`paroxysmal phenomena can be associated with MS, including tonic
`
`
`
`FEGURE 46-1 © A diagrammatic representation of disability by time for
`different subtypes of MS. 4, Relapsing-remitting M5. B, Secondary
`progressive MS. C, Primary progressive MS. D, Progressive relapsing M5.
`
`spasms, trigeminal neuralgia, and myokymia. New clinical symptom:
`are thought to result from new areas of inflammation and demyelin-
`ation, while the acquisition of long-term disability is morerelated te
`axonal damage.*?
`
`Diagnosis
`The diagnosis of MS can be challenging as thereis no single test with
`adequate sensitivity or specificity and there are several potential!
`' mimics. MS was classically diagnosed by the identification of lesions
`attributable to the CNS white matter that were separated in time and
`space with objective findings on neurologic exam and nobetter expla-
`nation.® However, the advent of magnetic resonance imaging (MRI
`has significantly changed how the diagnosis is made. ‘Currently, the
`most widely used diagnostic criteria are the McDonald criteria, which
`were last revised in 2005 (Table 46-1).’ These criteria endorsed the use
`of MRI as a surrogate marker for defining separation in time anc
`space.
`Brain MRI in MSclassically shows lesions that are iyberiitensean
`T2-weighted sequences (Fig. 46-2). Lesions are frequently in the peri-
`ventricular white matter, often extending perpendicular to the ven-
`tricle. Lesions of the corpus callosum are common in M$,asarelesions
`in the subcortical white matter, cerebellum, brainstem, and spinal cord.
`Newerimaging techniques are also identifying an increased numbero7
`lesions in the cortex. Acute lesions will often enhance with gadolinium
`indicating active inflammation with blood-brain barrier (BBB) break-
`down. Areas of hypointensity on Tl sequences are also seen. Ti
`hypointensity is observed transiently in acute lesions. However, when
`itis present chronically,it likely represents an area of significant axonal
`damage. Disability correlates more strongly with the T1 hypointensit:
`volume than the volume of T2 hyperintensities. With time, the accu-
`mulating axonal damage will often manifest as global cerebral atrophy.
`Only about 5% to 10%of lesions seen on MRI are associated with
`clinical symptoms. Gray matter lesions are also common in MS, but
`are not well seen on conventional MRI.
`
`
`Additional Baa Needed for MS Diagnosis
`*« None
`
` ical Presentation
`
`2 or more attacks; objective clinical evidence of 2 or
`morelesions
`
`2 or more attacks; objective clinical evidence of 4
`lesion
`
`Dissemination in space, demonstrated’ by:
`MRI
`or
`
`*~ attack; objective clinical evidence of 2 or more
`lesions
`
`% attack; objective clinical evidence of1 lesion
`{monosymptomatic presentation; clinicalWiisolated
`syndrome)
`
`i
`
`,
`
`‘
`
`5
`
`Insidious neurologic progression suggestive of MS
`
`-92 or more MRi-detected lesions consistent with MS plus positive CSF
`or
`Await further clinical attack implicating a different site
`Dissemination in time, demonstrated by:
`—MRI
`or
`Second clinical attack
`
`Dissemination in space, demonstrated by:
`—MRI
`or
`2 of more MRI-detected lesions consistent with MSplus positive CSF
`and
`Dissemination in time, demonstrated by:
`-—3MRI
`or
`Second clinical attack
`
`°
`
`* One year of disease progression (retrospectively or prospectively determined)
`and
`Two out of three of the following:
`a. Positive brain MRI (9 T2 lesions or 4 or more T2 lesionswith positive visua)
`evoked potentials)
`;
`b. Positive spinal cord MRI {2 or more focal T2 lesions) °
`c. Positive CSF
`
`CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis.
`From Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005:58:840-846.
`
`Page 10 of 26
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`687
`
`Chapter 46 Multiple Sclerosis
`
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`FIGURE 46-2 + Brain MRI of a patient with MS. A, Axial fluid-attenuated inversion recovery (FLAIR) image showing multiple hyperintensities. B, Axial T1-
`weighted image at the same jevel. Some of the areas of FLAIR hyperintensity are also hypointense on T1-weighted images. C, Sagittal FLAIR image showing
`periventricular hyperintensities.
`
`In the past, a cerebrospinal fluid (CSF) exam was a common part of
`the MS diagnosis. The presence of an elevated protein, oligoclonal
`bands, or an elevated immunoglobulin G index is supportive of the
`diagnosis. Although CSF analysis is still important in some cases to
`rule out other diagnoses such as infections, it is often unnecessary in
`routine cases, Evoked potentials of the visual, auditory, or somatosen-
`sory pathways can be helpfulin somecasesto detect subclinical lesions
`that cannot be seen on MRI.
