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`Pharmacology
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`Principles to Practice
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`. Pha‘rmacolbgy
`and Therapeutics
`Principles to Practice
`
`Page 2 of 26
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`Page 2 of 26
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`

`

`ASSOCIATE EDITORS
`
`Laurence J.‘Egan. MD, FRCPI
`Professor, National University of Ireland, Galway; Department of
`Pharmacology and Therapeutics, Clinical Science Institute, University
`College Hospital Galway, Newcastle, Galway, Ireland
`
`Mental D. Léwis. MA, NIB BCI‘I. MD, FRCP (London)
`Professor. of Medicine/Pharmacology and Toxicology, Department '
`of Medicine, Dartmouth Medical School and Dartmouth Hitchcock
`Medical Center, Lebanon, New Hampshire
`
`Jean-Luis Elghozi, MD, PhD
`Professor of Pharmacology, Faculté de Me'decine, UniversitéParis—
`Descartes; Head, Clinical Pharmacology Unit, Hopital Necker,
`Paris, France
`
`.
`
`Arshacl Jahangir, 'MD
`Associate Professor of- Medicine, Division of Cardiovascular Diseases,
`Mayo Clinic, Rochester, Minnesota
`
`Garvan C. Kane, MD, PhD
`. Assistant Professor of Medicine, Division of Cardiovascular Diseases,
`Mayo Clinic, Rochester, Minnesota
`
`Walter K. Kraft, MD, MS
`Associate Professor of Pharmacology and Experimental Therapeutics
`and Medicine, Director of the Jefferson Clinical Research Unit,
`Thomas Jefferson University, Philadelphia, Pennsylvania
`
`Jason D Morrow, MD
`Chief, Division of Clinical Pharmacology, P. Tremaine Billings
`Professor of Medicine and Pharmacology, and Director of the
`Research'Center for Pharmacology and Drug Toxicology, Vanderbilt
`University Medical Center, Nashville, Tennessee
`
`.
`Leonid V. zingman, MD
`Assistant Professor of Medicine, Department of Medicine, University
`of Iowa, l‘owa City, Iowa
`
`
`
`EDITORIAL BOARD*
`
`f‘
`
`
`
`Peter K. Honig, MD, MPH
`ExecutiveVice President, Worldwide Regulatory Affairs and Product
`Safety, Merck Research Laboratories, West Point. Pennsylvania
`
`Gregory L. K‘earns, 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. Le‘vey, MD
`Adjunct Professor, Medicine, and Molecular and Medical
`Pharmacology, David Geffen School of Medicine at UCLA, Assistant
`Vice Chancellorfor Biomedical Affairs, UCLA, Les Angeles, California
`
`Stephen P. Spielberg, MD, PhD
`_ Dean and P10fesSor of Pediatrics, Pharmacology and Toxicology,
`Dartmouth Medical School, Hanover, New Hampshire
`
`Richard Wei'nshilbou'm, MD
`Professor of Molecular Pharmacology and Experimental Therapeutics
`and Medicine, Mayo Clinic, Rochester, Minnesota
`
`Raymond I... Woosley, MD, PhD
`CEO, President, and Chairman of the Board of Directors, Critical
`Path Institute; Director, Arizona Center for Education and Research
`on Therapeutics, Tucson, Arizona
`
`l D
`
`arrell R. Abernethy, MD, PhD
`Professor of Medicine and Pharmacology and Molecular Science,
`lohns 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, Illinois
`
`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), .1351: (Hon),
`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 (ASCPT).
`
`Page 3 of 26
`
`Page 3 of 26
`
`

`

`Principles to Practice
`
`Pharmacology
`and Therapeutics
`
`ScottA. Waldman, MD, PhD, FCP
`5 Past President, American Society for Clinical Pharmacology and Therapeutics .
`; Samuel MV. Hamilton Professor of Medicine
`'.
`.
`l Professor of Pharmacology and Experimental Therapeutics and MedICIne
`Chair, Department of Pharmacologyand Experimental Therapeutics
`; Director Division of Clinical Pharmacol0gy, Departmentof Medicine
`.7 “Director, Gastrointestinal Malignancres Program, Kim'mél Cancer Center
`
`, Director, NIH Training Program in ”Clinical Pharmacology"
`j Thomas Jeffersonflniversit‘y .
