Conn's Current Therapy 2012: Expert Consult - Online and Print

CONN’S

CURRENT THERAPY

2012

CONN’S

CURRENT THERAPY

2012 EDWARD T. BOPE, MD

Chief of Primary Care Columbus VA Assistant Dean for VA Medical Students and Clinical Professor, Family Medicine The Ohio State University Faculty, Riverside Family Practice Residency Program Riverside Methodist Hospital Columbus, Ohio

RICK D. KELLERMAN, MD

Professor and Chair Department of Family and Community Medicine University of Kansas School of Medicine–Wichita Wichita, Kansas

Latest Approved Methods of Treatment for the Practicing Physician

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CONN’S CURRENT THERAPY 2012 with Expert Consult–Online and Print

ISBN: 978-1-4557-0738-6 ISSN: 8755-8823

Copyright # 2012, 2011, 2010, 2009, 2008 by Saunders, an affiliate of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, 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 method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-1-4557-0738-6 Acquisitions Editor: Kate Dimock Developmental Editor: Joan Ryan Publishing Services Manager: Pat Joiner-Myers Project Manager: Marlene Weeks Designer: Steven Stave

Printed in the United States Last digit is the print number:

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Contributors

Charles S. Abrams, MD

Associate Chief, Division of Hematology-Oncology, University of Pennsylvania School of Medicine; Staff Physician, Division of Hematology-Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Platelet-Mediated Bleeding Disorders

Mark J. Abzug, MD

Professor of Pediatrics (Infectious Diseases), University of Colorado–Denver School of Medicine; Medical Director, The Children’s Hospital Clinical Trials Organization, The Children’s Hospital, Aurora, Colorado Viral Meningitis and Encephalitis

Horacio E. Adrogue´, MD

Medical Director, Pancreas Transplant Program and Medical Director, Methodist Transplant Network, The Methodist Hospital Transplant Center, Houston, Texas Hypertension

Tod C. Aeby, MD

Residency Program Director, Generalist Division Chief, Department of Obstetrics, Gynecology, and Women’s Health, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii Uterine Leiomyomas

Lee Akst, MD

Assistant Professor, Department of Otolaryngology, Johns Hopkins University, Baltimore, Maryland Hoarseness and Laryngitis

Mahboob Alam, MD

Staff Cardiologist, Kennedy Veterans Affairs Medical Center; Assistant Professor, University of Tennessee Health Sciences Center, Memphis, Tennessee Hypertrophic Cardiomyopathy

Brian K. Albertson, MD

University Physicians Group, Harrisburg, Pennsylvania Osteomyelitis

Madson Q. Almeida, MD

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Cushing’s Syndrome

Girish Anand, MD

Fellow in Gastroenterology, Albert Einstein Medical Center, Philadelphia, Pennsylvania Dysphagia and Esophageal Obstruction

Deverick J. Anderson, MD

Clinical Associate, Duke University Medical Center, Durham, North Carolina Rickettsial and Ehrlichial Infections (Rocky Mountain Spotted Fever and Typhus)

Kelley P. Anderson, MD

Clinical Associate Professor of Medicine, University of Wisconsin School of Medicine and Public Health–Marschfield Clinic Campus, Marshfield, Wisconsin Heart Block

Emmanuel Andre`s, MD, PhD

Service de Me´decine Interne, Diabe`te et Maladies Me´taboliques, Clinique Me´dicale B, Hoˆpital Civil–Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France Pernicious Anemia and Other Megaloblastic Anemias

Gregory M. Anstead, MD

Associate Professor of Medicine, University of Texas Health Science Center at San Antonio School of Medicine; Director, Immunosuppression and Infectious Diseases Clinics, South Texas Veterans Healthcare System, San Antonio, Texas Coccidioidomycosis

Aydin Arici, MD

Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut Abnormal Uterine Bleeding

Ann M. Aring, MD

Associate Program Director, Family Medicine Residency, The Ohio State University College of Medicine; Assistant Program Director, Family Medicine Residency, Riverside Methodist Hospital, Columbus, Ohio Fever

Isao Arita, MD

Chair, Agency for Cooperation in International Health– Kumamoto, Kumamoto City, Japan Smallpox

Cecilio Azar, MD

Associate in Medicine, Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon Bleeding Esophageal Varices

Masoud Azodi, MD

Associate Professor, Division of Gynecology/Oncology, Yale University School of Medicine, New Haven, Connecticut Endometrial Cancer

Adrianne Williams Bagley, MD

Pediatrician, Lincoln Community Health Center, Inc., Durham, North Carolina Pelvic Inflammatory Disease

Justin Bailey, MD, FAAFP

Clinical Instructor, Department of Family Medicine, University of Washington, Seattle, Washington; Family Medicine Residency of Idaho, Boise, Idaho Nausea, Vomiting, Gaseousness, and Dyspepsia

Diana Bolotin, MD, PhD

Section of Dermatology, The University of Chicago, Chicago, Illinois Cancer of the Skin

Mary Ann Bonilla, MD

Assistant Clinical Professor, Columbia University College of Physicians and Surgeons, New York, New York; Attending Physician, St. Joseph’s Regional Medical Center, Paterson, New Jersey Neutropenia

Federico Balague´, MD

Privat Docent, Rheumatology, Medical School, Geneva University, Geneva, Switzerland; Adjunct Associated Professor, Orthopedics, New York University, New York, New York; Me´decin Chef Adj Service de Rhumatologie, HFR-Hoˆpital, Cantonal Fribourg, Switzerland Spine Pain

Ashok Balasubramanyam, MD

Professor of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas

Zuleika L. Bonilla-Martinez, MD

Wound Healing Fellow, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida Venous Ulcers

David Borenstein, MD

Clinical Professor of Medicine, The George Washington University Medical Center, Washington, DC Spine Pain

Diabetes Insipidus

Arna Banerjee, MD

Assistant Professor of Anesthesiology and Surgery, Department of Anesthesiology and Critical Care and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee Delirium

Contributors

Nurcan Baykam, MD

Associate Professor of Infectious Diseases, University of Ankara Faculty of Medicine; Staff, Infectious Diseases and Clinical Microbiology Clinic, Ankara Numune Education and Research Hospital, Ankara, Turkey

Chief, Breast Service, Department of Surgery, Memorial SloanKettering Cancer Center, New York, New York Breast Disease

Krystene I. Boyle, MD

Clinical Instructor, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine; Clinical Fellow, Department of Obstetrics/Gynecology, Division of Reproductive Endocrinology, University of Cincinnati Medical Center, Cincinnati, Ohio Menopause

Brucellosis

Meg Begany, RD, CSP, LDN vi

Patrick Borgen, MD

Neonatal Nutritionist; Nutrition Support Service Coordinator, Newborn/Infant Intensive Care Unit, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Normal Infant Feeding

David I. Bernstein, MD

Professor of Medicine and Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio Hypersensitivity Pneumonitis

John P. Bilezikian, MD

Professor, Department of Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, New YorkPresbyterian Hospital, New York, New York Primary Hyperparathyroidism and Hypoparathyroidism

Federico Bilotta, MD, PhD

University of Rome La Sapienza, Rome, Italy Hiccups

Natalie C. Blevins, PhD

Assistant Professor of Clinical Psychology in Clinical Psychiatry, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana Anxiety Disorders

Roberta C. Bogaev, MD

Texas Heart Institute, Houston, Texas Hypertrophic Cardiomyopathy

Mark E. Brecher, MD

Adjunct Professor, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina; Chief Medical Officer and Senior Vice President, Laboratory Corporation of America Holdings, Burlington, North Carolina Therapeutic Use of Blood Components

Sylvia L. Brice, MD

Associate Professor of Dermatology, University of Colorado, Denver, Colorado Viral Diseases of the Skin

Patricia D. Brown, MD

Associate Professor of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine; Chief of Medicine, Detroit Receiving Hospital, Detroit, Michigan Pyelonephritis

Patrick Brown, MD

Assistant Professor of Oncology and Pediatrics, The Johns Hopkins University School of Medicine; Director, Pediatric Leukemia Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Acute Leukemia in Children

Richard B. Brown, MD

Professor of Medicine, Tufts University School of Medicine, Boston; Senior Clinician, Baystate Medical Center, Springfield, Massachusetts Toxic Shock Syndrome

Interim Dean, School of Medicine, Medical College of Georgia, Augusta, Georgia Schizophrenia

Irina Burd, MD, PhD

Instructor, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine; Staff, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Menopause

Diego Cadavid, MD

Consultant in Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts Relapsing Fever

Grant R. Caddy, MD

Consultant Physician and Gastroenterologist, Ulster Hospital, Belfast, Northern Ireland Cholelithiasis and Cholecystitis

Thomas R. Caraccio, PharmD

Associate Professor of Emergency Medicine, Stony Brook University Medical Center School of Medicine, Stony Brook, New York; Assistant Professor of Pharmacology and Toxicology, New York College of Osteopathic Medicine, Old Westbury, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions

Enrique V. Carbajal, MD

Associate Clinical Professor of Medicine, University of California– San Francisco School of Medicine, San Francisco, California; Department of Medicine, Veterans Affairs Central California Health Care System, Fresno, California Premature Beats

Steve Carpenter, MD

Associate Professor, Baylor College of Medicine, St. Luke’s Episcopal Hospital, Houston, Texas Hodgkin’s Disease: Radiation Therapy

Petros E. Carvounis, MD, FRCSC

Assistant Professor, Cullen Eye Institute, Baylor College of Medicine; Chief of Ophthalmology (interim), Ben Taub General Hospital, Harris County Hospital District, Houston, Texas Uveitis

Donald O. Castell, MD

Professor of Medicine, Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina Gastroesophageal Reflux Disease

Miriam M. Chan, BSc Pharm, PharmD

Clinical Assistant Professor of Family Medicine, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio; Clinical Assistant Professor of Pharmacy, The Ohio State University College of Pharmacy, Columbus, Ohio; Adjunct Professor of Pharmacy, Ohio Northern University, Ada, Ohio; Program Director of Research and EBM Education, Medical Education, Riverside Methodist Hospital, Columbus, Ohio Herbal Products; New Drugs in 2010 and Agents Pending FDA Approval

Emery L. Chen, MD

Endocrine Surgeon, Woodland Clinic, Woodland, California Thyroid Cancer

Venkata Sri Cherukumilli, MD

Pediatric Resident, University of California–San Diego School of Medicine, La Jolla, California Rheumatoid Arthritis

Meera Chitlur, MD

Associate Professor of Pediatrics, Division of Hematology/ Oncology, Children’s Hospital of Michigan, Detroit, Michigan Hemophilia and Related Bleeding Disorders

Saima Chohan, MD

Assistant Professor of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois Hyperuricemia and Gout

Peter E. Clark, MD

Associate Professor of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee Malignant Tumors of the Urogenital Tract

Claus-Frenz Claussen, MD

Julius-Maximilians-Universitat Wurzburg, Wurzburg; Head, 4-G Research Institute, Neurootologisches Forschungsinstitut, Bad Kissingen, Germany Tinnitus

Keith K. Colburn, MD

Professor of Medicine and Chief of Rheumatology, Loma Linda University, Loma Linda, California Bursitis, Tendinitis, Myofascial Pain, and Fibromyalgia

Gary C. Coleman, DDS, MS

Associate Professor, Department of Diagnostic Sciences, Baylor College of Dentistry, Dallas, Texas Diseases of the Mouth

Patricia A. Cornett, MD

Associate Chair for Education, Medicine, University of California–San Francisco; Chief, Hematology/Oncology, Veterans Affairs Medical Center San Francisco, San Francisco, California Nonimmune Hemolytic Anemia

Alvaro Cervera, MD

University of Barcelona, Barcelona, Spain; National Stroke Research Institute, Heidelberg Heights, Victoria, Australia Ischemic Cerebrovascular Disease

Lawrence Chan, MD

Professor of Medicine, Rutherford Chair, and Division Chief, Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine; Chief, Diabetes, Endocrinology, and Metabolism, St. Luke’s Episcopal Hospital, Houston, Texas Dyslipoproteinemias; Primary Aldosteronism

Fiona Costello, MD

Clinical Associate Professor, Departments of Clinical Neurosciences and Surgery, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada Optic Neuritis

John F. Coyle, II, MD

Clinical Professor, Department of Medicine, University of Oklahoma College of Medicine–Tulsa, Tulsa, Oklahoma Disturbances Caused by Heat

Contributors

Peter Buckley, MD

vii

Lester M. Crawford, PhD

Formerly Research Professor, Georgetown University School of Medicine, Washington, DC; Head, Department of Physiology, University of Georgia College of Medicine, Athens, Georgia Foodborne Illness

Prakash C. Deedwania, MD

Professor of Medicine, University of California–San Francisco School of Medicine, San Francisco, California; Chief, Cardiology Section, Veterans Affairs Central California Health Care System, Fresno, California Premature Beats

Burke A. Cunha, MD

Professor of Medicine, Stony Brook University Medical Center School of Medicine, Stony Brook, New York; Chief, Infectious Disease Division, Winthrop–University Hospital, Mineola, New York Bacterial Infection of the Urinary Tract In Women; Viral and Mycoplasmal Pneumonias

F. William Danby, MD, FRCPC

Adjunct Assistant Professor of Surgery (Dermatology), Dartmouth Medical School, Hanover, New Hampshire Anogenital Pruritus

Ralph C. Daniel, MD

Department of Dermatology, St. Dominic-Jackson Memorial Hospital, Jackson, Mississippi Diseases of the Nails

Athena Daniolos, MD

Associate Professor, Department of Dermatology, University of Wisconsin School of Medicine and Public Health; Attending Physician, University Health Services, University of Wisconsin, Madison, Wisconsin

Contributors

Condyloma Accuminata (Genital Warts)

Stella Dantas, MD

Physician, Department of Obstetrics and Gynecology, Beaverton Medical Office, Northwest Permanente PC Physicians and Surgeons, Beaverton, Oregon Uterine Leiomyomas

Andre Dascal, MD, FRCPC viii

Associate Professor, Departments of Medicine, Microbiology, and Immunology, McGill University Faculty of Medicine; Senior Infectious Disease Physician, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada Acute Infectious Diarrhea

Susan Davids, MD, MPH

Associate Professor of Medicine, Medical College of Wisconsin; Associate Program Director, Internal Medicine Residency, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin Acute Bronchitis

Susan A. Davidson, MD

Associate Professor, University of Colorado–Denver School of Medicine; Chief, Gynecologic Oncology, University of Colorado Hospital, Aurora, Colorado Neoplasms of the Vulva

Melinda V. Davis-Malesevich, MD

Resident, Bobby R. Alford Department of Otolaryngology – Head & Neck Surgery, Baylor College of Medicine, Houston, Texas

Phyllis A. Dennery, MD

Professor of Pediatrics, University of Pennsylvania School of Medicine; Werner and Gertrude Henle Chair and Chief, Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Hemolytic Disease of the Fetus and Newborn

Stephen R. Deputy, MD

Assistant Professor of Neurology, Louisiana State University School of Medicine; Staff Neurologist, Children’s Hospital, New Orleans, Louisiana Traumatic Brain Injury in Children

Richard D. deShazo, MD

Professor of Medicine and Pediatrics and Billy S. Guyton Distinguished Professor, University of Mississippi College of Medicine; Chair, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi Pneumoconiosis

Clio Dessinioti, MD, MSc

Attending Dermatologist, Andreas Sygros Hospital, Athens, Greece Parasitic Diseases of the Skin

Gretchen M. Dickson, MD, MBA

Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas Otitis Media

Douglas DiOrio, MD

Adjunct Clinical Professor, The Ohio State University College of Medicine; Fellowship Director, Riverside Sports Medicine, Riverside Methodist Hospital, Columbus, Ohio Common Sports Injuries

Sunil Dogra, MD, DNB, MNAMS

Associate Professor, Department of Dermatology, Venereology & Leprology, Postgraduate Institute of Medical Education & Research, Chandigarh, India Leprosy

Basak Dokuzoguz, MD

Chief, Infectious Diseases and Clinical Microbiology Clinic, Ankara Numune Education and Research Hospital, Ankara, Turkey Brucellosis

Joseph Domachowske, MD

Professor of Pediatrics, Microbiology, and Immunology, State University of New York Upstate Medical University, Syracuse, New York Infectious Mononucleosis

Obstructive Sleep Apnea

Francisco J.A. de Paula, MD, PhD

Assistant Professor, Department of Internal Medicine, School of Medicine of Ribeirao Preto, USP, Ribeirao Preto, Brazil Osteoporosis

Geoffrey A. Donnan, MD

Department of Neurology, University of Melbourne Faculty of Medicine, Dentistry, and Health Sciences; Florey Neuroscience Institutes, Carlton South, Victoria, Australia Ischemic Cerebrovascular Disease

Dartmouth Medical School, Hanover, New Hampshire; Chief, Child and Adolescent Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Attention Deficit/Hyperactivity Disorder

John Dorsch, MD

Associate Professor, Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas The Red Eye

Douglas A. Drevets, MD, DTM&H

Professor and Chief, Section of Infectious Diseases, University of Oklahoma Health Sciences Center; Staff Physician, Veterans Affairs Medical Center, Oklahoma City, Oklahoma Plague

Jean Dudler, MD

Me´decin-chef, Service de Rhumatologie, HFR Fribourg–Hoˆpital Cantonal, Fribourg, Switzerland; Privat Docent, Division of Rheumatology, University of Lausanne, Lausanne, Switzerland Rat-Bite Fever

Peter R. Duggan, MD

Associate Clinical Professor of Medicine, University of Calgary, Calgary, Alberta, Canada Polycythemia Vera

Kim Eagle, MD

Albion Walter Hewlett Professor of Internal Medicine, Chief of Clinical Cardiology, and Director, Cardiovascular Center, University of Michigan Health System, Ann Arbor, Michigan Angina Pectoris

Genevieve L. Egnatios, MD

Department of Dermatology, Mayo Clinic Scottsdale, Scottsdale, Arizona Contact Dermatitis

Julian Elliott, MB, BS, FACP

Conjoint Senior Lecturer, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney; Infectious Diseases Physician, Alfred Hospital, Melbourne; HIV Clinical Advisor, International Health Research Group, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, New South Wales, Australia Psittacosis

Sean P. Elliott, MD, MS

Associate Professor of Urology and Director of Urologic Reconstruction, University of Minnesota School of Medicine, Minneapolis, Minnesota Trauma to the Genitourinary Tract