`.
`
`PATHOPHYSIOLOGY
`
`Classically, MS has been described as an immune-mediated demyelin-.
`ating disease affecting the brain, spinal cord, and optic nerves.* Recent
`research has reemphasized the concomitant presence of both gray
`_ matter pathology and extensive axonal damagein the brainsofpatients
`diagnosed with MS.”"° Theexact cause(s) of MS have not been deter-
`mined, but a combination of genetic and environmental factors
`coalesces in some people to lead to demyelination and axonal damage.
`Onetheory is that certain viruses may share sequence homology with
`myelin proteins and, through molecular mimicry, mediate aberrant
`activation of cross-reactive T cells. Viruses may also cause bystander
`activation through release of cytokines or stimulation of antigen-pre-
`senting cells. It is possible that MS is actually a syadromeof various
`related diseases that causc episodic demyelination and neuronal
`damage. Four pathologic subtypes of MS have been described, as dis-
`cussed later, confirming a variety of immunopathogenetic mechanisms
`involved in different types of MS. While most of these types have an
`immune-mediated component,there are some aspects of MS that may
`be independentof the immunesystem. For example, the degeneration
`of chronically demyelinated axons that occurs in the secondary pro-
`gressive phase of the disease appears to be noninflammatory. To date,
`the only successful treatment strategies for MS have involved immu-
`nomodulatory or immunosuppressive approaches, supporting therole
`that the immunesystem plays. Moreover, these therapies generally are
`effective only during the relapsing-remitting phase, the most inflam-
`matory phase of the disease.
`Pathologic examination of the CNS in patients with MS§ typically
`identifies an inflammatory response involving cellular and humoral
`immune systems. Whether or not the immune system begins by rec-
`ognizing a foreign antigen and then strays against self or begins. by
`recognizing self-antigens is unknown. Fundamental
`to the classic
`description of MS pathogenesis is the inappropriate disruption of the
`BBB. Normally, the BBB is composed of specialized endothelial cells
`with an intricate network of tight junctions. Functionally, the BBB
`
`significantly restricts the diffusion of molecules from the periphery
`into the CNS. Disruption of the BBB by immunecells in MSis respon-
`sible for gadolinium-enhancing lesions on MRI and “attacks” in MS
`patients. Lymphocytes are able to migrate across the BBB via a series
`of adhesion molecule interactions. Critical to this process is a connec-
`tion between very late antigen-4 (VLA-4) on lymphocytes and mono-
`cytes andits ligands vascular cell adhesion molecule-1 (VCAM-1) on
`endothelial cells and fibronectin in the basement membrane.'' Pre-
`“sumably, once effector cells from the immune system have gained
`access to the CNS, they secrete a cascade of cytokines that lead to
`demyelination and ultimately axonal damage(Fig. 46-3).
`Numerous studies have analyzed the relative role that CD4* and
`CD8* T cells play in disease pathogenesis. Epidemiologic studies and
`mouse models have linked MS to MHC class II genes, which present
`antigens to CD4* T cells.’*“ Thus, CD4* Tcells have been ofinterest
`for years. The production of tumor necrosis factor (TNE) from CD4
`T cells correlates with the number of T2-hyperintense lesions on
`MRI."? While autoreactive T cells have been identified in patients with’
`MS and in healthy volunteers, the CD4*T cells are functionally differ-
`ent in patients with MS. Specifically, they tend to be more differenti-
`ated and have a higher level of T helpercell type 1 (Th1) phenotypes
`in patients with MS compared to controls.’* Yet, therapy directed
`against CD4* T cells made only a smal} difference in patients treated
`in clinicaltrials.'""* Therapy that depleted both CD4* and CD8*T cells,
`however, led to a reduction in disease activity.""*! The role of T helper
`type 17 (Th17) cells in MSis less clear. This newly described subset of
`T cells has been implicated in an animal model of MS, experimental
`autoimmune encephalomyelitis, and interleukin (IL)-17 expression
`can be seen in MSbrain-infiltrating cells.
`Several studies have identified the potential rele of CD8* T cells in
`MS. Genetic studies have implicated varions MHC class I genes as
`being associated with increased risk of MS while some MHCclass T
`genes are protective.””* Persistence of autoreactive CD&*T cells in the
`CSF ofpatients with MS has been described.” In mouse studies, CD8*
`T cells have been shown to potentiate immune-mediated demyeli-
`nating disease.” Yet,
`there are also data that suggest