`I
`7
`‘
`Philadelphia, Pennsylvania
`
`‘
`
`.
`
`I
`
`
`' Andre Terzic, MD, PhD
`Past President, American Societyfor Clinical Pharmacology and Therapeutics
`Marriott Family Professor of Cardiovascular Research
`'
`. Professor of Medicine and Pharmacology, Medical Genetics
`I Director, Marriott Heart Disease Research Program
`3 Director, NIH Training Program in "'Cardiovasology'”
`5 Mayo Clinic Associate Director for Research
`5 Co-Director, Mayo Clinic Center for individualized Medicine, I
`I Mayo Clinic
`'
`'
`I Rochester, Minnesota
`
`‘
`
`
`
`Page 4 of 26
`
`Page 4 of 26
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`

`

`
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`u
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`.. .
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`,
`
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`. K
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`SAUNDERS
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`PHARMACOLOGY AND THERAPEUTICS: PRINCIPLES TO PRACTICE
`CopyTight © 2009 by Saunders. an imprint of Elsevier Inc.
`
`ISBN: 9784-4160-3316
`Expert Consult: 9784-4160-3291-5
`Expert Consult Premium: 978—17416076098-7
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`our knowledge. changes in practice, treatment and drug therapy may become necessary or appropriate.
`Readers are advised to check the most current information provided (i) on procedures featured or (ii) by
`the manufacturer of each product to be administered, to verify the recommended dose or formula, the
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`Library of Congress Cataloging-imPublicatiun Data
`Pharmacology and therapeutics: principles to practice I [edited by] Scott A. Waldman, Andre Teflic.~lst ed.
`.
`; cm.
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`ISBPN 978—1-4160-329l—5
`H. Terzic, Andre.
`I. Waldman, Scott A.
`i. Pharmacology.
`2. Chemotherapy:
`[DNLll/l:
`l. Pharmacology, Clinical—methods.
`2, Drug Therapy. QV 38 l’53603 2008]
`RM300.P5193 2008
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`

`
`I CONTENTS 3'
`
`Part 1
`
`1
`Principles,
`'PHARMACOTHERAPEUTIC CONTINUUM:
`ENGINEERING THE FUTURE OF INDIVIDUALIZED
`MEDICINE,
`3
`_ Scott A. Waldman and Andre Terzlc
`
`SECTION 1 Pharmacotherapeutic
`Continuum,
`7
`
`1 DRUG DISCOVERY,
`Patrick Vallance
`
`7
`
`2 DRUG DEVELOPMENT,
`Steven Ryder and Ethan Weiner
`
`15
`
`3 REGULATIONS AND PHARMACOVIGILANCE,
`Robert G. Sharrar, Linda S. Hosteiley, and Filip Mussen
`
`29
`
`4 EVIDENCEBASED DRUG UTILIZATION. 41
`Christine Laine
`.