Dirk M. Elston, MD

Director, Department of Dermatology, Geisinger Medical Center, Danville, Pennsylvania Diseases of the Hair

John M. Embil, MD, FRCPC

Associate Professor of Internal Medicine (Section of Infectious Diseases) and Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada Blastomycosis

Tobias Engel, MD

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Pheochromocytoma

Scott K. Epstein, MD

Dean for Educational Affairs and Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts Acute Respiratory Failure

Andrew M. Evens, DO, MSc

Associate Professor of Medicine; Deputy Director for Clinical and Translational Research and CRO Medical Director, UMass Memorial Cancer Center, Division of Hematology/Oncology; Director, Lymphoma Program, The University of Massachusetts Medical School, Worcester, Massachusetts Non-Hodgkin’s Lymphoma

Walid A. Farhat, MD

Associate Professor, Department of Surgery and Pediatric Urologist, The Hospital for Sick Children, Toronto, Ontario, Canada Childhood Incontinence

Dorianne Feldman, MD, MSPT

Instructor of Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine, Baltimore, Maryland Rehabilitation of the Stroke Patient

Gregory Feldman, MD

Surgical Resident, Stanford Hospitals and Clinics, Stanford, California Peripheral Arterial Disease

Steven R. Feldman, MD, PhD

Professor of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Acne Vulgaris and Rosacea

Barri J. Fessler, MD, MSPH

Associate Professor of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama Polymyalgia Rheumatica and Giant Cell Arteritis

Terry D. Fife, MD

Associate Professor of Clinical Neurology, University of Arizona; Director, Arizona Balance Center, Barrow Neurological Institute, Phoenix, Arizona Me´nie`re’s Disease

David Finley, MD

Surgeon, Thoracic Service, Memorial Sloan-Kettering, New York, New York Pleural Effusions and Empyema Thoracis

Robert S. Fisher, MD

Lorber Professor of Medicine and Chief, Gastroenterology Section and Digestive Disease Center, Temple University School of Medicine, Philadelphia, Pennsylvania Irritable Bowel Syndrome

William E. Fisher, MD

Professor of Surgery, Baylor College of Medicine, Houston, Texas Acute and Chronic Pancreatitis

Contributors

Craig L. Donnelly, MD

ix

Alan B. Fleischer, Jr., MD

Professor and Chair, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Acne Vulgaris and Rosacea

Robert Giusti, MD

Associate Professor of Pediatrics, Division of Pediatric Pulmonology, New York University School of Medicine; New York University Langone Medical Center, New York, New York Cystic Fibrosis

Raja Flores, MD

Professor and Chief, Division of Thoracic Surgery, Mount Sinai Medical Center, New York, New York Pleural Effusions and Empyema Thoracis

Brian J. Flynn, MD

Associate Professor of Urology, University of Colorado–Denver School of Medicine, Aurora, Colorado Urethral Strictures

Nathan B. Fountain, MD

Professor of Neurology and Director, Dreifuss Comprehensive Epilepsy Program, University of Virginia, Charlottesville, Virginia Seizures and Epilepsy in Adolescents and Adults

Jennifer Frank, MD

Theda Care Physicians, Neenah, Washington Syphilis

Robert S. Freelove, MD

Clinical Associate Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas; Program Director, Smoky Hill Family Medicine Residency Program, Salina, Kansas

Contributors

Nongonococcal Urethritis

Ellen W. Freeman, PhD

Research Professor, Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Premenstrual Syndrome

x

Theodore M. Freeman, MD

San Antonio Asthma and Allergy Clinic, San Antonio, Texas Allergic Reaction to Stinging Insects

Aaron Friedman, MD

Ruben Bentson Professor and Chair, Pediatrics, University of Minnesota, Minneapolis, Minnesota Parenteral Fluid Therapy in Children

R. Michael Gallagher, DO

Director, Headache Center of Central Florida, Melbourne, Florida Headache

John Garber, MD

Instructor in Medicine, Harvard Medical School; Fellow in Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts Acute and Chronic Viral Hepatitis

Khalil G. Ghanem, MD, PhD

Associate Professor of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland Gonorrhea

Donald L. Gilbert, MD, MS

Professor of Pediatrics and Neurology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio Gilles de la Tourette Syndrome

Mark T. Gladwin, MD

Professor of Medicine, University of Pittsburgh School of Medicine; Chief; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Sickle Cell Disease

Andrew W. Goddard, MD

Professor of Psychiatry, Indiana University Hospital, Indianapolis, Indiana Anxiety Disorders

Mark S. Gold, MD

Distinguished Professor and Chair, Psychiatry, Neuroscience, Anesthesiology, and Community Health and Family Medicine, University of Florida College of Medicine, Gainesville, Florida Drug Abuse

Robert Goldstein, MD

Director of Cardiac Device Clinic, Assistant Professor of Medicine, Division of Cardiology, Case Medical Center, Cleveland, Ohio Tachycardias

Robert C. Goldstein, MD

Fellow, Infectious Diseases, Beth Israel Medical Center, New York, New York Toxoplasmosis

Marlı´s Gonza´lez-Ferna´ndez, MD, PhD

Assistant Professor of Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine; Medical Director, Outpatient Physical Medicine and Rehabilitation Clinics, The Johns Hopkins Hospital, Baltimore, Maryland Rehabilitation of the Stroke Patient

E. Ann Gormley, MD

Professor of Surgery (Urology), Dartmouth Medical School, Hanover, New Hampshire; Staff Urologist, DartmouthHitchcock Medical Center, Lebanon, New Hampshire Urinary Incontinence

Eduardo Gotuzzo, MD

Principal Professor of Medicine, Universidad Peruana Cayetano Heredia; Chief, Department of Infectious, Tropical, and Dermatologic Diseases, Hospital National Cayetano Heredia, Lima, Peru Cholera

Luigi Gradoni, PhD

Research Director, Vector-Borne Diseases and International Health, Istituto Superiore di Sanita`, Rome, Italy Leishmaniasis

Jane M. Grant-Kels, MD

Professor and Chair, Department of Dermatology; Dermatology Residency Director and Assistant Dean of Clinical Affairs, University of Connecticut School of Medicine; Director of Dermatopathology and Director, Cutaneous Oncology and Melanoma Center, University of Connecticut Health Center, Farmington, Connecticut Melanocytic Nevi

William Greene, MD

Assistant Professor of Psychiatry, University of Florida, Gainesville, Florida Drug Abuse

Joseph Greensher, MD

Professor of Pediatrics, Stony Brook University Medical Center School of Medicine, Stony Brook, New York; Medical Director and Associate Chair, Department of Pediatrics, Long Island Regional Poison and Drug Information Center, WinthropUniversity Hospital, Mineola, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions

Amita Gupta, MD, MHS

Assistant Professor, Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland The Patient with HIV Disease

David Hadley, MD

Urology Resident, University of Utah Health Sciences Center, Salt Lake City, Utah Urethral Strictures

Rebat M. Halder, MD

Professor and Chair, Department of Dermatology, Howard University College of Medicine, Washington, DC Pigmentary Disorders

David Gregory, MD

Assistant Clinical Professor of Family Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; Assistant Clinical Professor of Family Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Director of Didactic Curriculum, Lynchburg Family Medicine Residency; Staff Physician in Family Medicine and Obstetrics, Lynchburg General Hospital and Virginia Baptist Hospital, Lynchburg, Virginia Resuscitation of the Newborn

Priya Grewal, MD

Assistant Professor, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York Cirrhosis

Ronald Hall, II, PharmD

Associate Professor, Texas Tech University Health Sciences Center School of Pharmacy, Dallas, Texas Tuberculosis and Other Mycobacterial Diseases

Nicola A. Hanania, MD, MS

Associate Professor of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine; Director, Asthma Clinical Research Center, Baylor College of Medicine, Houston, Texas Chronic Obstructive Pulmonary Disease

Rashidul Haque, MB, PhD

International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh Amebiasis

Professor of Pediatrics, University of Iowa Carver College of Medicine; Director of Infectious Diseases Division, Children’s Hospital of Iowa, Iowa City, Iowa Varicella (Chickenpox)

Robert Grossberg, MD

Assistant Professor of Medicine, Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York Fungal Diseases of the Skin

Michael Groves, MD

Resident, Bobby R. Alford Department of Otolaryngology–Head & Neck Surgery, Baylor College of Medicine, Houston, Texas Nonallergic Perennial Rhinitis

Eva C. Guinan, MD

Associate Professor of Pediatrics and Director, Linkages Program, Harvard Catalyst, Harvard Medical School, Boston, Massachusetts Aplastic Anemia

Tawanda Gumbo, MD

Associate Professor of Medicine, University of Texas Southwestern Medical School; Attending Physician, Parkland Memorial Hospital and University Hospital-St. Paul, Dallas, Texas Tuberculosis and Other Mycobacterial Diseases

David R. Harnisch, Sr., MD

Associate Professor, Department of Family Medicine, University of Nebraska Medical Center, Omaha, Nebraska Dysmenorrhea

George D. Harris, MD, MS

Professor and Dean, Year 1 and 2 Medicine, University of Missouri–Kansas City School of Medicine; Faculty, Family Medicine Residency Program at Truman Medical Center– Lakewood, Kansas City, Missouri Osteomyelitis

Emily J. Herndon, MD

Assistant Professor, Department of Family and Preventive Medicine, Emory University School of Medicine; Staff Physician, Department of Community Medicine, Grady Health System, Atlanta, Georgia Contraception

David G. Hill, MD

Assistant Clinical Professor, Yale University School of Medicine, New Haven, Connecticut; Waterbury Pulmonary Associates, Waterbury, Connecticut Cough

L. David Hillis, MD

Chair, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas Congenital Heart Disease

Juliet Gunkel, MD

Assistant Professor, University of Wisconsin School of Medicine and Public Health; Staff Physician, University of Wisconsin Hospitals and Clinics and Meriter Hospital, Madison, Wisconsin Premalignant Cutaneous and Mucosal Lesions

Christopher D. Hillyer, MD

President and CEO, New York Blood Center; Professor, Division of Hematology, Department of Medicine, Weill Cornell Medical College, New York, New York Adverse Effects of Blood Transfusion

Contributors

Charles Grose, MD

xi

Stacey Hinderliter, MD

Clinical Assistant Professor of Family Medicine, University of Virginia School of Medicine, Charlottesville, Virginia; Clinical Assistant Professor of Family Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Pediatric Faculty, Lynchburg Family Medicine Residency; Staff Physician, Lynchburg General Hospital, Lynchburg, Virginia Resuscitation of the Newborn

Molly Hinshaw, MD

Assistant Professor of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Dermatopathologist, Dermpath Diagnostics, Brookfield, Wisconsin Autoimmune Connective Tissue Disease; Cutaneous Vasculitis

Bryan Ho, MD

Assistant Professor of Neurology, Tufts Medical Center, Boston, Massachusetts

Joseph M. Hughes, MD

Associate Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons, New York, New York; Attending Physician, Department of Medicine, Division of Endocrinology, Bassett Healthcare, Cooperstown, New York Adrenocortical Insufficiency

Scott A. Hundahl, MD

Professor of Surgery, University of California–Davis School of Medicine, Sacramento, California; Chief of Surgery, Veterans Affairs Northern California Health Care System, Mather, California Tumors of the Stomach

Stephen P. Hunger, MD

Professor of Pediatrics, University of Colorado–Denver School of Medicine; Section Chief, Center for Cancer and Blood Disorders and Ergen Family Chair in Pediatric Cancer, The Children’s Hospital, Aurora, Colorado Acute Leukemia in Children

Myasthenia Gravis

Raymond J. Hohl, MD, PhD

Professor of Internal Medicine and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa

Khawaja O. Husain, MD

Fellow, Section of Infectious Diseases, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Plague

Thalassemia

Sarah A. Holstein, MD, PhD Contributors

Assistant Professor, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa

xii

Thalassemia

Marisa Holubar, MD

Clinical Teaching Fellow, Warren Alpert Medical School of Brown University, Providence, Rhode Island Severe Sepsis and Septic Shock

M. Ekramul Hoque, MBBS, MPH (Hons), PhD

Lecturer in Community Health, School of Medicine, Deakin University, Geelong, Victoria, Australia Giardiasis

Ahmad Reza Hossani-Madani, MD

Department of Dermatology, Howard University College of Medicine, Washington, DC Pigmentary Disorders

Christine Hsieh, MD

Department of Family Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania Constipation

Judith M. Hu¨bschen, PhD

Scientist, Institute of Immunology, Laboratoire National de Sante´/ Centre de Recherche Public-Sante´, Luxembourg Rubella and Congenital Rubella

Christine Hudak, MD

Summa Health System, Akron, Ohio Vulvovaginitis

William J. Hueston, MD

Professor and Chair, Department of Family Medicine, Medical University of South Carolina, Charleston, South Carolina Hyperthyroidism; Hypothyroidism

Gerald A. Isenberg, MD

Professor of Surgery and Director of Surgical Undergraduate Education, Jefferson Medical College of Thomas Jefferson University; Program Director, Colorectal Residency, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Tumors of the Colon and Rectum

Alan C. Jackson, MD, FRCPC

Professor of Medicine (Neurology) and Medical Microbiology, University of Manitoba Faculty of Medicine; Head, Section of Neurology, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada Rabies

Danny O. Jacobs, MD, MPH

David C. Sabiston, Jr., Professor and Chair, Department of Surgery, Duke University School of Medicine, Durham, North Carolina Diverticula of the Alimentary Tract

Kurt M. Jacobson, MD

Cardiovascular Medicine Consultant, Billings Clinic, Billings, Montana; Interventional Cardiovascular Fellow, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Mitral Valve Prolapse

Robert M. Jacobson, MD

Professor of Pediatrics, College of Medicine, Mayo Clinic; Chair, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota Immunization Practices

James J. James, MD, DrPH, MHA

Director, Center for Public Health Preparedness and Disaster Response; Editor-in-Chief, Journal of Disaster Medicine and Public Health Preparedness, American Medical Association, Chicago, Illinois Biologic Agents Reference Chart: Symptoms, Tests, and Treatment; Toxic Chemical Agents Reference Chart: Symptoms and Treatment

Associate Professor of Medicine, University of Iowa, Iowa City, Iowa Chronic Leukemias

James N. Jarvis, MD

Children’s Medical Research Institute/Arthritis Foundation Oklahoma Chapter Endowed Chair, Professor of Pediatrics and Section Chief, Pediatric Rheumatology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma Juvenile Idiopathic Arthritis

Nathaniel Jellinek, MD

Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island Diseases of the Nails

Roy M. John, MD, PhD

Clinical Assistant Professor, Harvard Medical School; Associate Director, Cardiac Electrophysiology Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts Cardiac Arrest: Sudden Cardiac Death

James F. Jones, MD

Research Medical Officer, Chronic Viral Diseases Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Chronic Fatigue Syndrome

Marc A. Judson, MD

Professor of Medicine, Medical University of South Carolina, Charleston, South Carolina Sarcoidosis

Tamilarasu Kadhiravan, MD

Assistant Professor of Medicine, Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research–Puducherry, Puducherry, India Typhoid Fever

Harmit Kalia, DO

Division of Gastroenterology, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey Cirrhosis

Walter Kao, MD

Associate Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Attending Cardiologist, Heart Failure and Transplant Program, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin Heart Failure

Dilip R. Karnad, MD

Department of Medicine, King Edward Memorial Hospital, Mumbai, India Tetanus

Andreas Katsambas, MD, PhD

Professor of Dermatology, Department of Dermatology, University of Athens School of Medicine; Andreas Sygzos Hospital, Athens, Greece Parasitic Diseases of the Skin

Philip O. Katz, MD

Clinical Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chairman, Division of Gastroenterology, Albert Einstein Medical Center, Philadelphia, Pennsylvania Dysphagia and Esophageal Obstruction

Arthur Kavanaugh, MD

Professor of Medicine, University of California–San Diego, School of Medicine, La Jolla, California Rheumatoid Arthritis

Clive Kearon, MRCPI, FRCPC, PhD

Professor of Medicine, McMaster University Faculty of Health Sciences; Attending Physician, Henderson General Hospital, Hamilton, Ontario, Canada Venous Thromboembolism

B. Mark Keegan, MD, FRCPC

Associate Professor and Section Chair, Multiple Sclerosis and Autoimmune Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota Multiple Sclerosis

Paul R. Kelley, MD

Assistant Professor, Psychiatry, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee Mood Disorders: Depression and Mood Instability

Stephen F. Kemp, MD

Professor of Medicine and Associate Professor of Pediatrics, University of Mississippi College of Medicine; Director, Allergy and Immunology Fellowship Program, Departments of Medicine and Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi Anaphylaxis and Serum Sickness

Haejin Kim, MD

Paul S. Kingma, MD, PhD

Contributors

Katarzyna Jamieson, MD

Care of the High-Risk Neonate

xiii

University of Cincinnati Medical Center, Cincinnati, Ohio Hypersensitivity Pneumonitis

Assistant Professor, The Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Robert S. Kirsner, MD, PhD

Professor, Vice Chairman, and Stiefel Laboratories Chair, Department of Dermatology and Cutaneous Surgery and Chief of Dermatology, University of Miami Miller School of Medicine, Miami, Florida Venous Ulcers

Joseph E. Kiss, MD

Associate Professor of Medicine, Division of HematologyOncology, University of Pittsburgh School of Medicine; Medical Director, Hemapheresis and Blood Services, The Institute for Transfusion Medicine, Pittsburgh, Pennsylvania Thrombotic Thrombocytopenic Purpura

Joel D. Klein, MD, FAAP

Professor of Pediatrics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania; Division of Pediatric Infectious Diseases, Alfred I. duPont Hospital for Children, Wilmington, Delaware Mumps

Luciano Kolodny, MD

Merck & Co., Inc., North Wales, Pennsylvania Erectile Dysfunction

Gerald B. Kolski, MD, PhD

Clinical Professor of Pediatrics, Temple University School of Medicine; Adjunct Clinical Professor of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania; Attending Physician, Crozer Chester Medical Center, Upland, Pennsylvania

Seema Kumar, MD

Assistant Professor of Pediatrics, Mayo Clinic College of Medicine; Consultant, Division of Pediatrics, Endocrinology, and Metabolism, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota Obesity

Asthma in Children

Frederick K. Korley, MD

Robert E. Meyerhoff Assistant Professor of Emergency Medicine, Johns Hopkins University School of Medicine; Staff, The Johns Hopkins Medicine Institutions, Baltimore, Maryland Disturbances Caused by Cold