`
`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
`Sarah A. Holstein and Raymond J. Hohl
`
`SECTION 3 Systems Pharmacology,
`
`91
`
`8 NEUROTRANSMITTERS, 91'
`Eduardo E. Benarroch
`
`9 AUTONOMIC PHARMACOLOGY,
`Anastasios Lymperopoulos and Walter J. Koch
`
`115
`
`10 FLUID AND ELECTROLYTE HOMEOSTASIS,
`Bruce C. Kone
`
`141
`
`11
`
`“
`
`INFLAMMATION AND
`IMMUNOMODULATION,
`Laurence J. Egan
`
`157
`
`173
`12 PHARMACO‘BIOLOGY OF INFECTIONS,
`Dio'nissios Neofytos, Claudine E|»Beyrouty, and Joseph A. DeSimone, Jr,
`
`SECTION4 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,
`Julia Kirchheiner and Matthias Schwab
`
`225
`
`239
`17 PEDIATRIC PHARMACOLOGY,
`Kathleen A. Neville, Michael J. Blake, Michael DI. Reed, and
`Gregory L. Kearns
`
`18 SEX DIFFERENCES IN PHARMACOLOGY,
`Jean Gray
`19 PHARMACOLOGY ACROSS THE AGING
`CONTINUUM,
`257
`Naomi Gronich and Darrell R. Abernathy
`
`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 ill
`
`,
`,
`289
`Practice,
`SECTION 5 , Cardiovascular Therapeutics,
`22 HYPERTENSION,
`291
`Jean-Luc Elghozi, Michel Azizi, and Pierre—Francois Plouin
`
`291
`
`303
`23 DYSLIPID EMIAS,
`Matthew S. Murphy and Timothy O'Brien
`
`24 CORONARY ARTERY DISEASE 321
`Arshad Jahangir and quar Maria
`
`367
`25 RHYTHM DISORDERS,
`Dawood Darbar and Dan M. Roden
`
`26 HEART FAILURE,
`Arthur M. Feldman
`
`389
`
`I SECTION 6 Pulmonary Therapeuticsf 401
`27 PULMONARY ARTERIAL HYPERTENSION,
`Azad Raiesdana and Joseph Loscalzo
`
`401
`
`28 , ASTHMA AND CHRONIC OBSTRUCTIVE
`PULMONARY DISEASE,
`417 ., _
`Walter K. Kraft and Frank T. Leone
`
`SECTION? Renal Therapeutics,
`
`435
`
`‘29 RENAL INSUFFICIENCY,
`Kumar Sharma
`
`435
`
`445
`30 VOIDING DYSFUNCTION,
`. Alan J. Wein, Rajiv Sainl, and David R. Staskin
`SECTIONS Gastroenterologic Therapeutics,
`31 ACID REFLUX ANDULCER 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
`
`53 DEPRESSION AND BIPOLAR DISORDERS,
`Wade Berrettini
`
`787
`
`33-
`
`INFLAMMATORY BOWEL DISEASES,
`Laurence J. Egan and Christian Maaser
`
`487
`
`505
`34 HEPATIC CIRRHOSIS,
`Jictor J. Navarro, Simona Rossi, and Steven K. Herrine
`
`>35 NFECTIOUS HEPATITISf 527'
`Steven K. Herrine, Simona Rossi, and Victor J. Navarro
`
`SECTION 9 Endocrinologic Therapeutics.
`36 OBESITY AND NUTRITION,
`549
`Robert F. Kushner
`
`549 _
`
`557
`37 DIABETES MELLITUS,
`7 Fobert A. Rizza and Adrian Vella
`
`38 DISORDERS OF THE THYROID,
`I-elen L. Baron and Peter A. Singer
`
`‘571
`
`39 DISORDERS OF CALCIUM METABOLISM AND
`EONE MINERALIZATION,
`587
`Bart L. Clarke and Sundeep Khosla
`
`40 DISORDERS OF THE HYPOTHALAMIC-PITUITARY
`AXIS,
`611
`Rin Yu and Glenn D, Braunstein
`
`41 ADRENAL DISORDERS,
`Lisa Hamaker and Serge Jabbour
`
`623
`
`631
`4-2 REPRODUCTIVE HEALTH,
`Dale W. Stovall and Jerome F. Strauss,
`lII
`
`SECTION 10 Neuropharmacologic
`Therapeutics,
`641
`
`43 ALZHEIMER’S DISEASE AND DEMENTIAS,
`Wael N. Haidar and Ronald C. Petersen
`
`.
`
`641
`
`44 PARKINSON’S DISEASE,
`Ludy 5th and Daniel Tarsy
`
`6S1
`
`‘ 45 SEIZURE DISORDERS,
`Scott Mintzer
`
`663
`
`685
`46 MULTIPLE SCLEROSIS,
`Benjamin M. Greenberg, John N. Ratchford, and Peter A. Calabresi
`
`703
`47 DYSAUTONOMIAS,
`I Kyoko Sato, Andre Diedrich, and David Robertson
`
`48 HEADACHE,
`Alfredo Blanché
`
`719
`
`743
`49 STROKE,
`Rocney Bell, Kiwon Lee, Carissa Pineda, and David Brock
`
`SECTION 11 Psychopharmacologic
`Therapeutics,
`753
`
`50 OBSESSIVE—COMPULSIVE DISORDERS,
`Dar'm D. Dougherty and Michael A. Jenike
`
`753
`
`5‘1 ATTENTION—DEFICITIHYPERACTIVITY
`DISORDER,
`759
`David A. Mrazek and Kathryn M. Schak
`
`769
`52 ANXIETY,
`Chi-Jn Fae and Ashwin A. Patkar
`
`797
`54 PSYCHOSIS AND SCHIZOPHRENIA,
`Steven J. Siegel, Mary E. Dankert, and Jennifer M. Phillips
`
`817‘
`55 DRUG ADDICTION,
`DoovSup Choi, Victor M. Karpyak, Mark A. Frye,
`Daniel K.7Hall-Flavin, and David A. Mrazek
`
`56 NICOTINE DEPENDENCE,
`Neal L. Benovvitz
`
`837
`
`57 INSOMNIA (NARCOLEPSY)-RELATED
`DISORDERS,
`849
`Teofilo Lee-Chlong and James F. Page]
`
`SECTION 12 Ophthalmologic Therapeutics,
`58 DRUGS IN OPHTHALMOLOGY,
`857
`Douglas J. Rhee and William S. Tasman'
`
`657
`
`SECTION 13 Anesthesia,
`
`863
`
`59 LOCAL ANESTHESIA,
`John E. Tetzlafl‘
`
`863
`
`60 GENERAL ANESTHESIA AND SEDATION,
`Joseph F. Foss and Marco A. Maurtua
`
`873
`
`‘833
`61 TREATMENT OF PAIN,
`Kishor Gandhi, James W. Heitz, and Eugene R. Viscusi
`
`SECTION 14 Hematologic Therapeutice,
`62 ANEMIAS AND CYTOF’ENIAS,
`895
`Nandi J. Reddy and Lionel D, Lewis
`
`895
`
`63 DISORDERS OF HEMOSTASIS'AND
`THROMBOSIS,
`909
`Erev E. Tubb and Steven E. McKenzre
`
`SECTION 15 Oncologic Therapeutics,
`
`921
`
`' 921
`54 LUNG CANCER,
`Sarah A. Holstein and Raymond J. Hohl
`
`- 933
`65 BREAST CANCER,
`Vivek Roy and Edith A. Perez
`
`66 HEMATOLOGIC MALIGNANCIES,
`Jasmine Nabi and Raymond J. Hohl
`
`945
`
`951
`67 PROSTATE CANCER,
`Sarah A. Holstein and Raymond J. Hohl
`68 COLON CANCER,
`959
`Muhammad Wasif Saif and Robert B. Diasio
`
`969
`69 MELANOMA,
`Jasmine Nabi and Raymond J. HohI
`
`SECTION 16 Dermatologic Therapeutics,
`
`973
`
`973
`70 ACNE,
`Joseph Genebriera and Mark Davis
`
`'
`
`71
`
`983
`PSORIASIS,
`Mark R. Pittelkow and Joseph Genebriera
`
`72 DERMATITIS,
`Mark Davis
`
`1007
`
`Page 7 of 26
`
`Page 7 of 26
`
`

`

`Contents
`
`xix
`
`SECTION 17 Rheumatologic Therapeutics,
`73 CSTEOARTHRITIS,
`1015
`William F. Harvey and Davrd J. Hunter
`
`74 RHEUMATOID ARTHRITIS,
`Richard M. Keatin'g
`
`1025
`
`1015
`
`85 SEXUALLY TRANSMITTED DISEASES,
`Kristine E. Johnson and Anne M. Rompalo
`
`1201
`
`SECTION 19 Practical Therapeutics.
`
`1213 ‘
`
`36 MEDICAL TOXICOLOGY AND ANTIDOTES,
`Thomas P. Moyer
`.