Kristin Kozakowski, MD

Pediatric Urology Senior Fellow, The Hospital for Sick Children, Toronto, Ontario, Canada Childhood Incontinence

Robert A. Kratzke, MD

John Skoglund Chair of Lung Cancer Research, University of Minnesota Medical School; Associate Professor, University of Minnesota Medical Center, Minneapolis, Minnesota Primary Lung Cancer

Jeffrey A. Kraut, MD

Professor of Medicine, David Geffen School of Medicine at UCLA; Chief of Dialysis, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

Contributors

Chronic Renal Failure

xiv

Jacques Kremer, PhD

Postdoctoral Program, Institute of Immunology, National Laboratory of Health, Luxembourg Measles (Rubeola)

John N. Krieger, MD

Professor of Urology, University of Washington School of Medicine; Chief of Urology, Veterans Affairs Puget Sound Health Care System, Seattle, Washington Bacterial Infections of the Male Urinary Tract

Leonard R. Krilov, MD

Chief, Pediatric Infectious Diseases and International Adoption, Winthrop University Hospital, Pediatric Specialty Center, Mineola, New York Travel Medicine

Lakshmanan Krishnamurti, MD

Department of Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sickle Cell Disease

Roshni Kulkarni, MD

Professor, Department of Pediatrics and Human Development, Michigan State University College of Medicine, East Lansing, Michigan Hemophilia and Related Bleeding Disorders

Bhushan Kumar, MD, MNAMS, FRCP (Edin), FRCP (London)

Former Professor and Head, Department of Dermatology, Venerology & Leprology, Postgraduate Institute of Medical Education & Research, Chandigarh, India Leprosy

Louis Kuritzky, MD

Assistant Professor, Family Medicine Residency Program, University of Florida, Gainesville, Florida Prostatitis

Robert A. Kyle, MD

Professor of Medicine, Laboratory Medicine, and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota Multiple Myeloma

Lori M.B. Laffel, MD, MPH

Associate Professor of Pediatrics, Harvard Medical School; Chief, Pediatric, Adolescent, and Young Adult Section and Investigator, Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts Diabetes Mellitus in Children and Adolescents

Richard A. Lange, MD

Executive Vice Chairman, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas Congenital Heart Disease

Julius Larioza, MD

Attending Physician, Bay State Medical Center, Springfield, Massachusetts Toxic Shock Syndrome

Jerome Larkin, MD

Assistant Professor of Medicine, Warren Alpert Medical School at Brown University; Attending Physician, Rhode Island Hospital, Providence, Rhode Island Severe Sepsis and Septic Shock

Andrew B. Lassman, MD

Department of Neurology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York Brain Tumors

Barbara A. Latenser, MD

Clara L. Smith Professor of Burn Treatment, Department of Surgery, University of Iowa Carver College of Medicine; Medical Director, Burn Treatment Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa Burn Treatment Guidelines

Christine L. Lau, MD

Assistant Professor of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia School of Medicine, Charlottesville, Virginia Atelectasis

Susan Lawrence-Hylland, MD

Clinical Assistant Professor, Rheumatology Section, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Autoimmune Connective Tissue Disease; Cutaneous Vasculitis

Miguel A. Leal, MD

Clinical Instructor and Cardiovascular Medicine Fellow, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Pericarditis and Pericardial Effusions

Winthrop University Hospital, Pediatric Specialty Center, Mineola, New York Travel Medicine

Jerrold B. Leikin, MD

Professor of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Professor of Medicine, Rush Medical College, Chicago, Illinois; Director of Medical Toxicology, Evanston Northwestern HealthcareOmega, Glenbrook Hospital, Glenview, Illinois Disturbances Caused by Cold

Jana Lewis, MD

Department of Surgery, Maimonides Medical Center, Brooklyn, New York Breast Disease

Albert P. Lin, MD

Assistant Professor, Ophthalmology, Baylor College of Medicine; Staff Physician, Eye Care Line, Michael E. DeBakey VA Medical Center, Houston, Texas Glaucoma

Morten Lindbaek, MD

Professor of General Practice, University of Oslo, Oslo, Norway Sinusitis

Janet C. Lindemann, MD, MBA

Professor of Family Medicine and Dean of Medical Student Education, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota Fatigue

Jeffrey A. Linder, MD, MPH, FACP

Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Division of General Medicine and Primary Care, Brigham and Women’s Hospital, Boston, Massachusetts Influenza

Gary H. Lipscomb, MD

Professor and Director, Division of General Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Ectopic Pregnancy

James A. Litch, MD, DTMH

Clinical Assistant Professor, University of Washington School of Medicine and School of Public Health and Community Medicine, Seattle, Washington High-Altitude Illness

James Lock, MD

Professor of Child Psychiatry and Pediatrics, Stanford University School of Medicine; Medical Director, Eating Disorder Program, Lucile Packard Children’s Hospital, Stanford, California Bulimia Nervosa

Robert C. Lowe, MD

Associate Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts Gastritis and Peptic Ulcer Disease

Benjamin J. Luft, MD

Edmund D. Pellegrino Professor of Medicine, Stony Brook University Medical Center School of Medicine, Stony Brook, New York Toxoplasmosis

Michael F. Lynch, MD

Medical Epidemiologist, Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia Malaria

Kelly E. Lyons, PhD

Research Associate Professor, Department of Neurology, University of Kansas School of Medicine, Kansas City, Kansas Parkinsonism

James M. Lyznicki, MS, MPH

Associate Director, Center for Public Health Preparedness and Disaster Response, American Medical Association, Chicago, Illinois Biologic Agents Reference Chart: Symptoms, Tests, and Treatment; Toxic Chemical Agents Reference Chart: Symptoms and Treatment

Kimberly E. Mace, PhD

Malaria Branch, Centers for Disease Control and Prevention, Atlanta, Georgia Malaria

Judith Mackall, MD

Associate Professor of Medicine, Division of Cardiology, University Hospitals of Cleveland, Cleveland, Ohio Tachycardias

Bahaa S. Malaeb, MD

Resident Urologist, University of Minnesota Medical School, Minneapolis, Minnesota Trauma to the Genitourinary Tract

Christopher R. Mantyh, MD

Associate Professor, Faculty of Biology, Chemistry, and Pharmacy, Free University of Berlin; Head of Laboratory, Division of Viral Infection, Robert Koch Institute, Berlin, Germany Diverticula of the Alimentary Tract

Woraphong Manuskiatti, MD

Professor of Dermatology, Department of Dermatology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Keloids

Lynne Margesson, MD, FRCPC

Adjunct Assistant Professor of Surgery (Dermatology) and Obstetrics and Gynecology, Dartmouth Medical School, Hanover, New Hampshire Anogenital Pruritus

Paul Martin, MD

Chief, Division of Hepatology, Schiff Liver Institute/Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida Cirrhosis

Vickie Martin, MD

Resident, Department of Obstetrics and Gynecology, Kingston General Hospital, Kingston, Ontario, Canada Amenorrhea

Maria Mascarenhas, MBBS

Associate Professor of Pediatrics, University of Pennsylvania School of Medicine; Section Chief, Nutrition Division of Gastroenterology and Nutrition and Director, Nutrition Support Service, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Normal Infant Feeding

Contributors

Paul J. Lee, MD

xv

Pinckney J. Maxwell, IV, MD

Assistant Professor of Surgery, Division of Colon and Rectal Surgery, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania Tumors of the Colon and Rectum

Ali Mazloom, MD

University of Texas School of Public Health, Houston, Texas Hodgkin’s Disease: Radiation Therapy

Anthony L. McCall, MD, PhD

James M. Moss Professor of Diabetes, University of Virginia School of Medicine; Endocrinologist, University of Virginia Health Care System, Charlottesville, Virginia Diabetes Mellitus in Adults

Jill D. McCarley, MD

Assistant Professor of Psychiatry, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee Mood Disorders: Depression and Mood Instability

Laura J. McCloskey, PhD

Assistant Professor of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University; Associate Director, Clinical Laboratories, Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania Reference Intervals for the Interpretation of Laboratory Tests

Contributors

Michael McGuigan, MD

xvi

Medical Director, Long Island Regional Poison and Drug Information Center, Winthrop-University Hospital, Mineola, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions

Donald McNeil, MD

Associate Professor of Clinical Medicine, Department of Immunology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Allergic Reactions to Drugs

Genevieve B. Melton, MD, MA

Assistant Professor of Surgery, University of Minnesota, Minneapolis, Minnesota Hemorrhoids, Anal Fissure, and Anorectal Abscess and Fistula

Mario F. Mendez, MD, PhD

Professor, Department of Neurology and Department of Psychiatric and Biobehavioral Sciences, David Geffen School of Medicine at UCLA; Attending Physician, Neurobehavior Unit, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California Alzheimer’s Disease

Moises Mercado, MD

Professor of Medicine, Faculty of Medicine, Universidad Nacional Autonoma de Mexico; Head, Endocrine Service, and Experimental Endocrinology Unit, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Institute Mexicano del Segero Social, Mexico City, Mexico Acromegaly

Jeffrey Wm. Milks, MD

Director, Geriatric Fellowship, Riverside Methodist Hospital; Medical Director, Senior Independence Hospice–Ohio, Ohio Presbyterian Retirement Services, Columbus, Ohio Pain

Brian Miller, MD, MPH

Assistant Professor of Psychiatry, Medical College of Georgia, Augusta, Georgia Schizophrenia

Peter A. Millward, MD

Medical Director, Transfusion Medicine, William Beaumont Hospital, Royal Oak, Michigan Therapeutic Use of Blood Components

Howard C. Mofenson, MD

Professor of Pediatrics and Emergency Medicine, Stony Brook University Medical Center School of Medicine, Stony Brook, New York; Professor of Pharmacology and Toxicology, New York College of Osteopathic Medicine, Old Westbury, New York Medical Toxicology: Ingestions, Inhalations, and Dermal and Ocular Absorptions

Enrique Morales, MD

Attending Nephrologist, Hospital 12 de Octubre, Madrid, Spain Primary Glomerular Diseases

Jaime Morales-Arias, MD

Assistant Professor of Pediatrics; Pediatric Hematology/Oncology, Louisiana State University Health Sciences Center; New Orleans, Louisiana Disseminated Intravascular Coagulation

Timothy I. Morgenthaler, MD

Associate Professor of Medicine, Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic and Foundation, Rochester, Minnesota Sleep Disorders

Warwick L. Morison, MD

Professor of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Sunburn

Scott Moses, MD

Medical Staff, Fairview Lakes Regional Medical Center, Wyoming, Minnesota Pruritus

Ladan Mostaghimi, MD

Clinical Associate Professor, University of Wisconsin School of Medicine and Public Health; Clinical Assistant Professor, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Psychocutaneous Medicine

Judd W. Moul, MD

Professor and Chief, Division of Urology; Director, Duke Prostate Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina Benign Prostatic Hyperplasia

Claude P. Muller, MD

Scientist, Institute of Immunology, Laboratoire National de Sante´/ Centre de Recherche Public-Sante´, Luxembourg Measles (Rubeola); Rubella and Congenital Rubella

Michael Murphy, MD

Associate Professor, Department of Dermatology, University of Connecticut School of Medicine; Attending Physician, John Dempsey Hospital-University of Connecticut Health Center, Farmington, Connecticut Melanocytic Nevi

Diya F. Mutasim, MD

Chair, Department of Dermatology and Professor of Dermatology and Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio

Silvia Orengo-Nania, MD

Professor of Ophthalmology, Baylor College of Medicine, Houston, Texas Glaucoma

Bullous Diseases

Nicole Nader, MD

Instructor, Mayo Clinic College of Medicine; Fellow, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota

Bernhard Ortel, MD

Associate Professor of Dermatology, University of Chicago, Chicago, Illinois Cancer of the Skin

Obesity

Resident, Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia Atelectasis

Tara J. Neil, MD

Clinical Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita; Associate Director, Via Christi Family Medicine Residency Program, Wichita, Kansas Postpartum Care

David G. Neschis, MD

Clinical Associate Professor of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Vascular Surgeon, The Maryland Vascular Center, Glen Burnie, Maryland Acquired Diseases of the Aorta

David H. Neustadt, MD

Clinical Professor of Medicine, University of Louisville School of Medicine; Senior Attending, University Hospital, Jewish Hospital, Louisville, Kentucky Osteoarthritis

Douglas E. Ney, MD

Assistant Professor, University of Colorado–Denver School of Medicine; Attending Physician, University of Colorado Hospital, Aurora, Colorado Brain Tumors

Lucybeth Nieves-Arriba, MD

Case Western Reserve University School of Medicine; Gynecologic Oncology, Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio Cervical Cancer

Enrico M. Novelli, MD

Department of Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sickle Cell Disease

Jeffrey P. Okeson, DMD

Professor and Chair, Oral Health Science; Director, Orofacial Pain Program, College of Dentistry, University of Kentucky, Lexington, Kentucky Temporomandibular Disorders

David L. Olive, MD

Professor of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Endometriosis

Peck Y. Ong, MD

Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Keck School of Medicine of the University of Southern California; Attending Physician, Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, Los Angeles, California Atopic Dermatitis

Matthew T. Oughton, MD, FRCPC

Assistant Professor, Department of Medicine, McGill University Faculty of Medicine; Infectious Disease Physician, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada Acute Infectious Diarrhea

Gary D. Overturf, MD

Professor Emeritus of Pediatrics and Pathology, University of New Mexico School of Medicine; Medical Director, Infectious Diseases, TriCore Reference Laboratories, Albuquerque, New Mexico Bacterial Meningitis

Kerem Ozer, MD

Texas Diabetes and Endocrinology, Austin, Texas Diabetes Insipidus; Dyslipoproteinemias

Karel Pacak, MD, PhD, DSc

Professor of Medicine and Chief of the Section on Medical Neuroendocrinology, National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Pheochromocytoma

Richard L. Page, MD

George R. and Elaine Love Professor and Chair, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Atrial Fibrillation

Rajesh Pahwa, MD

Professor of Neurology, University of Kansas School of Medicine, Kansas City, Kansas Parkinsonism

Pratik Pandharipande, MD, MSCI

Anesthesiology Service, Veterans Administration Tennessee Valley Healthcare Systems; Associate Professor of Anesthesiology/ Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee Delirium

Sangtae Park, MD, MPH

Clinical Assistant Professor of Urology, University of Chicago Pritzker School of Medicine, Chicago, Illinois Renal Calculi

Jotam Pasipanodya, MD

Research Scientist, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Tuberculosis and Other Mycobacterial Diseases

Manish R. Patel, DO

Assistant Professor, University of Minnesota Medical Center, Minneapolis, Minnesota Primary Lung Cancer

Contributors

Alykhan S. Nagji, MD

xvii

Paul Paulman, MD

Assistant Dean for Clinical Skills and Quality, Family Medicine, University of Nebraska College of Medicine, Omaha, Nebraska Iron Deficiency

Daniel Pratt, MD

Assistant Professor of Medicine, Harvard Medical School; Director, Liver-Biliary-Pancreas Center, Massachusetts General Hospital, Boston, Massachusetts Acute and Chronic Viral Hepatitis

Alexander Perez, MD

Assistant Professor of Surgery, Duke University School of Medicine, Durham, North Carolina Diverticula of the Alimentary Tract

Allen Perkins, MD, MPH

Professor and Chairman, Department of Family Medicine, University of South Alabama College of Medicine, Mobile, Alabama Marine Poisonings, Envenomations, and Trauma

William A. Petri, Jr., MD, PhD

Chief, Division of Infectious Disease and International Health, University of Virginia Medical Center, Charlottesville, Virginia Amebiasis

Vesna Petronic-Rosic, MD, MSc

Associate Professor and Clinic Director, University of Chicago Section of Dermatology, Chicago, Illinois Melanoma

Michael E. Pichichero, MD

Director of Research, Department of Immunology and Center for Infectious Disease, Rochester General Hospital Research Institute, Rochester, New York

Contributors

Whooping Cough (Pertussis)

Claus A. Pierach, MD

Professor of Medicine, University of Minnesota Medical School, Abbott Northwestern Hospital, Minneapolis, Minnesota Porphyrias

Antonello Pietrangelo, MD, PhD

Professor of Internal Medicine, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy xviii

Hemochromatosis

Daniel K. Podolsky, MD

Professor of Internal Medicine, University of Texas Southwestern Medical School; Philip O’Bryan Montgomery Jr., MD, Distinguished Presidential Chair in Academic Administration and Doris and Bryan Wildenthal Distinguished Chair in Medical Science, University of Texas Southwestern Medical Center, Dallas, Texas Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis

Michael A. Posencheg, MD

Medical Director, Newborn Nursery; Associate Medical Director, Intensive Care Nursery; Assistant Professor of Clinical Pediatrics, Division of Neonatology and Newborn Services, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania

Richard A. Prinz, MD

Helen Shedd Keith Professor and Chair, Department of General Surgery, Rush Medical College; Chair, Department of General Surgery, Rush University Medical Center, Chicago, Illinois Thyroid Cancer

David Puchalsky, MD

Associate Professor of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Papulosquamous Eruptions—Psoriasis

David M. Quillen, MD

Associate Professor, Department of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville, Florida Allergic Rhinitis Caused by Inhalant Factors; Epididymitis

Beth W. Rackow, MD

Assistant Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut Abnormal Uterine Bleeding

Peter S. Rahko, MD

Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Director of Echocardiography, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin Mitral Valve Prolapse

S. Vincent Rajkumar, MD

Professor of Medicine and Chair, Myeloma Amyloidosis Dysproteinemia Group, Division of Hematology, Mayo Clinic, Rochester, Minnesota Multiple Myeloma

Kirk D. Ramin, MD

Associate Professor and Director, Maternal-Fetal Medicine Fellowship Program, Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota Antepartum Care

Julio A. Ramirez, MD

Professor of Medicine, University of Louisville School of Medicine; Chief, Division of Infectious Diseases, Department of Veterans Affairs Medical Center, Louisville, Kentucky Legionellosis

Hemolytic Disease of the Fetus and Newborn

Manuel Praga, MD

Associate Professor of Medicine, Universidad Complutense; Head, Nephrology Department, Hospital 12 de Octubre, Madrid, Spain Primary Glomerular Diseases

Abhiram Prasad, MD

Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota Acute Myocardial Infarction

Didier Raoult, MD, PhD

Universite´ de la Me´diterrane´e, Faculte´ de Me´decine, Marseille, France Q Fever

Lakshmi Ravindran, MD

Assistant Professor, University of Toronto Faculty of Medicine; Staff Psychiatrist, Mood and Anxiety Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Panic Disorder