`
`1213
`
`1039 ’
`75 GOUT,
`Michael P. Keith, William R. Gilliland, and Kathleen Uhl
`
`87 OVER-THE-COUNTER MEDICATIONS,
`Barbara A. Levey
`
`1221
`
`1047
`'75 SYSTEMIC LUPUS ERYTHEIVIATOSUS,
`William R. Gilliland, Michael P. Keith, and Kathleen UhI
`
`88 PRESCRIPTION AND ORDER WRITING,
`Carol L. Beck
`.
`
`1225
`
`SECTION 13 Therapy of Infectious
`Diseases,
`1063
`77 INFLUENZA AND VIRAL RESPIRATORY
`INFECTIONS,
`1063
`Joseph P, Lynch,
`
`III
`
`78 COMMUNITY—ACQUIRED PNEUMONIA,
`Andrew R. Haasand Paul E. Marik
`
`1081
`
`‘79 TUBERCULOSIS,
`Ying Zhang
`
`1089
`
`1109
`80 E-ACTERIAL MENINGITIS,
`Eiederik van de Beek, Martijn Weisfelt, and Jan de Gans
`
`1121
`81 ENDOCARDITIS,
`Lsa G. Winston, Daniel Deck, and Ann F. Bolger
`
`1141
`32 'I‘J’IALARIA,
`Myaing Nyunt and Christopher V. Plowe
`
`83 PROTOZOAN AND HELIVIINTHIC
`INFECTIONS,
`1171
`Eric R. Houpt and Omer Chaudhry
`
`84 HIV INFECTIONS AND AIDS,
`Faul A. Pham and Charles W. Flexner
`
`1187'
`
`89 PHARMACY AND THERAPEUTICS COMMITTEES
`AND THE HOSPITAL FORMULARY,
`1233
`‘
`Joseph S. Bertlno, Jr.
`
`SECTION _20 Emerging Therapeutics,
`90 COMPLEMENTARY AND ALTERNATIVE
`MEDICINE, NUTRACEUTICALS, AND DIETARY
`SUPPLEMENTS,‘ 1237
`Christine A. Haller
`
`1237
`
`1247
`91 VACGNES
`Paul V. 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 Grosso, and Neal Flomenberg
`
`93 GENE THERAPY,
`
`1295
`
`Stephen J. Russell and Kah Whye Peng
`94 REGENERATIVE MEDICINE AND STEM CELL
`THERAPEUTICS,
`1317
`Timothy J. Nelson, Atta Behfar, and Andre Terzrc
`
`INDEX,
`
`1333
`
`Page80f26
`
`Page 8 of 26
`
`

`

`
`
`
`
`MULTIPLE SCLEROSIS
`
`Benjamin M. G'reenberg, John N. Ratchford, and Peter A. C'a'labresi
`
`OVERVIEW 685
`INTRODUCTION 6235
`Epidemiology 685
`Genetics
`685
`Clinical Features
`
`685
`
`Diagnosis #686
`PATHOPHYSIOLOGY 687
`THERAPEUTICS AND CLINICAL
`PHARMACOLOGY 689
`Goals of Therapy 689
`Therapeutics by Class
`
`689
`
`689
`lmmunomodulators
`691
`immunosuppressants
`692
`Therapeutic Approach
`Treatment with DMT: Patient
`Selection and Initiation
`692
`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
`Reiapses
`695 .
`. Treatments Helpful for Common
`MS~Re|ated Symptoms
`696
`Treatment Considerations Related
`to Pregnancy
`697
`Treating the Pediatric IVIS
`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 Americans are currently diag
`nosed with MS, and the direct and indirect costs associated with the
`disease are about $14 billion per year.1 MS is the most common non—
`:raumatic cause of neurologic disability in early to middle adulthood.
`There is an inherent variability from patient to patient with regard to
`disease course and severity. Some patients experience frequent exacer—
`bations with escalating disability while others have a 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 microgiia. According to
`this hypothesis, an autoimmune response against CNS myelin is initiu
`lied, leading to demyelination and axonal injury. To date, the most
`effective therapies have been immunosuppressant and immunornodu—
`Eatery 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 I
`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: i and 2.5 : 1, although the ratio is more even at older ages
`of onset. Several important epidemiologic observations have been
`made shout the geographic distribution of MS. In both the northern
`and southern hemispheres, the prevalence ofthe disease increases with
`increasing distance from the equator. There is also a difference in risk
`for different ethnic groups, independent of latitude. For example,
`England and lapan are at the same latitude, but the prevalence of MS
`' differs significantly in the two countries (85 per 100,000 for England
`versus 1.4 per 100,000 in Iapan). Caucasians tend to have the highest
`risk, while lower risk 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 to 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.2 By analyzing the ages
`. of migrants, it was suggested that one’s environmental risk was deter:
`mined by about age 15.2 This has led to hypotheses that the risk ofMS
`is partly determined by viral exposures during childhood. Recent data
`suggest that the incidence of MS may be increasing, especially in
`women, although issues regarding ascertainment and diagnosis make
`these studies challenging.
`
`Genetics
`
`In addition to environmental factors, genetics 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. Dizygotic 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'MS patients is slightly lower than for siblings. Second- and
`thirdvdegree relatives of an MS patient also carry some elevated risk.
`Genetic studies have found the strongest association with the major
`histocompatibility complex (Ml-1C), particularly the HLA-DRBl locus.
`More recently, have additional genes were identified in genomeewide
`scans,3 the interleukin—2 receptor alpha gene and the interleukin-7
`receptor alpha gene. The fact that all three genes are part of the immune
`system serves as an important confirmation ofthe autoimmune nature
`of this disease.
`
`Clinical Features
`
`MS has classically 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 common clinical subtype, representing about 85% ofpatients
`at diagnosis. It is marked by intermittent exacerbations that may partly
`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 prior relapses that healed incompletely.
`After a variable period of time, a majority of RRMS patients will enter '
`a secondary progressive phase of the disease (SPMS). SPMS patients
`experience a slowly progr‘esSive 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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`
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`Page 9 of 26
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`

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`686
`
`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.
`‘
`MS can present with a large number of symptoms possibly referable
`to the CNS. The symptoms may be transient and often difficult to
`describe. Classic MS symptoms include unilateral blurred vision with
`bow 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, common signs include
`v;sual
`impairment, brainstem dysfunction, nystagrnus, dysarthria,
`spasticity,'hyperrel'lexia, weakness, sensory loss, and ataxia. Several
`paroxysmal phenomena can be associated with MS, including tonic
`
`
`
`FIGURE 46-1 I A diagrammatic representation of disability by time for
`different subtypes of M5. A, Relapsing—remitting MS. B, Secondary
`progressive MS. C, Primary progressive MS. D. Progressive relapsing MS.
`
`spasms, trigeminal neuralgia, and myokymia. New clinical symptoms
`are thought to result from new areas of inflammation and demyelin—
`ation, while the acquisition of long~term disability is more related tc
`axonal damaged5
`
`Diagnosis
`
`The diagnosis of MS can be challenging as there is 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 no better explas
`nationP 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).7 These criteria endorsed the use
`of MRI as a surrogate marker for defining separation in time and
`space.
`'
`'
`Brain MRI in MS classically shows lesions that are hyperintense on
`T2—weighted sequences (Fig. 46—2). Lesions are frequently in the peri-
`ventricular white matter, often extending perpendicular to the var:-
`t‘ricle. Lesions ofthe corpus callosum are common in MS, as are lesions
`in the subcortical white matter, cerebellum, brainstem, and spinal cord.
`Newer imaging techniques are also identifying an increased number of
`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 T1 sequences are also seen. TL
`hypointensity is observed transiently in acute lesions. However, wher‘
`it is present chronically, it likely represents an area of significant axon:
`damage. Disability correlates more strongly with the T] hypointensir-
`volume than the volume of T2 hyperintensities. With time, the accu-
`mulating axonal damage will often manifest as global cerebral atropl‘.‘-.
`Only about 5% to 10% of lesions seen on MRI are associated wit:
`clinical symptoms. Gray matter lesions are also common in MS, bil‘
`are not well seen on conventional MRI.