Elizabeth Reddy, MD

Fellow, Department of Medicine, Division of Infectious Disease, Duke University, Durham, North Carolina Intestinal Parasites

Clifford J. Rosen, MD

Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Senior Scientist, Maine Medical Center Research Institute, Maine Medical Center, Portland, Maine Osteoporosis

Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota Acute Myocardial Infarction

Ian R. Reid, MD

Professor of Medicine and Endocrinology, University of Auckland Faculty of Medical and Health Sciences School of Medicine, Auckland, New Zealand Paget’s Disease of Bone

Robert L. Reid, MD

Professor, Department of Obstetrics and Gynecology, Queen’s University Faculty of Medicine; Chair, Division of Reproductive Endocrinology and Infertility, Kingston General Hospital, Kingston, Ontario, Canada Amenorrhea

John D. Reveille, MD

Professor of Internal Medicine and Director, Rheumatology and Clinical Immunogenetics, The University of Texas Medical School, Houston, Texas Ankylosing Spondylitis

Robert W. Rho, MD

Associate Professor of Medicine, Division of Cardiology, University of Washington Medical Center, Seattle, Washington Atrial Fibrillation

Jason R. Roberts, MD

Gastrointestinal Fellow, Medical University of South Carolina, Charleston, South Carolina Gastroesophageal Reflux Disease

Malcolm K. Robinson, MD

Assistant Professor of Surgery, Harvard Medical School; Metabolic Support Service, Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts Parenteral Nutrition in Adults

Nidra Rodriguez, MD

Assistant Professor of Pediatric Hematology, University of Texas Medical School at Houston and University of Texas M. D. Anderson Cancer Center, Houston Texas Autoimmune Hemolytic Anemia

Giovanni Rosa, MD

University of Roma La Sapienza, Rome, Italy Hiccups

Jonathan Rosand, MD, MSc

Director, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital; Independent Faculty, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts Intracerebral Hemorrhage

Peter G. Rose, MD

Case Western Reserve University School of Medicine; Section Head, Gynecologic Oncology, Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio Cervical Cancer; Ovarian Cancer

Richard N. Rosenthal, MD

Arthur J. Antenucci Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons; Chair, Department of Psychiatry, St. Luke’s-Roosevelt Hospital Center, New York, New York Alcoholism

Anne E. Rosin, MD

Associate Professor of Dermatology, University of Wisconsin School of Medicine and Public Health; Attending Physician, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Warts (Verruca)

Anne-Michelle Ruha, MD

Clinical Assistant Professor, Department of Emergency Medicine, University of Arizona College of Medicine, Tucson, Arizona; Director, Medical Toxicology Fellowship, Department of Medical Toxicology, Banner Good Samaritan Medical Center, Phoenix, Arizona Spider Bites and Scorpion Stings

Susan L. Samson, MD, PhD

Assistant Professor, Department of Medicine, Baylor College of Medicine; Attending Physician, Ben Taub General Hospital, Houston, Texas Hyponatremia

J. Terry Saunders, PhD

Assistant Professor of Medical Education in Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia Diabetes Mellitus in Adults

Barry M. Schaitkin, MD

Professor of Otolaryngology, University of Pittsburgh School of Medicine; Residency Program Director, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Acute Peripheral Facial Paralysis (Bell’s Palsy)

Ralph M. Schapira, MD

Professor and Vice Chair, Department of Medicine, Medical College of Wisconsin; Staff Physician, Milwaukee Veterans Affairs Medical Center, Milwaukee, Wisconsin Acute Bronchitis

Michael Schatz, MD, MS

Clinical Professor, Department of Medicine, University of California–San Diego, School of Medicine, La Jolla, California; Chief, Department of Allergy, Kaiser Permanente, San Diego, California Asthma in Adolescents and Adults

Stacey A. Scheib, MD

Resident Physician, Department of Obstetrics and Gynecology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania Menopause

Lawrence R. Schiller, MD

Clinical Professor of Internal Medicine, University of Texas Southwestern Medical School; Attending Physician, Digestive Health Associates of Texas; Program Director, Gastroenterology Fellowship, Baylor University Medical Center, Dallas, Texas Malabsorption

Contributors

Guy S. Reeder, MD

xix

Janet A. Schlechte, MD

Professor, Department of Internal Medicine, University of Iowa Hospital, Iowa City, Iowa Hyperprolactinemia

Kerrie Schoffer, MD, FRCPC

Assistant Professor in Neurology, Dalhousie University Faculty of Medicine; Neurologist, QEII Health Sciences Centre, Halifax, Nova Scotia, Canada Peripheral Neuropathies

Kevin Schroeder, MD

Program Director, Transitional Year, and Medical Director of Acute Dialysis, Riverside Methodist Hospital, Columbus, Ohio Acute Renal Failure

Dan Schuller, MD

Professor of Medicine and Chief, Pulmonary-Critical Care and Sleep Medicine Division, Creighton University, Omaha, Nebraska Primary Lung Abscess

Carlos Seas, MD

Associate Professor of Medicine, Universidad Peruana Cayetano Jeredia; Chief, Inservice Department, Hospital National Cayetano Heredia, Lima, Peru Cholera

Contributors

Steven A. Seifert, MD, FAACT, FACMT

xx

Professor, University of New Mexico School of Medicine; Medical Director, New Mexico Poison Center, Albuquerque, New Mexico Venomous Snakebite

Edward Septimus, MD

Affiliated Professor, George Mason University School of Public Policy, Fairfax, Virginia; Medical Director, Infection Prevention, HCA Healthcare System, Nashville, Tennessee Bacterial Pneumonia

Daniel J. Sexton, MD

Professor of Medicine, Duke University School of Medicine, Durham, North Carolina Rickettsial and Ehrlichial Infections (Rocky Mountain Spotted Fever and Typhus)

Beejal Shah, MD

Assistant Professor, Department of Medicine, Baylor College of Medicine; Attending Physician, Ben Taub General Hospital, Houston, Texas Hyponatremia; Primary Aldosteronism

Jamile M. Shammo, MD

Associate Professor of Medicine and Pathology, Division of Hematology/Oncology, Rush University Medical Center, Chicago, Illinois Myelodysplastic Syndromes

Amir Sharafkhaneh, MD, PhD

Associate Professor of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine; Director, Sleep Fellowship Program, Baylor College of Medicine, Houston, Texas Chronic Obstructive Pulmonary Disease

Ala I. Sharara, MD

Professor of Medicine and Head, Division of Gastroenterology, American University of Beirut Medical Center; Consulting Professor, Duke University Medical Center, Durham, North Carolina Bleeding Esophageal Varices

Chelsea A. Sheppard, MD

Principal, Gold Standard Laboratory Consulting Group, LLC, Springfield, Missouri Adverse Effects of Blood Transfusion

Julie Shott, MD

Sports Medicine Fellow, Riverside Methodist Hospital, Columbus, Ohio Common Sports Injuries

Dan-Arin Silasi, MD

Assistant Professor, Gynecologic Oncology, Yale University School of Medicine, New Haven, Connecticut Endometrial Cancer

Michael J. Smith, MD, MSCE

Assistant Professor, Department of Pediatrics, University of Louisville School of Medicine; Attending Physician, Division of Pediatric Infectious Diseases, Kosair Children’s Hospital, Louisville, Kentucky Cat-Scratch Disease

Suman L. Sood, MD

Assistant Professor of Medicine, Division of Hematology/ Oncology, University of Michigan, Ann Arbor, Michigan Platelet-Mediated Bleeding Disorders

Erik K. St. Louis, MD

Senior Associate Consultant, Neurology, Mayo Clinic and Foundation, Rochester, Minnesota Sleep Disorders

Murray B. Stein, MD, MPH

Professor of Psychiatry and Family and Preventive Medicine, University of California–San Diego School of Medicine, La Jolla, California; Adjunct Professor of Psychology, San Diego State University, San Diego, California Panic Disorder

Todd Stephens, MD

Clinical Instructor, Family and Community Medicine, University of Kansas School of Medicine–Wichita; Associate Director, Via Christi Family Medicine Residency Program, Wichita, Kansas Genital Ulcer Disease: Chancroid, Granuloma Inguinale, and Lymphogranuloma

Dennis L. Stevens, MD, PhD

Professor of Medicine, University of Washington School of Medicine, Seattle, Washington; Chief, Infectious Diseases, Veterans Affairs Medical Center, Boise, Idaho Bacterial Diseases of the Skin

Brenda Stokes, MD

Assistant Clinical Professor of Family Medicine, Instructional Faculty, University of Virginia School of Medicine, Charlottesville, Virginia; Assistant Clinical Professor, Department of Family Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Medical Staff, Central Health-Lynchburg General and Virginia Baptist Hospitals, Lynchburg, Virginia Hypertensive Disorders of Pregnancy

Constantine A. Stratakis, MD, PhD

Program Head, Program on Developmental Endocrinology and Genetics and Director, Pediatric Endocrinology Training Program, National Institutes of Health, Bethesda, Maryland

Maria Trent, MD, MPH

Assistant Professor of Pediatrics, The Johns Hopkins University School of Medicine; Active Staff, The Johns Hopkins Hospital Children’s Center, Baltimore, Maryland Pelvic Inflammatory Disease

Cushing’s Syndrome

Child and Adolescent Psychiatrist, Northwestern Counseling and Support Services, Saint Albans, Vermont Attention Deficit/Hyperactivity Disorder

Prabhakar P. Swaroop, MD

Assistant Professor of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis

Jessica P. Swartout, MD

Fellow in Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota Antepartum Care

Masayoshi Takashima, MD

Director, The Sinus Center, and Director, Sleep Medicine Fellowship–OTO Section, Bobby R. Alford Department of Otolaryngology–Head and Neck Surgery, Baylor College of Medicine, Houston, Texas Nonallergic Perennial Rhinitis; Obstructive Sleep Apnea

Matthew D. Taylor, MD

Resident, Department of Surgery, University of Virginia Medical Center, Charlottesville, Virginia Atelectasis

Edmond Teng, MD, PhD

Assistant Professor, Department of Neurology, David Geffen School of Medicine at UCLA; Neurobehavioral Unit and Geriatric Research Education and Clinical Center, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California Alzheimer’s Disease

Joyce M.C. Teng, MD, PhD

Assistant Professor of Dermatology and Pediatrics, University of Wisconsin School of Medicine and Public Health; Attending Physician, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Urticaria and Angioedema

Nathan Thielman, MD, MPH

Duke Global Health Institute, Duke University, Durham, North Carolina Intestinal Parasites

David R. Thomas, MD

Professor of Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine; Attending Physician, Saint Louis University Hospital, St. Louis, Missouri Pressure Ulcers

Kenneth Tobin, DO

Clinical Assistant Professor and Director, Chest Pain Center, University of Michigan Medical Center, Department of Internal Medicine, Division of Cardiovascular Disease Angina Pectoris

David E. Trachtenbarg, MD

Medical Director, Methodist Diabetes Care Center; Clinical Professor, Family and Community Medicine, University of Illinois College of Medicine, Peoria, Illinois Diabetic Ketoacidosis

Debra Tristram, MD

Clinical Professor, Department of Pediatrics, Brody School of Medicine, Greenville, North Carolina Necrotizing Skin and Soft Tissue Infections

Elaine B. Trujillo, MS, RD

Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, Maryland Parenteral Nutrition in Adults

Arvid E. Underman, MD, FACP, DTMH

Clinical Professor of Medicine and Microbiology, Keck School of Medicine of the University of Southern California, Los Angeles, California; Director of Graduate Medical Education, Huntington Hospital, Pasadena, California Salmonellosis

Utku Uysal, MD

Epilepsy and EEG Fellow, University of Virginia, Charlottesville, Virginia Seizures and Epilepsy in Adolescents and Adults

David van Duin, MD, PhD

Assistant Professor, Medicine, Cleveland Clinic Lerner College of Medicine; Staff Physician, Infectious Diseases, Cleveland Clinic Foundation, Cleveland, Ohio Histoplasmosis

Mary Lee Vance, MD

Professor of Internal Medicine and Neurosurgery and Associate Director, General Clinical Research Center, Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System Hypopituitarism

Erin Vanness, MD

Clinical Assistant Professor, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

Vahan Vartanian, BS

Department of Urology, University of Chicago Pritzker School of Medicine, Chicago, Illinois Renal Calculi

Brenda R. Velasco, MD

Gastroenterology Fellow, Temple University Hospital, Philadelphia, Pennsylvania Irritable Bowel Syndrome

Donald C. Vinh, MD, FRCPC

Division of Infectious Diseases, Department of Medicine, and Department of Medical Microbiology, McGill University Health Center, Montreal General Hospital, Montreal, Quebec, Canada Blastomycosis

Contributors

Harris Strokoff, MD

xxi

Todd W. Vitaz, MD

Assistant Professor, Department of Neurological Surgery, University of Louisville School of Medicine; Director of Neurosurgical Oncology and Co-Director, Neurosciences ICU, Norton Hospital, Louisville, Kentucky Management of Head Injuries

Thomas W. Wakefield, MD

S. Martin Lindenauer Professor of Surgery, Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan Venous Thrombosis

Ellen R. Wald, MD

Professor and Chair, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Pediatricianin-Chief, American Family Children’s Hospital, Madison, Wisconsin Urinary Tract Infections in Infants and Children

Anne Walling, MB, ChB, FFPHM

Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas Migraine Headache

Andrew Wang, MD

Associate Professor of Medicine/Cardiology, Duke University Medical Center, Durham, North Carolina

Contributors

Infective Endocarditis

xxii

Bryan K. Ward, MD

Resident Physician, The Johns Hopkins University School of Medicine, Baltimore, Maryland Acute Peripheral Facial Paralysis (Bell’s Palsy)

Ruth Weber, MD, MSEd

Clinical Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita; Associate Program Director, Wesley Family Medicine Residency, Wichita, Kansas Pharyngitis

Anthony P. Weetman, MD, DSc

Professor of Medicine, The Medical School, University of Sheffield; Honorary Consultant Endocrinologist, Sheffield Teaching Hospitals, Sheffield, United Kingdom Thyroiditis

Arthur Weinstein, MD, FACP, FACR

Professor of Medicine, Georgetown University School of Medicine; Associate Chairman, Department of Medicine, and Director, Section of Rheumatology, Washington Hospital Center, Washington, DC Lyme Disease

David N. Weissman, MD

Adjunct Professor of Medicine and Microbiology (Immunology), West Virginia University School of Medicine; Director, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, West Virginia Pneumoconiosis

Robert C. Welliver, Sr., MD

Professor, State University of New York at Buffalo School of Medicine; Co-Director, Division of Infectious Diseases, Women and Children’s Hospital of Buffalo, Buffalo, New York Viral Respiratory Infections

Ryan Westergaard, MD

Postdoctoral Fellow, Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland The Patient with HIV Disease

Meir Wetzler, MD, FACP

Professor of Medicine and Chief, Leukemia Section, Roswell Park Cancer Institute, Buffalo, New York Acute Leukemia in Adults

Kimberly Williams, MD

Clinical Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas; Smoky Hill Family Medicine Residency, Salinas, Kansas Otitis Externa

Steven R. Williams, MD

Clinical Assistant Professor, Department of Obstetrics and Gynecology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio Infertility

Tracy L. Williams, MD

Clinical Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita; Associate Program Director, Via Christi Family Medicine Residency, Wichita, Kansas Chlamydia trachomatis

Elaine Winkel, MD

Associate Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Attending Cardiologist, Heart Failure and Transplant Program, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Heart Failure

Jennifer Wipperman, MD

Assistant Professor, Department of Family and Community Medicine, University of Kansas School of Medicine–Wichita, Wichita, Kansas Dizziness and Vertigo

Michael Wolfe, MD

The Charles H. Rammelkamp Jr. Professor of Medicine, Case Western Reserve University; Chair, Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio Gastritis and Peptic Ulcer Disease

Gary S. Wood, MD

Professor and Chair, Department of Dermatology, University of Wisconsin School of Medicine and Public Health; Attending Physician, Veterans Affairs Medical Center, Madison, Wisconsin Cutaneous T-Cell Lymphomas, Including Mycosis Fungoides and Se´zary Syndrome

Jamie R.S. Wood, MD

Instructor in Pediatrics, Harvard Medical School; Research Associate, Sections on Genetics and Epidemiology and Vascular Cell Biology; Staff Physician, Pediatric, Adolescent, and Young Adult Section, Joslin Diabetes Center, Boston, Massachusetts Diabetes Mellitus in Children and Adolescents

Jon B. Woods, MD

Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland; Pediatric Infectious Diseases, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas Anthrax

Assistant Professor, University of Cincinnati College of Medicine; Assistant Professor, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Gilles de la Tourette Syndrome

Elizabeth Yeu, MD

Assistant Professor of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas Vision Correction Procedures

James A. Yiannias, MD

Associate Professor and Chair, Department of Dermatology, Mayo Clinic Scottsdale, Scottsdale, Arizona Contact Dermatitis

Ronald F. Young, MD

Medical Director, Swedish Radiosurgical Center, Swedish Medical Center and Swedish Neuroscience Institute, Seattle, Washington Trigeminal Neuralgia

Jami Star Zeltzer, MD

Associate Professor, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts Vaginal Bleeding in Late Pregnancy

Wei Zhou, MD

Associate Professor of Surgery, Stanford University School of Medicine, Stanford, California Peripheral Arterial Disease

Mary Zupanc, MD

Heidi Marie Bauman Chair of Epilepsy and Professor, Departments of Neurology and Pediatrics; Chief, Division of Pediatric Neurology, Medical College of Wisconsin; Director, Pediatric Comprehensive Epilepsy Program; Director, Pediatric Neurology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Epilepsy in Infants and Children

Contributors

Steve W. Wu, MD

xxiii

Preface

A colleague recently said that when he finished medical school many years ago, his father, also a physician, gave him two pieces of advice: “If you remember the art of medicine and use this textbook, you will stay out of trouble!” The book: Conn’s Current Therapy. Whether this advice is altogether sage today is doubtful. But Conn’s Current Therapy remains a bestselling source of desktop and online information for the busy practicing physician. Family physicians and general internists use Conn’s Current Therapy for easy-to-access practical information about day-to-day problems in patient care, for a quick review of advances in clinical medicine, and to study for their maintenance of certification. Surgical specialists such as general surgeons, orthopedic surgeons, and ophthalmologists buy the book as a comprehensive reference for up-to-date background information on a wide variety of medical topics. In its 64 years of publication, there have been only four editors. When Dr. Thomas Conn died suddenly in 1994, Robert Rakel, MD, signed on as editor. He was joined by co-editors Edward T. Bope, MD, in 2001 and Rick D. Kellerman, MD, in 2010. This 64th edition marks the first that has not been co-edited by either Dr. Conn or Dr. Rakel. We are honored to continue the tradition established by Dr. Conn and Dr. Rakel. Recent changes in the book include expanded online options such as electronic access to previous editions and convenient key-word searchability, new topics, a revised table of contents, time-saving tables and graphs, figures that highlight important information, and quick-reference Current Diagnosis and Current Therapy boxes.

What will not change is the melding of evidence-based medicine with the best practices of expert clinicians. This makes the book unique. Each chapter is updated every year by authors who are recognized for their expertise. Each author explains his or her “method,” bringing a practical tone to each chapter. The authors are committed to providing up-to-date information. Each chapter is, indeed, an “expert consult.” Miriam Chan, Pharm D, is an invaluable help in reviewing the manuscripts that go into this book. Dr. Chan checks each drug dosage and formulation. The book uses both generic and trade names so they are familiar to the clinician. Footnotes are added when a drug has not been FDA approved for an indication. Dosages outside the usual FDA-approved range are similarly footnoted. The editorial staff at Elsevier, particularly Kate Dimock, Joan Ryan, and the copy editors, are the best in the business. We thank them for their help with this project. We sincerely appreciate the authors who write each chapter. Many have become friends, oftentimes over e-mail, during the editing process. We are amazed at how an invitation to write for Conn’s Current Therapy is met with a distinct and proud “Of course, I will!” response. Authors are chosen based on recommendations from other experts for their clinical expertise as well as their scholarly activity and research. Finally, we want to thank our families for their patience while we devote time to making Conn’s Current Therapy a clinically valuable “go-to” book. Edward T. Bope, MD Rick D. Kellerman, MD

1

Symptomatic Care Pending Diagnosis

CONSTIPATION Method of

Christine Hsieh, MD

CURRENT DIAGNOSIS • A thorough history and physical examination are needed to exclude secondary medical causes of constipation. • Review the patient’s medication lists to evaluate for medications that can cause constipation. • Patients with alarm symptoms such as weight loss, gastrointestinal bleeding, and anemia and patients 50 years and older need a thorough evaluation with radiography or endoscopy. • Patients who fail conservative medical management should be referred to a specialist for further diagnostic evaluation including colonic motility, anorectal manometry, defacography, and balloon expulsion test to assess colonic transit and anorectal function.

CURRENT THERAPY • If a secondary cause of constipation is identified, eliminating the offending medication or treating the underlying medical condition can relieve the constipation. • Counseling on normal bowel habits and simple lifestyle changes such as increasing dietary fiber can improve bowel regularity. • Empiric treatment with fiber and laxatives can increase bowel movement frequency and improve symptoms of constipation. • Biofeedback therapy is the treatment of choice for pelvic floor dysfunction. • Surgery is reserved for patients proved to have slow colonic transit constipation without small bowel motility delay or pelvic floor dysfunction. Constipation is a common complaint and accounts for about 2.5 million physician visits annually. The estimates of the prevalence of constipation vary widely from 2% to 28%, with increasing prevalence in older adults, women, and persons from lower socioeconomic levels.

Definition

Physicians generally define constipation as having fewer than three bowel movements per week; however, patients might also consider hard stools, excessive straining, or a sense of incomplete evacuation to be constipation. An international working group of experts has revised a consensus definition of constipation, known as the Rome III criteria (Box 1).

Pathophysiology

Constipation can be divided into primary or secondary disorder. A thorough medical history and physical examination are needed to exclude constipation secondary to an underlying medical condition (Box 2) or medication (Box 3). Primary causes of constipation can be classified into three groups: normal-transit constipation, slow-transit constipation, and pelvic floor dysfunction. Normal transit constipation, also known as functional constipation, occurs most commonly. In functional constipation, stool passes through the colon at a normal rate. Slow-transit constipation, colonic inertia, is a colonic motor disorder characterized by prolonged delay in the passage of stool through the colon. Pelvic floor dysfunction is the inefficient coordination of the pelvic musculature in the emptying of stool from the rectum. The cause for pelvic floor dysfunction is unclear, but is likely multifactorial.

Clinical Features and Diagnosis

Secondary medical conditions may be excluded with a thorough history and physical examination, as well as specific laboratory tests such as metabolic panel and thyroid function test. A barium enema or colonoscopy may be indicated to exclude structural diseases such as colon cancer, especially in patients age 50 years and older. Alarm symptoms such as weight loss, gastrointestinal bleeding, and anemia also necessitate a thorough evaluation with radiography or endoscopy. A comprehensive review of the patient’s medication lists, including prescription and over-thecounter medications, is important. Medications are a common secondary cause of constipation, especially those that affect the central nervous system, nerve conduction, and smooth muscle function. Patients with normal or slow-transit constipation might complain of abdominal bloating and infrequent bowel movements. A colonic transit marker study is useful once secondary causes are excluded to differentiate normal transit, slow transit, or pelvic floor dysfunction. Slow transit is characterized by markedly delayed colonic transit time. Pelvic floor dysfunction is characterized by normal transit time but stagnant markers in the rectum. Patients with pelvic floor dysfunction are more likely to complain of a feeling of incomplete evacuation, a sense of obstruction, and a need for digital manipulation. Additional studies to diagnose pelvic floor dysfunction are anal manometry demonstrating inappropriate contraction of the anal sphincter during straining, impaired expulsion of barium in defecography, and impaired balloon expulsion from the rectum.

Treatment

General Measures for Treating Constipation If a secondary cause of constipation is identified, treating the underlying medical condition or eliminating certain medications might relieve the constipation. Otherwise, initial management should begin with nonpharmacologic methods to improve bowel regularity but may proceed to the use of laxatives to relieve constipation. Patients who fail conservative medical management should be referred to a specialist for further diagnostic evaluation.

1

Box 1

ROME III Criteria for Functional Constipation

Must include 2 or more of the following: • Straining during at least 25% of defecations • Lumpy or hard stools in at least 25% of defecations • Sensation of incomplete evacuation for at least 25% of defecations • Sensation of anorectal obstruction or blockage for at least 25% of defecations • Manual maneuvers to facilitate at least 25% of defecations • Fewer than three defecations per week • Loose stools are rarely present without the use of laxatives. There are insufficient criteria for irritable bowel syndrome. Note: Criteria must be fulfilled for the last 3 months, with symptom onset at least 6 months before diagnosis.

1 Symptomatic Care Pending Diagnosis

Box 2

2

Medical Causes of Secondary Constipation

Endocrine and Metabolic Diseases Diabetes mellitus Hypercalcemia Hypothyroidism Renal failure Neurologic Diseases Cerebrovascular disease Hirshsprung’s disease Multiple sclerosis Parkinson’s disease Spinal cord injury Structural Abnormalities Colonic mass lesions, strictures Anal fissures, strictures, hemorrhoids Inflammatory bowel disease Rectal prolapsed or rectocele

should be encouraged to attempt to stimulate defecation first thing in the morning when the bowel is 2 to 3 times more active and 30 minutes after meals to take advantage of the gastrocolic reflex. In Western society, inadequate fiber intake is a common reason for constipation. The daily recommended fiber intake is 20-35 g per day. If fiber intake is substantially less, patients should be encouraged to increase their intake of fiber-rich foods such as bran, fruits, vegetables, and nuts. The recommendation is to increase fiber by 5 g per day until reaching the daily recommended intake. Adding fiber to the diet too quickly can cause excessive gas and bloating. Adequate hydration and physical activity is considered important in maintaining bowel motility, but there has been inconsistent evidence that hydration and regular exercise relieves constipation.

Pharmacologic Treatment There are few studies comparing specific treatment approaches for constipation. There are limited data about the superiority among the various treatments and the long-term benefits and harms of laxatives and fiber preparations. There are no evidence-based guidelines for the order of use of the various types of laxatives (Table 1). Bulk laxatives can contain soluble (psyllium [Metamucil], wheat dextrin [Benefiber], pectin,7 or guar7) or insoluble (cellulose [Citrucel]) products. Both types absorb water from the intestinal lumen and increase stool mass and soften the stool consistency. Patients with normal-transit constipation have the most benefit, but slow-transit constipation or functional outlet problems might not be relieved with bulking agents. Similar to increasing fiber-rich foods, bloating and excessive gas production may be a complication of bulk laxatives. Emollient laxatives or stool softeners such as docusates (Colace, Surfak) act by lowering surface tension, allowing water to penetrate and soften the stool. They are generally well tolerated but are not as effective in the treatment of constipation. Stool softeners may be more useful for patients with anal fissures or hemorrhoids 7

Myopathic Conditions Amyloidosis Scleroderma

TABLE 1

Bulk Laxatives Psyllium (Metamucil) Methylcellulose (Citrucel) Polycarbophil (Fibercon, Konsyl) Wheat dextrin (Benefiber) Guar gum7

Medications Commonly Associated with Secondary Constipation

Stool Softner Docusate sodium (Colace) Docusate calcium (Surfak)

Antacids: aluminum, calcium, bismuth Anticholinergics Antihypertensives: calcium channel blockers, clonidine (Catapres), diuretics Antihistamines Antidepressants Anti-Parkinson drugs Calcium supplements Diuretics Iron supplements Narcotics Nonsteroidal antiinflammatory drugs Psychotropics Sympathomimetics

Osmotic Laxatives Magnesium hydroxide (Milk of Magnesia) Magnesium citrate Sorbitol 70% Lactulose (Cephulac) Polyethylene glycol 3350 (MiraLax)3 Stimulant Laxatives Bisacodyl (Ducolax, Correctol) Senna (Senokot)

DOSAGE 1 tbsp, qd-tid 1 tbsp, qd-tid 2–4 tabs/day 1–2 tsp, qd-tid

100 mg bid 240 mg daily 30–60 mL daily 296 mL (0.5–1 bottle) daily 15–30 mL qd-bid 15–30 mL qd-bid 17 g qd-bid 5–15 mg qd 8.6 mg tab, 2–4 tabs/day

Prokinetic Agents Tegaserod (Zelnorm)* New Agent Lubiprostone (Amitiza)

Nonpharmacologic Treatments Counseling on normal bowel habits and simple lifestyle changes might improve bowel regularity. Having a bowel movement may be partly a conditioned reflex, and patients should be educated on recognizing and responding to the urge to defecate. Patients

Medication Treatment for Chronic Constipation MEDICATION

Other Irritable bowel syndrome Pregnancy

Box 3

Available as dietary supplement.

3

24 mg bid

Exceeds dosage recommended by the manufacturer. Available as a dietary supplement. *Suspended from marketing in March 2007. tab, tablet. 7

Biofeedback Biofeedback or pelvic floor retraining is beneficial for patients with pelvic floor dysfunction. Biofeedback is used to emphasize normal coordination and function of the anal-sphincter and pelvic-floor muscles. A systematic review of biofeedback studies revealed an overall success rate of 67%.

Surgery Surgery is considered only in patients proved to have slow colonic transit constipation without small bowel motility delay or pelvic floor dysfunction. A subtotal colectomy with ileorectostomy is the procedure of choice for patients with slow-transit constipation that is persistent and intractable. 1 2

Not FDA approved for this indication. Not available in the United States.

References

Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of Prucalopride for severe chronic constipation. N Engl J Med 2008;358:2344–54. Diamant NE, Kamm MA, Wald A, Whitehead WE. AGA technical review on constipation. American Gastroenterological Association. Gastroenterology 1999;116:735–60. Enck P. Biofeedback training in disordered defecation: A critical review. Dig Dis Sci 1993;38:1953–60.

Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: A double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharm Ther 2007; 25:1351–61. Koch A, Voderholzer WA, Klauser AG, Muller-Lissner SA. Symptoms in chronic constipation. Dis Colon Rectum 1997;40:902–6. Lembo A, Camilleri M. Chronic constipation. NEJM 2003;349:1360–8. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91. Muller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001;15:1655–66. Prather CM, Ortiz-Camacho CP. Evaluation and treatment of constipation and fecal impaction in adults. Mayo Clin Proc 1998;73:881–996. Rao SSC. Constipation: Evaluation and treatment. Gastroenterol Clin North Am 2003;32:659–83. Schiller LR. Constipation and fecal incontinence in the elderly. Gastroenterol Clin North Am 2001;30:497–515. Stocchi L, Pemberton JH. Surgical management of constipation. In: Cameron JL, editor. Current Surgical Therapy. St. Louis: Mosby; 2001. p. 260–4. Tramonte SM, Brand MB, Mulrow CD, et al. The treatment of chronic constipation in adults: A systematic review. J Gen Intern Med 1997;12:15–24. Voderholzer WA, Schtke W, Mihldorfer BE, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997;92:95–8.

COUGH Method of

David G. Hill, MD

CURRENT DIAGNOSIS All Patients Presenting With Cough • Perform thorough history and physical examination. • Review timing and nature of cough along with exacerbating or mitigating factors. • Review prior history of cough, allergies, asthma, or gastroesophageal reflux. • Take medication history, particularly use of ACE inhibitors. • Focus physical examination on head, neck, and thorax. Patients With Postinfectious or Chronic Cough • Obtain chest radiograph, particularly in patients with an abnormal respiratory examination. • Evaluate airflow obstruction with spirometry. • Stop ACE inhibitors and assess for improvement. • Administer empiric therapy for postnasal drip, asthma, or gastroesophageal reflux. • Consider methacholine challenge testing to evaluate for airway hyperreactivity. • Induce sputum for eosinophils or empiric trial of corticosteroids for eosinophilic bronchitis. • If cough persists, consider esophagoscopy, 24-hour pH probe monitoring, high-resolution chest CT, or bronchoscopy. Abbreviations: ACE ¼ angiotensin-converting enzyme; CT ¼computed tomography.

CURRENT THERAPY Treatment of Acute Cough • Common cold: Supportive care with over-the-counter decongestant and cough suppressant or ipratropium nasal spray (Atrovent, 0.06%), two 42-mcg sprays in each nostril 3 times daily for 4 to 7 d depending on duration of symptoms. • Acute sinusitis: Treat as a common cold. Add oxymetazoline (Afrin), two sprays twice daily for three days. If symptoms

Cough

that cause painful defecation. Mineral oil is not recommended due to the potential risk of aspiration. Saline or osmotic laxatives, such as magnesium salts, cause secretion of water into the intestinal lumen by osmotic activity. In general, these agents are thought to be relatively safe because they work within the colonic lumen and do not have a systemic effect. However, they should be used cautiously in patients with congestive heart failure and chronic renal insufficiency because they can precipitate electrolyte imbalance and volume overload. Alternative hyperosmotic laxatives are sorbitol, lactulose (Cephulac), and polyethylene glycol (PEG) 3350 (MiraLax). Sorbitol and lactulose are indigestible agents that are metabolized by bacteria to hydrogen and organic acids. Poor bacterial absorption of these agents can lead to flatulence and abdominal distention. PEG is not degraded by bacteria and is associated with less abdominal discomfort. The stimulant laxatives include products containing senna (Senokot) and bisacodyl (Dulcolax). These laxatives increase intestinal motility and stimulate fluid secretion into the bowel. They generally produce bowel movements within hours, but they can cause abdominal cramping due to the increased peristalsis. Chronic use of stimulant laxatives containing anthraquinones (cascara [Black Draught], senna) can cause a brown-black pigmentation of the colonic mucosa, known as melanosis coli. This condition is benign and might resolve as the stimulant laxative is discontinued. A number of prokinetic agents have been studied for the treatment of slow-transit constipation. Colchicine1 and misoprostol (Cytotec)1 have been found to accelerate colonic transit time and increase stool frequency in constipated patients, but neither has received FDA approval for this indication. In women with irritable bowel syndrome characterized by constipation, Tegaserod (Zelnorm)2 is a colonic prokinetic agent that improves stool consistency and frequency. However, Tegaserod was removed from the market in March 2007 due to increased cardiovascular events. Lubiprostone (Amitiza) is an intestinal chloride channel activator that promotes intestinal fluid secretion of chloride, enhancing intestinal motility. A common side effect is nausea, which is dose dependent, occurring in about 30% of patients. The long-term safety of this medication has not been established. Prucalopride is a prokinetic, selective serotonin (5-HT4) receptor agonist, that stimulates colonic motility and transit. The most common side effects are headache, nausea, and abdominial pain. Prucalopride (Resolor) is available in Europe for the treatment of chronic constipation in women who fail standard laxative therapy.

3

1 Symptomatic Care Pending Diagnosis

persist, consider antibiotic therapy directed against Haemophilus influenzae and Streptococcus pneumoniae such as azithromycin (Zithromax), 500 mg daily for 3 d. • Exacerbation of chronic obstructive pulmonary disease: Antibiotics directed against H. influenzae and S. pneumoniae for 3 to 7 d such as clarithromycin (Biaxin), 500 mg twice daily for 7 d; systemic corticosteroids such as prednisone (Deltasone), 40 mg tapered over 10 d; inhaled anticholinergics such as tiotropium (Spiriva), one inhalation daily; and short-acting b-agonists such as albuterol (Proventil), two inhalations every 4 h as needed; smoking cessation. • Allergic rhinitis: Nasal corticosteroids such as mometasone (Nasonex), two sprays in each nostril daily; nonsedating antihistamines such as fexofenadine (Allegra), 180 mg daily; allergen avoidance if possible. • Bordetella pertussis: Erythromycin 500 mg four times daily for 14 d or trimethoprim 160 mg/sulfamethoxazole (Bactrim DS),1 800 mg twice daily for 14 d. Other macrolide antibiotics such as azithromycin (Zithromax)1 or clarithromycin (Biaxin)1 are likely effective and may be better tolerated.