`
`
`a"
`.1;
`an
`in
`
`Additional Data Needed for MS Diagnosis
`Cli
`ical Presentation
`
`2 or more attacks; objective clinical evidence of 2 or
`' None
`more lesions
`
`2 or more attacks; objective clinical evidence of 1
`lesion
`‘
`
`'
`
`- Dissemination in space, demonstrated by:
`AMRE
`I
`or
`
`-
`
`’ attack; objective clinical evidence of 2 or more
`lesions
`
`'
`
`lesion
`’= attack; objective clinical evidence of l
`,lmonosymptomatic presentation; clinically isolated
`syndrome)
`-
`
`Insidious neurologic progression suggestive of M5
`
`'
`
`$2 or more MRI-detected lesions consistent with MS plus positive CSF
`or
`.
`—9Await further clinical attack implicating a different site
`0 Dissemination in time, demonstrated by:
`—>MR1
`or
`—)Second clinical attack
`- Dissemination in space, demonstrated by:
`—)MRl=
`or
`—>2 or more MRI—detected lesions consistent with MS, plus positive CSF
`and
`- Dissemination in time. demonstrated by:
`——>MRl
`or
`——>Second clinical attack
`
`d
`
`- 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 lesions with positive visual
`evoked potentials)
`‘
`'
`b. Positive spinal cord MRI (2 or more focal 'l? lesions)‘
`c. Positive CSF
`
`‘
`
`CSF, cerebrosplnal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis.
`From Polman CH, Relngold SC, Eden 6, et al. Diagnostic criteria for multiple sclerosis: 2005 revrsions to the "McDonald Criteria." Ann Neurol 2005;58:840-846.
`
`Page 10 of 26
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`Chapter 46 Multiple Sclerosis
`
`687
`
`
`
`FIGURE 46-2 0 Brain MRI of a patient with M5. A, Axial fluid-attenuated inversion recovery {FL/MR) image showing multiple hyperintensities. B, Axial T1-
`weighted image at the same level. Some of the areas of FLAIR hyperintensity are also hypointense on T1—weighted images. C, Sagittal FLAER image showing
`periventricular hyperintensitles.
`
`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 helpful in some cases to detect subclinical lesions
`that cannot be seen on MRI.
`'
`
`PATHOPHYSIOLOGY
`
`Classically, MS has been described as an immunemediated demyelin—_
`sting disease affecting the brain, spinal cord, and optic nerves.8 Recent
`research has reemphasized the concomitant presence of both gray
`. matter pathology and extensive axonal damage in the brains ofpatients
`diagnosed with MS.“"10 The exact 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.
`One theory 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 syndrome of various
`related diseases that cause 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. VJhile most of these types have an
`immuueamediated component, there are some aspects of MS that may
`be independent of the immune system. For example, the degeneration
`of chronically demyelinated axons that occurs in the secondary prof
`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 the role
`that the immune system 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 selfrantigens is unknown. Fundamental
`to the classic
`description of MS pathogenesis is the inappropriate disruption of the
`BBB. Normally, the BBB is composed of specialized endotheiial 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 immune cells in MS is reSpon-
`sible for gadoliniumaenhancing 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 antigeirll (VLA~4) on lymphocytes and mono—
`cytes and its ligands vascular cell adhesion moleculevl (VCAMJ) on
`endothelial cells and fibronectin in the basement membrane.” Pre—
`' sumabiy, 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 CD11" 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+ T cells have been of interest
`for years. The production of tumor necrosis factor (TNF) from CD4+
`T cells correlates with the number of TZ—hyperintense lesions on
`MRI.'5 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 ofT helper cell type 1 (Th1) phenotypes
`in patients with MS compared to controls.16 Yet, therapy directed
`against CD4+ T cells made only a small difference in patients treated
`in clinical trials.”‘”‘ 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 MS is less clear. This newly described subset of
`T cells has been implicated in an animal model of MS, experimental
`autoimmune encephalomyelitis, and interleukin (ID-17 expression
`can be seen in MS brain-infiltrating cells.
`Several studies have identified the potential role of CD8+ T cells in
`MS. Genetic studies have