4

Treatment of Postinfectious Cough • Postnasal drip syndrome: Dexbrompheniramine, 6 mg, and pseudoephedrine, 120 mg for up to 3 wk; ipratropium (Atrovent), 0.06% nasal spray for up to 3 wk; azelastine (Astelin) nasal spray (137 mcg), two sprays each nostril twice daily for up to 3 wk. • Bronchospasm: Inhaled corticosteroid such as budesonide (Pulmicort),1 two inhalations daily with or without inhaled long-acting b-agonist such as formoterol (Foradil), two inhalations twice daily; short-acting b-agonist such as albuterol (Ventolin), two puffs every 4 h as needed. Oral steroids such as prednisone (Deltasone), 40 mg tapered over 10 d. • Bordetella pertussis: Erythromycin, 500 mg four times daily for 14 d, or trimethoprim 160 mg/sulfamethoxazole, 800 mg (Bactrim DS)1 twice daily for 14 d. Other macrolide antibiotics such as azithromycin (Zithromax)1 or clarithromycin (Biaxin)1 are likely effective and may be better tolerated. • Bacterial sinusitis: Dexbrompheniramine, 6 mg, and pseudoephedrine (Drixoral Cold and Allergy Tablets), 120 mg for up to 3 wk; oxymetazoline (Afrin), two sprays twice daily for 3 d; azithromycin (Zithromax), 500 mg daily for 3 d. • Chlamydia/mycoplasma: Clarithromycin (Biaxin), 500 mg twice daily for 14 d. Treatment of Chronic Cough • Postnasal drip syndrome Nonallergic: Dexbrompheniramine, 6 mg, and pseudoephedrine, 120 mg for up to 3 wk; ipratropium (Atrovent), 0.06% nasal spray for up to 3 wk; azelastine (Astelin) nasal spray (137 mcg), two sprays each nostril twice daily for up to 3 wk. Allergic: Fluticasone (Flonase) (50 mcg), two sprays each nostril daily; fexofenadine (Allegra), 180 mg daily; allergen avoidance. • Asthma: Albuterol (Proventil), two puffs every 4 hours as needed; inhaled corticosteroid such as budesonide (Pulmicort), two inhalations daily with or without inhaled long-acting b-agonist such as formoterol (Foradil), two inhalations twice daily; combination of long-acting b-agonist and inhaled steroid such as fluticasone/salmeterol (Advair) (100/50 mcg), inhaled twice daily; montelukast (Singulair), 10 mg daily; prednisone (Deltasone), 40 mg daily with tapering dose over 10 d. • Gastroesophageal reflux: Dietary and lifestyle modifications, lansoprazole (Prevacid), 30 mg daily for up to 3 mo; metoclopramide (Reglan), 10 mg before meals and sleep. • Eosinophilic bronchitis: Fluticasone (Flovent)1 (110 mcg), two inhalations twice daily; prednisone (Deltasone), 30 mg daily for 3 wk. • ACE inhibitor: Discontinue medication. 1

Not FDA approved for this indication.

Cough is among the most common presenting complaints of outpatients in the United States. It serves as a protective reflex against foreign material and as a method to clear secretions from the airway. The cough center is located in the medulla, and the cough reflex is mediated by way of multiple nervous system pathways including the trigeminal, glossopharyngeal, vagus, and phrenic nerves. Cough is mediated by separate neural pathways from bronchoconstriction. When cough occurs there is a synchronized activation of muscles, the glottis opens, and the lungs expand. At the peak of inspiration the glottis closes and expiratory muscles contract. This results in increased intrathoracic pressure; when the glottis opens airflow can reach 500 miles per hour. The cough reflex varies in different patient populations. Women have a more sensitive cough reflex than men. Smokers’ cough reflexes are depressed despite the increased frequency of cough in this population. Patients who have a decreased cough sensitivity following cerebral vascular accidents have an increased incidence of pneumonia. Angiotensin-converting enzyme (ACE) inhibitors increase cough reflex sensitivity and have been shown to decrease the risk of pneumonia in patients with cerebrovascular accidents. The evaluation of cough as a patient complaint may best be pursued by examining the duration of the symptoms. Cough can be subcategorized into acute and chronic cough. Cough that occurs following an acute respiratory infection may narrow the differential diagnosis and is addressed separately.

Acute Cough

Acute cough may be defined as cough that has been present for less than 8 weeks. Because all causes of chronic coughs initially cause acute symptoms, patients with acute cough may actually have cough caused by one of the etiologies discussed later in this section; however, acute cough more commonly is the result of a less indolent process (Box 1). Infectious etiologies are a frequent cause of acute cough. Most acute cough is the result of viral infections, specifically the common cold. Most cough resulting from the common cold is self-limited and lasts less than 3 weeks. Most episodes of sinusitis are of viral etiology; however, bacterial sinusitis can also result in acute cough. The presence of a significant smoking history raises the possibility of an acute exacerbation of chronic obstructive pulmonary disease (COPD) as the cause of acute cough, especially in patients with previously documented COPD. Bordetella pertussis infection may also be the etiology of an acute episode of cough. Noninfectious processes that lead to acute cough include allergic rhinitis, congestive heart failure, asthma, and aspiration. The clinical history, physical examination, and diagnostic testing are of particular importance in differentiating these disease states and often point to the diagnosis.

Postinfectious Cough

Postinfectious cough begins with an acute upper respiratory tract infection but persists following the resolution of the other acute symptoms (Box 2). Postnasal drip syndrome may present following

Box 1 • • • • •

Viral upper respiratory infections (the common cold) Acute sinusitis (usually viral, occasionally bacterial) Exacerbation of chronic obstructive pulmonary disease Allergic rhinitis Bordetella pertussis infection

Box 2 • • • • •

Causes of Acute Cough

Causes of Postinfectious Cough

Postnasal drip syndrome Bronchospasm Bordetella pertussis infection Bacterial sinusitis Mycoplasma pneumoniae/Chlamydia pneumoniae infection

Chronic Cough

Chronic cough presents the most difficult diagnostic dilemma for the health care practitioner. Cough of greater than 8 weeks’ duration can be considered chronic. Lesser duration of symptoms may still be indicative of one of the etiologies discussed in this section, but such cough is more likely the result of one of the infectious or postinfectious etiologies described previously. In patients who have never smoked, chronic cough is most likely the result of asthma, postnasal drip syndrome, or gastroesophageal reflux. These three etiologies are the most common cause of chronic cough regardless of patient age. In nonsmokers with a normal chest radiograph who are not taking an ACE inhibitor, these three etiologies alone or in combination are the cause of more than 85% of chronic cough (Box 3). Postnasal drip syndrome is the most common of these etiologies. Cough may be the sole presenting symptom of any of these conditions; they are not mutually exclusive and may coexist, particularly in the patient with troublesome, persistent symptoms. Most patients with problematic, persistent cough have multiple etiologies contributing to their symptoms. COPD must be considered in current smokers and in those patients with a significant smoking history. Smokers can have a cough of any etiology, however, and it should not be assumed that their cough is the result of smoking or COPD. Although smokers frequently admit to cough when a history is taken, they infrequently seek medical attention for this symptom. Cough resulting from the use of ACE inhibitors must be considered in all patients being treated with these medications. Less common, yet frequent causes of cough include chronic bronchitis from irritants other than tobacco smoke and eosinophilic bronchitis. Occasionally, chronic cough may be the result of: • Bronchogenic carcinoma • Metastatic carcinoma • Bronchiectasis • Sarcoidosis • Pulmonary fibrosis • Pneumoconiosis • Hypersensitivity pneumonitis • Congestive heart failure • Chronic infection, such as tuberculosis or Mycobacterium avium complex • Recurrent aspiration because of pharyngeal or esophageal abnormalities

Key Diagnostic Points

The evaluation of acute cough should focus on the history and physical examination. Most acute cough will be the result of self-limited viral upper respiratory infections. More thorough

Box 3 • • • • •

Causes of Chronic Cough

Postnasal drip syndrome Asthma Gastroesophageal reflux disease (GERD) Eosinophilic bronchitis Angiotensin-converting enzyme inhibitors

evaluation is necessary in the workup of cough of longer duration particularly if the cough has been present for more than 2 months. The history of onset of the cough and whether it was associated with an acute infectious episode should be elicited. Exposure to sick contacts particularly to a known case of B. pertussis are important historic considerations. The timing and nature of the cough and any associated sputum must be described. Factors that mitigate or worsen the cough should be examined, and prior history of episodic cough, allergies, wheezing, asthma, and gastroesophageal reflux should be questioned. A thorough medication history particularly regarding use of ACE inhibitors must be obtained. Environmental factors both at home and in the work place should be reviewed. Although smoking history is important, it is again noted that smoking-related cough is an infrequent reason for a patient to seek medical attention. The physical examination should focus most on the head, neck, and thorax with a thorough examination of the upper respiratory tract including the auditory canal, nose, and oropharynx. The cardiopulmonary examination should also be thorough to elicit signs of less common illnesses. Acute cough associated with an acute respiratory illness and prominent upper airway symptoms can be assumed to be secondary to the common cold. Diagnostic testing is not indicated in such patients; a chest radiograph would be normal and is thus not recommended. Patients who have abnormal sinus transillumination, purulent nasal secretions, sinus pain or tenderness, or maxillary toothache could possibly have bacterial sinusitis. Again, a viral etiology of sinusitis is more likely than bacterial sinusitis, and antibiotic therapy should be initiated only in patients with persistent symptoms despite symptomatic therapy. Patients with documented COPD who present with acute cough, purulent sputum, dyspnea, and wheezing have an exacerbation of their underlying COPD and should be treated appropriately. Allergic rhinitis usually presents with a clear clinical history of episodic nasal and other allergy symptoms, and allergen avoidance can be initiated. It is important to note that allergic rhinitis can present with perennial symptoms. Postinfectious cough should be evaluated with thorough history and physical examinations followed by limited diagnostic evaluation and empiric therapies. Patients should be treated for postnasal drip syndrome, particularly in the setting of described rhinitis, postnasal drip, or frequent throat clearing. The presence of nasal inflammation and congestion, cobblestoning of the pharyngeal mucosa, or mucus in the oropharynx should also lead to empiric therapy for postnasal drip syndrome. If cough persists in the patients with suspected postnasal drip syndrome, evaluation of the sinuses with imaging and treatment of those patients with evidence of bacterial sinusitis should be pursued. Computed tomography (CT) imaging of the sinuses is the gold standard for diagnosing bacterial sinusitis. Patients with postinfectious cough and an abnormal respiratory examination should have a chest radiograph. Patients with a normal radiograph and evidence of bronchospasm can be empirically treated for airway hyperreactivity. Again, the diagnosis of asthma requires recurrent airflow obstruction and cannot be made on the basis of a single episode of postinfectious wheezing or airway hyperreactivity. In subjects with cough and vomiting, known exposure to a case of B. pertussis, or in the presence of a B. pertussis epidemic in the community, empiric therapy for this illness should be pursued. Before the vaccine era, B. pertussis was an endemic disease, which occurred in cyclic epidemics. It has been documented that B. pertussis continues to circulate in the adult population despite control of the disease in the pediatric population by vaccination. Immunity to B. pertussis, whether as a result of primary infection or immunization, is shortlived. The longer the elapsed interval since prior infection or immunization and repeat infection, the more likely repeat infection will be symptomatic. Perhaps repeat adolescent and adult booster immunization programs should be implemented to effectively control or eliminate this infection. History and physical examinations remain paramount in the patient presenting with chronic cough. The majority of patients should have a chest radiograph obtained as part of their evaluation. If the history and physical examination suggest that postnasal

Cough

the common cold or sinusitis. Bronchospasm may lead to postinfectious cough either as a result of a single episode of postinfectious wheezing or an exacerbation of underlying asthma. Postinfectious cough may be the initial presentation of asthma. Recurrent episodes of airflow obstruction are required to confirm the diagnosis of this chronic illness. Because B. pertussis can present with an indolent course, this infection can be confused with a postinfectious cough. Similarly, bacterial sinusitis can be confused with postinfectious cough. Both of these etiologies of cough are the result of ongoing infection rather than true postinfectious cough. Mycoplasma pneumoniae and Chlamydia pneumoniae infections may also result in postinfectious cough likely because of persistent airway inflammation and increases in cough reflex sensitivity.

5

1 Symptomatic Care Pending Diagnosis 6

drip, asthma, or gastroesophageal reflux is the etiology of a patient’s symptoms, empiric therapy for these conditions should be initiated. Cough triggered by environmental factors or changes may be secondary to rhinitis and postnasal drip or airway hyperreactivity and asthma. Substernal burning or a sour taste in the mouth, particularly when triggered by supine positioning or bending, should increase the suspicion of gastroesophageal reflux. If asthma is suspected, spirometry should be performed to document whether airflow obstruction is present. Response to inhaled bronchodilator with normal spirometry is indicative of airway hyperreactivity. Improvement in symptoms and spirometry with empiric asthma therapy even in the setting of normal baseline flow rates also confirms an asthmatic etiology. A methacholine challenge can be performed to confirm airway hyperreactivity. If cough in the setting of a positive methacholine challenge shows absolutely no response to empiric asthma therapy with inhaled corticosteroids and bronchodilators, consider a trial of systemic steroids. If the cough does not respond to aggressive asthma therapy, the methacholine challenge test results were probably false positive; asthma therapy can be discontinued and diagnostic efforts focused elsewhere. Cough patients being treated with ACE inhibitors should cease these medications. Up to 30% of patients treated with ACE inhibitors will develop a persistent cough, more commonly in women, nonsmokers, and patients of Chinese ancestry. It may take 4 weeks or more for cough caused by ACE inhibitors to resolve following cessation of these medications. In the presence of ACE inhibitor use, further evaluation of dry cough should not be pursued until the patient has been withdrawn from these medications for 1 month. An abnormal chest radiograph can direct further diagnostic studies and therapies, whereas a normal chest radiograph makes less common etiologies of chronic cough such as carcinoma, congestive heart failure, sarcoidosis, or interstitial lung disease unlikely. Evidence of basilar infiltrates or fibrosis may suggest interstitial lung disease or chronic aspiration. Severe gastroesophageal reflux must be considered in those patients with radiographic evidence of chronic aspiration. Chronic cough without a definitive etiology can be troubling to both patient and health care provider. A systematic approach can simplify both diagnosis and treatment (Figure 1). It is again stressed that such a cough may be the result of multiple etiologic factors. In the absence of specific factors that help to point to an etiology of chronic cough, empiric treatment for postnasal drip syndrome should be pursued. Methacholine challenge testing will rule out asthma if it is negative and should also be performed early in the evaluation of chronic cough. Cough may be the sole manifestation of asthma in nearly 60% of patients presenting with chronic cough. A positive methacholine challenge does not have 100% predictive value but should lead to empiric asthma therapy. Empiric therapy for silent gastroesophageal reflux should be initiated in those who do not respond to treatment for postnasal drip syndrome and do not have evidence of or respond to treatment for asthma. Cough may be the only manifestation of gastroesophageal reflux up to 30% of the time. Definitive diagnosis of gastroesophageal reflux requires invasive testing and may require more than one testing modality. Therefore it is recommended that empiric therapy for reflux be pursued before diagnostic testing. Reflux therapy should include conservative approaches such as dietary and lifestyle changes, bed positioning, and pharmacologic treatment. Gastroesophageal reflux–related cough can be particularly troublesome and persistent and may take weeks or months to respond to appropriate and intensive antireflux therapy. This may include higher-than-normal doses of proton pump inhibitors and promotility agents. Surgical treatment of reflux may be necessary to effectively treat reflux related cough in some patients. In patients with persistent cough, the common etiologies of cough often coexist and exacerbate one another. Therapy should often be additive, for instance treating both asthma and reflux, rather than mutually exclusive. Persistent cough should result in further diagnostic evaluation including sputum studies, esophagoscopy, 24-hour pH probe esophageal monitoring, high-resolution chest CT, and possibly bronchoscopy. In the presence of normal chest

Is patient on ACE inhibitor? Yes

No

Stop medicine and observe for up to 4 weeks. If cough persists...

Treat empirically for postnasal drip syndrome. If cough persists after 3 weeks...

Pursue methacholine challenge testing. Is test positive? Yes

No

Treat for asthma. If no response to aggressive therapy...

Treat for gastroesophageal reflux. If no response after up to 12 weeks...

Pursue further diagnostic evaluation including esophagoscopy, 24-hour pH probe esophageal monitoring, high-resolution chest CT, and possibly bronchoscopy

Check induced sputum for eosinophils or empirically treat eosinophilic bronchitis. If no response after 3 weeks...

Figure 1. Approach to chronic cough of uncertain origin. Abbreviations: ACE ¼ angiotensin-converting enzyme; CT ¼ computed tomography. imaging, bronchoscopy is unlikely to yield beneficial diagnostic information in the patient with chronic cough. Eosinophilic bronchitis in the absence of asthma is also a frequent cause (up to 13% of cases) of chronic cough. Patients with eosinophilic bronchitis will have normal spirometry and a negative methacholine challenge. The disease may be diagnosed by appropriate induced sputum analysis showing at least 3% eosinophils. Alternatively it can be empirically treated with a course of inhaled corticosteroids. Most patients appear to respond to inhaled corticosteroids within 3 weeks. Systemic corticosteroids may be required to improve the symptoms in some cases. There may be an association of gastroesophageal reflux with eosinophilic bronchitis. Patients with gastroesophageal reflux have been found to have increased sputum eosinophilia. Bronchiectasis may infrequently result in chronic cough. Bronchiectasis is characterized by the abnormal dilatation of one or more branches of the bronchial tree. It can effectively be diagnosed by high resolution CT scan of the thorax. Bronchiectasis may occur following a severe infection, distal to an area of airway obstruction, congenitally, from chronic inflammatory processes, and as a result of chronic parenchymal scarring and traction. Patients with bronchiectasis may present with productive or nonproductive coughs. They may have recurrent episodes of infection resulting from persistent colonization of the abnormal bronchial segment. Infectious agents may include routine bacterial organisms and typical or atypical mycobacterium. Bronchiectasis may be seen in a variety of chronic illnesses. The presence of bronchiectasis in a patient without a known predisposing cause should prompt the clinician to look for appropriate clinical states such as: • Primary or acquired immunodeficiencies • Abnormalities of ciliary function, such as ciliary dyskinesia or cystic fibrosis • Postinfectious inflammatory processes, such as allergic bronchopulmonary aspergillosis

Collagen vascular diseases Inflammatory bowel disease Sarcoidosis Yellow nail syndrome The presence of localized bronchiectasis may be an indication to pursue flexible fiberoptic bronchoscopy to rule out an obstructing lesion and to obtain appropriate culture specimens. Treatment of bronchiectasis is aimed at the underlying disease state if one can be identified. Infections should be treated with appropriate antibiotics. Clearance of bronchial secretions can be aided with mucolytics and chest physiotherapy including use of percussive devices. In some cases surgical therapy to remove the bronchiectatic segment can be considered.

Treatment

The key treatments for cough are best described based on the suspected etiology. Acute cough therapy should focus on supportive treatment of the underlying suspected etiology, which will likely be a viral upper respiratory infection. Therapy for exacerbation of chronic obstructive pulmonary disease, allergic rhinitis, bacterial sinusitis, or B. pertussis infection is more specific. Postinfectious cough should focus on therapy for postnasal drip syndrome or airways reactivity if suspected. In chronic cough of uncertain etiology (see Figure 1), cough therapy should begin with empiric treatment of postnasal drip syndrome, evaluation and treatment of asthma, empiric treatment of gastroesophageal reflux syndrome, and finally evaluation or empiric therapy for eosinophilic bronchitis. Cough is a frequent and troublesome symptom for both patient and health care provider. Acute cough although at times troubling is usually self-limiting. Postinfectious cough and chronic cough are more problematic, but can effectively be evaluated and treated by performing a thorough history and physical examination and pursuing a systematic approach to diagnostic evaluation and both empiric and guided therapies. The resolution of chronic troubling cough is a therapeutic relief for the patient and a gratifying experience for the caregiver.

References

Barnes TW, Afessa B, Swanson KL, Lim KG. The clinical utility of flexible bronchoscopy in the evaluation of chronic cough. Chest 2004;126:268–72. Breitling CE, Ward R, Goh KL. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160:406–10. Cherry JD. Epidemiological, clinical, and laboratory aspects of pertussis in adults. Clin Infect Dis 1999;28(Suppl2):S112–7. Cohen M, Sahn SA. Bronchiectasis in systemic diseases. Chest 1999;116:1063–74. Irwin RS, Madison JM. Symptom research on chronic cough: A historical perspective. Ann Intern Med 2001;134:809–14. Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med 2000;343:1715–21. Irwin RS, Madison JM. The persistently troublesome cough. Am J Respir Crit Care Med 2002;165:1469–74. Kiljander TO. The role of proton pump inhibitors in the management of gastroesophageal reflux disease-related asthma and chronic cough. Am J Med 2003;115(3A): S65–71.

DIZZINESS AND VERTIGO Method of

Jennifer Wipperman, MD

• Vestibular neuritis • Single, severe, constant episode lasting days • Subacute onset • Positive head thrust test • Nystagmus is unilateral, horizontal, and spontaneous • Me´nie`re’s disease • Recurrent episodes of vertigo lasting hours • May have unilateral hearing loss, tinnitus, or ear fullness • Red flags for stroke include: • Sudden onset • Risk factors for stroke • Nystagmus with a central pattern • Negative head-thrust test • Additional neurologic signs • Inability to walk

CURRENT THERAPY • Benign paroxysmal positional vertigo • The canalith repositioning procedure (Epley maneuver) is the most effective treatment • Vestibular rehabilitation is effective • Consider observation with close follow-up if a patient will not tolerate the canalith repositioning procedure or if symptoms are mild • Avoid symptomatic medications • Vestibular neuritis • Brief symptomatic care with benzodiazepines, antiemetics, and antihistamines • Early vestibular rehabilitation speeds recovery • Use of corticosteroids is controversial The “dizzy” patient is often a frustrating phenomenon in clinical medicine. However, after a careful history and physical examination, most patients can be diagnosed and serious causes excluded. Peripheral causes of vertigo are usually benign, and include vestibular neuritis and benign paroxysmal positional vertigo (BPPV). Life-threatening central causes include stroke, vertebrobasilar insufficiency, demyelinating disease, and an intracranial mass. The first step in evaluating vertigo is differentiating among the four types of dizziness: near syncope or light-headedness, disequilibrium, psychogenic dizziness, and true vertigo. True vertigo is a false sense of motion, and patients typically report that “the room is spinning.” This chapter will focus on the two most common causes of episodic vertigo: BPPV and vestibular neuritis.

Epidemiology

Vertigo is a common office complaint. In fact, 7.5 million Americans are evaluated for dizziness in ambulatory care settings each year, and approximately 50% of these cases are vertigo. In primary care office settings, BPPV accounts for 42% of vertigo diagnoses, followed by vestibular neuritis (41%), Me´nie`re’s disease (10%), and vascular causes (3%). BPPV is the most common vestibular disorder across the lifespan.

Risk Factors CURRENT DIAGNOSIS • Benign paroxysmal positional vertigo • Repeated, brief episodes lasting less than 1 minute • Triggered by changes in head position • Positive Dix-Hallpike maneuver • Up-beating torsional nystagmus is seen after positional changes or the Dix-Hallpike maneuver

BPPV is seven times more likely in individuals over age 60, and it is also more common in women. A history of prior head trauma and other vestibular disorders place patients at risk for BPPV. There are no identified risk factors for vestibular neuritis.

Pathophysiology

BPPV is thought to occur when calcium carbonate debris (otoconia) are dislodged and float freely in the semicircular canals of the inner ear. The posterior canal is most often involved. During head movement, loose otoconia move in the canal and cause a

Dizziness and Vertigo

• • • •

7

continued sense of motion for a few seconds until they settle. The pathophysiology of vestibular neuritis is uncertain. Evidence supports a viral infection, most likely HSV-1, which causes inflammation of the eighth cranial nerve. When hearing loss accompanies vertigo, the condition is called acute labrynthitis.

1 Symptomatic Care Pending Diagnosis

Clinical Manifestations

8

The history and physical examination are fundamental in the evaluation of vertigo. Key questions include the frequency and duration of attacks, triggers such as positional or pressure changes, prior head trauma, associated neurologic symptoms, hearing loss, and headache. A personal history of diabetes, hypertension, and hyperlipidemia are risk factors for stroke. BPPV, stroke, and migraines can have a familial preponderance, and a family history of these disorders should be elicited. Many medications, including anticonvulsants and antihypertensives, cause dizziness. BPPV causes brief, recurrent episodes that last less than 1 minute and are brought on by changes in head movement or position. Nausea and vomiting may be associated. Vestibular neuritis usually has a subacute onset over several hours, peaks in intensity for 1 to 2 days, and then gradually subsides over the next few weeks. Symptoms of vertigo are constant, and nausea and vomiting can be severe during the first few days. Patients with vestibular neuritis may have difficulty standing and veer toward the affected side. Although changes in position worsen the vertigo in vestibular neuritis, vertigo is always present at baseline. In BPPV, patients are normal between attacks. General physical examination should include a thorough cardiovascular, ear, nose, throat, and neurologic examination. The neurologic examination can differentiate between benign (peripheral) and life-threatening (central) causes based on the ability to walk, type of nystagmus, results of the head-thrust test, and presence of associated neurologic signs (Table 1). Patients with vestibular neuritis may have difficulty walking, but the inability to walk is a red flag for a central lesion. Nystagmus is unidirectional (always beats in the same direction) and horizontal in vestibular neuritis, and is suppressed by visual fixation. Having a patient focus on an object in the room will stop the nystagmus, which reappears if a blank sheet of paper is placed a few inches in front of the patient’s face. Nystagmus in central causes is not suppressed by visual fixation, and may be direction-changing (nystagmus beats to the right when the patient looks right, and beats to the left when the patient looks left) or down-beating. The head-thrust maneuver (Figure 1) is positive in peripheral causes like vestibular neuritis. The examiner holds the patient’s head while the patient fixes her eyes on the examiner’s nose, and then the examiner quickly moves the patient’s head 10 degrees to the right and left. If a saccade (the eyes look away and then refixate on the examiner’s nose) is found, this indicates a peripheral

TABLE 1

Figure 1. Head-thrust test. Top panel shows a positive head-thrust test. The

examiner moves the patient’s head quickly 10 degrees to the side, in this case to the patient’s left. A catch-up saccade is observed when the patient looks away and then refixes on the visual target, indicating a peripheral lesion on the left. Lower figure shows a normal head-thrust test. The patient maintains visual fixation during head movement. (Adapted from Pract Neurol 2008; 8:211–221.)

lesion on the side that the head is turned towards. Central lesions will not cause saccades and the head thrust test will be normal. The Dix-Hallpike maneuver is diagnostic of posterior canal BPPV (Figure 2). The patient should be warned that nausea and vomiting may occur. After the patient is placed in the head-hanging position, there is a 5- to 20-second latency period before the nystagmus and symptoms appear. Both the nystagmus and vertigo will increase in severity and then resolve within 60 seconds. The nystagmus observed is up-beating and torsional. The maneuver should be repeated with the head held to the opposite side. The side which elicits the symptoms and nystagmus diagnoses BPPV in the ipsilateral ear. If both sides elicit symptoms, the patient may have bilateral BPPV. If the test is negative and BPPV is strongly suspected, the patient should lie supine and the examiner can turn the head to each side (supine roll test). This maneuver will cause symptoms and nystagmus in patients with horizontal canal BPPV.

Differentiating Peripheral and Central Causes of Vertigo PERIPHERAL CAUSES BPPV

CENTRAL CAUSES

VESTIBULAR NEURITIS

History

Brief, recurrent attacks of vertigo lasting less than 1 minute Triggered by positional changes No vertigo between attacks

Subacute onset Constant and severe vertigo lasting days Nausea and vomiting may be severe

Sudden onset Risk factors for stroke May have severe headache

Nystagmus

Up-beating and torsional

Horizontal and unidirectional

Direction changing Down-beating Pure torsional

Gait

Unaffected between episodes

May veer towards affected side

Unable to walk

Specialized physical examination tests

Positive Dix-Hallpike maneuver Positive supine roll test

Positive head thrust test Visual fixation stops nystagmus

Head thrust test negative Visual fixation does not stop nystagmus

Additional neurologic signs

Rare

Rare

Common (e.g., dysarthria, aphasia, incoordination, weakness, or numbness)

head trauma, heavy lifting or barotrauma. Pressure changes with sneezing or coughing trigger vertigo attacks. Postural hypotension should be ruled out in all patients. An acoustic neuroma presents with slowly progressive, unilateral sensorineural hearing loss and tinnitus. Many patients may have an unsteady gait, but true vertigo is rare. A

PSC E

D

C

B

UT E A

D

C

Figure 2. Treatment maneuver for benign paroxysmal positional vertigo affecting the right ear. To treat the left ear, the procedure is reversed. The drawing of the labyrinth in the center shows the position of the particle as it moves around the posterior semicircular canal (PSC) and into the utricle (UT). The patient is seated upright, with head facing the examiner, who is standing on the right. A, The patient is rapidly moved to headhanging right position (Dix-Hallpike test). This position is maintained until the nystagmus ceases. B, The examiner moves to the head of the table, repositioning hands as shown. C, The head is rotated quickly to the left with right ear upward. This position is maintained for 30 seconds. D, The patient rolls onto the left side while the examiner rapidly rotates the head leftward until the nose is directed toward the floor. This position is then held for 30 seconds. E, The patient is rapidly lifted into the sitting position, now facing left. The entire sequence should be repeated until no nystagmus can be elicited. After the maneuver, the patient is instructed to avoid head-hanging positions to prevent the particles from reentering the posterior canal. (Reprinted with permission from Rakel RE: Conn’s Current Therapy 1995. Philadelphia, WB Saunders, 1995, p 839.)

Diagnosis

BPPV and vestibular neuritis are diagnosed clinically. Further diagnostic testing is indicated if the diagnosis is uncertain or a central cause is suspected. Audiometry may be abnormal in Me´nie`re’s disease. MRI is the best imaging test for central lesions because it includes the posterior fossa and is most sensitive for stroke. Vestibular function testing is useful if the diagnosis is unclear or in cases of refractory vertigo. Vestibular function testing includes several different specialized tests that evaluate the ocular and vestibular response to position changes and caloric stimulation. Video-oculographic recordings of nystagmus can magnify the eye and allow for repeated viewings for further study. Some patients with BPPV may have additional vestibular disorders causing vertigo that vestibular function testing can elucidate.

Differential Diagnosis Me´nie`re’s disease is the third most common cause of vertigo, and is suspected in patients with the triad of tinnitus, fluctuating hearing loss, and vertigo. Episodes usually last hours, are disabling, and are recurrent over years. Migrainous vertigo features episodes lasting hours in patients with other migraine symptoms such as headache, photophobia, phonophobia or aura. Central lesions such as stroke, vertebrobasilar insufficiency, or intracranial mass are most concerning. Red flags for stroke include sudden onset, risk factors for stroke, associated neurologic signs, inability to walk, negative head-thrust test, severe associated headache and characteristic nystagmus. Posttraumatic vertigo may occur in patients after head trauma who present with vertigo, tinnitus, and headache. A perilymphatic fistula is rare, but may be suspected in a patient with episodic vertigo after

BPPV is best treated with the canalith repositioning procedure, also known as the Epley maneuver (Figure 2). Studies have shown the procedure is safe and effective with an odds ratio of 4.2 (95% CI. 2.3-11.4) for symptom resolution. Patients should be warned that nausea or vomiting may occur during the procedure, and may be pre-treated with an antiemetic medication. The procedure can be repeated if unsuccessful. Posttreatment activity restrictions are unnecessary. Vestibular rehabilitation is another valuable treatment for BPPV, but it is less effective than the canalith repositioning procedure. It enhances central compensation for peripheral deficits and leads to faster symptom recovery than observation alone, though most patients will improve spontaneously after 4 to 6 weeks. Observation is an option if symptoms are mild or if a patient will not tolerate the canalith repositioning procedure or vestibular rehabilitation. However, observation is associated with higher recurrence rates than the canalith repositioning procedure. Vestibular-suppressant medications such as antihistamines and benzodiazepines are discouraged because they interfere with central compensation and increase the risk for falling. Surgery is rarely needed for BPPV, but may be helpful in refractory cases. Vestibular neuritis is primarily treated with rest, vestibular suppressant medications, and vestibular rehabilitation. Patients may initially be admitted if symptoms, such as nausea and vomiting, are severe or if stroke is suspected. Treatment with antihistamines (dimenhydrinate [Dramamine]1 50 mg every 6 hours), antiemetics (promethazine [Phenergan]1 25 mg every 6 hours) or benzodiazepines (lorazepam [Ativan]1 1 to 2 mg every 4 hours) may be used to treat severe symptoms. However, these should not be continued more than 2 to 3 days because they inhibit central compensation. The use of corticosteroids is controversial. Although studies show that vestibular-function testing improves more quickly in patients treated with corticosteroids, there is no evidence that corticosteroids hasten the recovery of clinical signs and symptoms of vestibular neuritis. Antiviral medications have not been proven effective for vestibular neuritis. For patients with vestibular neuritis, a referral for vestibular rehabilitation should be given as soon as symptoms improve and a patient can tolerate the exercises. Exercises include balance and gait training as well as coordination of head and eye movements. Vestibular rehabilitation hastens recovery and improves balance, gait, and vision by increasing central compensation for vestibular dysfunction.

Monitoring

Patients diagnosed with BPPV should be reassessed in 1 month regardless of treatment. Failure to improve warrants further evaluation for other etiologies, including central causes. Similarly, patients with vestibular neuritis should slowly improve over several weeks, and failure to do so suggests alternative diagnoses.

Complications

Patients with BPPV are at increased risk for falls. Thirty percent of elderly patients with BPPV have multiple falls in a year. Thus, patients should be assessed for fall risk, functional mobility and balance. Home safety evaluation and home supervision should be considered. BPPV often recurs, with an estimated rate of 15% per year. Counseling patients about recurrence can lead to earlier recognition, earlier treatment and avoidance of falls. Patients with vestibular neuritis are at increased risk for BPPV and Me´nie`re’s disease. Vestibular neuritis rarely recurs. 1

Not FDA approved for this indication.

Dizziness and Vertigo

Treatment

9

References

1 Symptomatic Care Pending Diagnosis

Baloh RW. Vestibular neuritis. N Engl J Med 2003;348:1027–32. Bhattacharyya N, Baugh RF, Orvida L, et al. Clinical practice guideline: Benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2008;139:S47–S81. Chan Y. Differential diagnosis of dizziness. Otolaryngol Head Neck Surg 2009; 17:200–3. Epley JM. The canalith repositioning procedure: For treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 1992;107:399–404. Goudakos JK, Konstantinos DM, Franco-Vidal V, et al. Corticosteroids in the treatment of vestibular neuritis: A systematic review and meta-analysis. Otol Neurotol 2010;31:183–9. Hamid M. Medical management of common peripheral vestibular diseases. Curr Opin Otolaryngol Head Neck Surg 2010;18:407–12. Hillier SL, Holohan V. Vestibular rehabilitation for unilateral peripheral vestibular dysfunction. Cochrane Database Syst Rev 2007;4:CD005397. Hilton M, Pinder D. The Epley (canalith repositioning) manoeuvere for benign paroxysmal positional vertigo. Cochrane Database Syst Rev 2004;2: CD003162. Kerber KA. Vertigo and dizziness in the emergency department. Emerg Med Clin North Am 2009;27:39–50. Leveque M, Labrousse M, Siedermann L, et al. Surgical therapy in intractable benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2007;136:693–8. Seemungal BM, Bronstein AM. A practical approach to acute vertigo. Pract Neurol 2008;8:211–21.

FATIGUE Method of

Janet C. Lindemann, MD, MBA

CURRENT DIAGNOSIS • The clinical evaluation of fatigue begins with a thorough medical and psychosocial history. • Consider monitoring for a month before beginning a laboratory evaluation, because it usually does not yield a diagnosis. Initial evaluation should include a CBC, electrolytes, glucose, liver and kidney function tests, thyroid function tests, and urinalysis. • Among the many possible causes of fatigue, the most common include depression, environmental stress, anemia, and diabetes. In many cases, a cause is not determined.

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CURRENT THERAPY • Any underlying cause discovered in the history, examination, or laboratory evaluation should be treated. • If depression, anxiety, or environmental stress is suspected, early assessment and treatment is important. • Symptom relief includes exercise, regular sleep habits, family discussion about the impact of fatigue, and a symptom and sleep diary.

Epidemiology

Fatigue or tiredness is a common complaint in the general population, representing the chief complaint in nearly 10% of patients presenting to a primary care physician and reported as a symptom in 21% of all patient encounters. While acute, prolonged, and chronic fatigue are relatively common, chronic fatigue syndrome is relatively rare.

Risk Factors

Risk factors for fatigue in adolescence include having depressive symptoms, being highly sedentary, and, conversely, being highly physically active. In adults, risk factors include age over 65 years, presence of one or more chronic medical conditions, and female gender. Precipitating factors include physical stresses such as

infectious mononucleosis and psychological stresses such as jobrelated problems. Perpetuating factors include physical inactivity, emotional disorders, and disturbances of sleep.

Prevention

Because physical inactivity, psychological stress, and lack of sleep are predisposing and perpetuating factors for fatigue, it is helpful to advise patients about stress reduction, regular exercise, and proper sleep habits.

Clinical Manifestations

Fatigue is characterized by general malaise, vague physical discomfort, and an inability to perform routine activities. Acute fatigue is short-lived and generally attributable to physical exertion or an acute illness. Prolonged fatigue is defined as self-reported, persistent fatigue lasting 1 month or longer, whereas chronic fatigue is defined as similar symptoms lasting 6 months or more.

Diagnosis

The clinical evaluation begins with a thorough medical and psychosocial history. It is important to allow the patient to speak uninterrupted for the first minute or two of the interview, because this often provides pertinent clues. The history should include exploration of all medically unexplained symptoms, inquiry into work and life stressor issues, questions regarding alcohol and other substance use, and the current use of prescription, overthe-counter, and alternative therapies. A mental status examination and screening for depression and anxiety should follow. The Beck Depression Inventory or SIG-E-CAPS mnemonic (Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor retardation, Suicidal) are useful screening tools. The challenge with the diagnostic workup for fatigue is that most laboratory tests do not yield a significant diagnosis. Repeated studies show that only about 15% of patients in primary care settings will have an organic cause for their fatigue (Harrison, Ponka), and laboratory results affect management in as little as 5% of patients (Rosenthal). The following recommendations for the laboratory investigation of fatigue are adapted from guidelines developed by Dutch, Canadian, and Australian general practice groups (Harrison): • Consider monitoring for a month after initial presentation, while initiating conservative management. • CBC, electrolytes, glucose, liver and kidney function tests, thyroid function tests, urinalysis. • Clues from the history and examination may indicate the need for erythrocyte sedimentation rate, monospot, antinuclear antigen testing, or chest radiography.

Differential Diagnosis The common causes of fatigue are represented in the mnemonic DEAD TIRED (Box 1). Depression, environmental factors, such as lifestyle, anxiety and anemia are among the most common causes of fatigue. Diabetes and other endocrine disorders, including thyroid disease, should be considered, as well as an undiscovered tumor. Many infections, especially those of viral origin, cause fatigue, as well as insomnia and sleep disorders such as obstructive sleep apnea. Rheumatologic disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia, are often accompanied by fatigue. Endocarditis, while rare, is a must-not-miss diagnosis, as are other cardiac conditions such as coronary artery

Box 1 D E A D

Common Causes of Fatigue: DEAD TIRED

Depression Environment/lifestyle Anxiety, Anemia Diabetes/endocrine

T I R E D

Thyroid, Tumors Infection, Insomnia Rheumatologic Endocarditis/cardiovascular Drugs (medications or substance abuse)

disease. Finally, drugs, either prescription or of personal use or abuse, should be considered. Chronic Fatigue Syndrome is a specific clinical diagnosis characterized by unexplained, persistent or relapsing fatigue, not relieved by rest, that substantially limits daily activity. In addition, there must be at least four of the following: memory or concentration impairment, sore throat, tender cervical or axillary lymph nodes, muscle pain, multijoint pain without swelling or tenderness, new headaches, unrefreshing sleep, or postexertional malaise lasting more than 24 hours.

• Fever is beneficial but is associated with increased cardiac demand and increased metabolic needs. Benign febrile seizures can occur in young children with a fever. • Fever of unknown origin (FUO) in children merits a thorough evaluation based on the age of the child. FUO in adults is defined as a temperature higher than 101 F that is of at least 3 weeks’ duration and whose cause remains undiagnosed after 3 days in the hospital or after three outpatient visits. • Hyperthermia is characterized by a temperature above the upper limit of the hypothalamic set point of 41.1 C (106 F).

Treatment

Monitoring

Ongoing fatigue can be monitored through a three question assessment: • Are you experiencing fatigue? • If so, how severe has it been, on average, during the past week? (0–3 is mild fatigue, 4–6 moderate, and 7–10 severe) • How does fatigue interfere with your ability to function?

References

Beck A, Ward C, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561. Gialamas A, Beilby JJ, Pratt NL, et al. Investigating tiredness in Australian general practice. Aust Fam Physician 2003;32:663. Harrison M. Pathology testing in the tired patient: a rational approach. Aust Fam Physician 2008;37:908. Poluri A, Mores J, Cook DB, et al. Fatigue in the elderly population. Phys Med Rehabil Clin N Am 2005;16:91. Ponka D, Kirlew M. Top 10 differential diagnoses in family medicine: Fatigue. Can Fam Physician 2007;53:892. Rosenthal TC, Majeroni BA, Pretorius R, Malik K. Fatigue: An overview. Am Fam Physician 2008;78:1173. Sharpe M, Wilks D. Fatigue. BMJ 2002;325:480. Viner RM, Clark C, Taylor SJ, et al. Longitudinal risk factors for persistent fatigue in adolescents. Arch Pediatr Adolesc Med 2008;162:469.

FEVER Method of

Ann M. Aring, MD

CURRENT DIAGNOSIS • The definition of fever is arbitrary, because temperature varies within individual persons daily. Oral temperatures of 37.5 C (99.5 F) or rectal temperatures of 100.4 F (38 C) are consistent with fever. • Temperature accuracy depends on the measurement technique. Oral temperatures are preferred in patients older than 5 years. Rectal temperatures are preferred in infants. • Fever in infants younger than 3 months or in neutropenic patients is considered a medical emergency that warrants immediate further evaluation.

CURRENT THERAPY • Antipyretic therapy for children includes acetaminophen 10 to 15 mg/kg every 4 to 6 hours for children older than 3 months or ibuprofen 10 mg/kg every 6 hours for children older than 6 months. • Antipyretic therapy for adults and adolescents includes acetaminophen 650 mg to 1000 mg every 6 hours to a maximum of 4000 mg per day, or ibuprofen 200 to 400 mg every 6 hours. • Aspirin (salicylic acid) should not be used in children due to the risk of Reye’s syndrome. In adults, the dose is 325 to 650 mg every 6 hours as needed for fever. • Combining two antipyretics for fever, such as ibuprofen and acetaminophen, has not been proved to produce quicker or longer-lasting responses. • Sponge bathing should be done with tepid water and no alcohol.

Patients often come to the physician’s office with a fever. Fever can be present in a wide variety of clinical presentations ranging from self-limited viral illnesses to serious bacterial infections. Most febrile conditions can be easily diagnosed with other presenting symptoms and a problem-focused physical examination. However, fever produces anxiety for patients, parents, and health care providers, which can lead to overtreatment. Typically, fever is transient and only requires treatment to provide patient comfort.

Definitions

The definition of fever is arbitrary, because temperature varies daily within individual persons. The hypothalamic thermostat maintains core body temperature at about 37 C (98.6 F). Normal body temperature varies in a regular pattern each day. This circadian temperature rhythm, or diurnal variation, results in lower body temperatures in the early morning and temperatures approximately 1 C higher in the late afternoon or early evening. The word fever is derived from the Latin fovere (to warm). In adults and children older than 12 years, fever is generally accepted as a rectal temperature higher than 38 C (100.4 F), an oral temperature higher than 37.5 C (99.5 F), or an axillary temperature higher than 37 C (98.6 F). The methods of determining body temperature are oral, rectal, and axillary. The oral route of determining temperature is preferred in children older than 5 years and in adults. Typically, rectal temperatures are obtained in infants by placing a lubricated thermometer in the rectum. In general, axillary temperatures are inaccurate and should not be used. Liquid crystal strips applied to the forehead and temperature-sensitive pacifiers are popular with parents but are inaccurate and miss fevers in many children. The temperature considered to be the physiologic limit to febrile illness is 41.1 C (106 F). Hyperthermia is characterized by a temperature higher than this hypothalamic set point. Hyperthermia is due to an interference within the normal mechanisms that balance heat production and dissipation or an insult to the hypothalamus.

Fever

The treatment of fatigue begins with acknowledging the patient’s concern and providing reassurance and information about the natural course and most frequent causes of fatigue. Any underlying cause discovered in the history, examination, or laboratory evaluation should be treated. If depression, anxiety, or environmental stress is suspected, early assessment and treatment is important. In fatigue that remains unexplained, therapy should emphasize symptom relief and include exercise, regular sleep habits, family discussion about the impact of fatigue, and a symptom and sleep diary. These same therapies, along with cognitive behavioral therapy, have been shown to have moderate benefit in chronic fatigue syndrome.

11

When the cause of a fever is unknown, two terms may be used: fever of unknown origin (FUO) and fever of unknown source. The definition of FUO in adults includes a temperature higher than 101 F that is of at least 3 weeks’ duration and whose source remains undiagnosed after 3 days in the hospital or after three outpatient visits. FUO is also used to define a fever that occurs at different periods over weeks or months. Fever of unknown source is defined as a fever in the first week of an illness.

1 Symptomatic Care Pending Diagnosis

Pathogenesis and Physiology

12

Fever is a physiologic mechanism that occurs when an inciting stimulus causes an inflammatory response. Fever may be caused by infections, vaccines, tissue injury, malignancy, drugs, collagen vascular diseases, granulomatous disease, inflammatory bowel disease, endocrine disorders such as thyrotoxicosis and pheochromocytoma, and central nervous system abnormalities. Dehydration, increased physical activity, and heat exposure can all cause an elevation in temperature. Infections cause most fevers in all age groups. Monocytes or tissue macrophages are activated by the microbial or nonmicrobial stimuli to produce various cytokines with pyrogenic activity. The list of currently recognized pyrogenic cytokines includes interleukin-1 (IL-1), tumor necrosis factor a (TNF-a), IL-6, interferon-b (IFN-b), and interferon-g (IFN-g). These cytokines activate the arachadonic acid cascade and increase production of prostaglandin E2 (PGE2). PGE2 then resets the thermoregulatory set point in the hypothalamus at a higher level. Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, and behavioral responses such as seeking warmer or cooler environmental temperatures. The body dissipates heat via evaporation of water from the body surface and lungs through radiation (60%), convection (12%), and conduction (3%).

Risks and Benefits of Fever

Fever is beneficial and not usually harmful to the host, with a few exceptions. Fever is associated with increased cardiac demand and increased metabolic needs. In pregnancy, fever is associated with harmful clinical effects. Many animal studies have shown that fever enhances the immunologic response to infectious agents. Use of antipyretic medications to lower fever increases both morbidity and mortality in infected laboratory animals and prolongs varicella infections in humans. Febrile seizures are usually benign but can cause considerable parental anxiety. Febrile seizures are divided into two types: simple (generalized, last 2 months). Hiccups that are resistant to nonpharmacologic and pharmacologic therapies described in the literature should be defined as refractory.

1

Not FDA approved for this indication.

References

Astin JA, Ernst E. The effectiveness of spinal manipulation for the treatment of headache disorders: A systematic review of randomized clinical trials. Cephalalgia 2002;22:617–23. Diamond ML, Dalessio DJ, editors. Diamond and Dalessio’s The Practicing Physician’s Approach to Headache. 5th ed. Philadelphia: WB Saunders; 1999. Ferrari MD, Roon KI, Lipton RB, et al. Oral triptans (serotonin 5HT-IB/ID-agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001;358:1668–75. Gallagher RM, Kunkel R. Migraine medication attributes important for patient compliance: Concerns about side effects may delay treatment. Headache: J Head Face Pain 2003;43:36–43. Goadsby PJ, Lipton RB, Ferreri MD. Migraine current understanding and treatment. N Engl J Med 2002;346:257–70. Silberstein SD, Lipton EB, Dalessio DJ. Wolff’s Headache and Other Head Pain. 7th ed. New York: Oxford University Press; 2001. Vernon H, McDermaid C, Hagino C. Systematic review of randomized clinical trials of complementary/alternative therapies in the treatment of tension-type and cervicogenic headache. Complement Ther Med 1999;7:142–55.

Pathophysiology

Hiccups result from stimulation of one or more components of the “hiccup reflex arc” that comprises nerve and muscle structures between the base of the fourth cerebral ventricle, the vagus and phrenic nerves (from their origin at C3-C5 and along their course), the anterior scalene, intercostals, and diaphragmatic muscles. The hiccup reflex arc also has connections with the truncus and the mesencephali, the respiratory center, the medullary reticular formation, the hypothalamus, and the phrenic nerve nuclei. Benign, self-limited bouts of hiccups often arise after gastric distention from excessive food or alcohol intake, aerophagy, gastric insufflations, or strong thermic excursions. Persistent and refractory hiccups have different origins: organic, psychogenic, or idiopathic. Organic triggering mechanisms belong to three subgroups: central, peripheral, toxic, and metabolic or pharmacologic. Central causes include infectious organic lesions of the brain such as meningitis,

Complications

The major complications are dehydration and weight loss resulting from inability to tolerate fluids and food. Hiccups can occasionally lead to cardiac arrhythmias due to low blood potassium levels. Ingesting large amounts of fluids to stop hiccups can result in low blood sodium levels, a condition that itself stimulates neurogenic hiccup.

Therapy

Treatment modalities for hiccups can be roughly categorized as nonpharmacologic or pharmacologic. Nonpharmacologic management consists of reversing possible underlying causes, including relieving esophageal obstruction or gastric distention. Raising carbon dioxide pressure reduces hiccup frequency; this therapeutic approach provides the physiologic basis for the common and often effective “breathe-into-a-paper-bag” technique. Several methods of vagal stimulation, including tongue, larynx, and external auditory canal stimulation, have been used in attempts to terminate hiccup episodes. In selected cases phrenic nerve or diaphragmatic pacing stimulation or surgical interruption of the phrenic nerve have been used. Among the pharmacologic therapies, the selective infiltration of phrenic nerve with long-lasting local anesthetics (bupivacaine [Marcaine]1) has been described. Systemic pharmacologic therapies include administration of baclofen (Lioresal),1 carbamazepine (Tegretol),1 chlorpromazine (Thorazine), haloperidol (Haldol),1 ketamine (Ketalar),1 lidocaine (Xylocaine),1 metoclopramide (Reglan),1 nefopam (Acupan),2 nifedipin (Adalat),1 nimodipine (Nimotop),1 and phenytoin (Dilantin).1 Baclofen (Lioresal), a drug active on the smooth muscles with antispasticity properties, is often effective when given at 5 mg orally up to 3 times a day. Chlorpromazine and haloperidol, antipsychotic drugs, are among the most widely used systemic therapies for in-hospital hiccups treatment. Carbamazepine and phenytoin, anticonvulsant drugs, often effective in patients having hiccups of central origin. Metoclopramide, an antiemetic drug with central antidopaminergic effects, is effective in patients with hiccups of central or gastric origin; it should be given orally or IV at the dose of 10 mg up to 4 times daily. Nifedipine and nimodipine, calcium antagonist drugs, are often effective probably owing to antispasticity effects 1 2

Not FDA approved for this indication. Not available in the United States.

on smooth muscles. In some cases of hiccups resistant to several of these therapies, the nonopioid analgesic drug nefopam, injected at a dose of 10 mg IV over 10 seconds, was effective in treating hiccups of central and peripheral origin. Hiccup is a rare clinical condition that can occur as isolated symptom of an underlying disease; when persistent or chronic can lead to devastating consequences. A standard therapeutic approach does not exist. Noninvasive and nonpharmacologic therapies should be considered as first-line treatment. A dedicated diagnostic work-up for patients with persisting hiccups (lasting >48 hours) and chronic intractable hiccups might be helpful in ruling out underlying diseases that could be treated causally. A diagnostic work-up for persistent and chronic intractable hiccups includes the following: esophagogastroduodenoscopy, complete blood count, and chest x-ray and, if these investigations yield negative findings, noninvasive brain imaging.

References

Bilotta F, Doronzio A, Martini S. Bulbar compression due to vertebrobasilar artery dolichoectasia causing persistent hiccups in a patient successfully treated with diuretics and corticosteroids. J Clin Chin Med 2008;3:706–8. Bilotta F, Pietropaoli P, Rosa G. Nefopam for refractory postoperative hiccups. Anesth Analg 2001;93:1358–60. Bilotta F, Rosa G. Nefopam for severe hiccups. N Engl J Med 2000;343:1973–2204. Dunst MN, Margolin K, Horak D. Lidocaine for severe hiccups. N Engl J Med 1993;329:890–1. Hernandez JL, Fernandez-Miera MF, Sampedro E, et al. Nimodipine treatment for intractable hiccups. Am J Med 1999;106:600. Howard SR. Persistent hiccups. Br Med J 1992;305:1237–8. Kolodzik PW, Eilers MA. Hiccups (singultus): review and approach to management. Ann Emerg Med 1991;20:565–73. Newsom Davis J. An experimental study of hiccup. Brain 1970;93:851–72. Souadjian J, Cain J. Intractable hiccups: etiological factors in 220 cases. Postgrad Med 1968;43:72–7. Wagner M, Stapezynski J. Persistent hiccups. Ann Emerg Med 1982;11:24–6.

NAUSEA, VOMITING, GASEOUSNESS, AND DYSPEPSIA Method of

Justin Bailey, MD, FAAFP Nausea is a vague, subjective feeling that vomiting (forceful expulsion of gastric contents) is imminent. Dyspepsia (based on ROME III criteria) can include postprandial fullness, early satiety, epigastric pain, burning, and reflux (return of gastric content to the lower esophagus or mouth, accompanied by a sour taste or “heartburn” sensation). Gaseousness can present with a variety of complaints including belching, bloating, abdominal pain, or flatulence.

Epidemiology

Nausea and vomiting (ICD-9 Code 787.01) is one of the top reasons patients see a primary care provider. Infectious diseases causing nausea and vomiting, gastroenteritis, diarrhea, and dehydration are leading causes of death in developing countries, and of sick days and reduction of employee productivity in the United States. Nausea and vomiting postoperatively and during cancer chemotherapy add significant costs, pain, and discomfort to hospital and ambulatory treatment. Dyspepsia occurs in an estimated 25% of the population U.S. population every year, many of whom do not seek care. Gaseousness is ubiquitous in the population and is troubling to a small portion.

Risk Factors

Previous gastrointestinal surgery, certain medications, chemotherapeutic regimens, substance abuse, pregnancy, infectious diseases, medical conditions, and central nervous system disorders increase the risk for nausea and vomiting symptoms. Dyspepsia risk is increased significantly with ingestion of NSAIDs, tobacco use, H. pylori infection, obesity, anxiety, somatization, neuroticism, depression, and unemployment. Increased upper gastrointestinal

Nausea, Vomiting, Gaseousness, and Dyspepsia

encephalitis, and syphilis; cerebral or spinal tumor; vascular causes, such as ischemic episodes and hemorrhagic stroke (especially subarachnoid hemorrhage); head trauma; and cerebral arteriovenous malformations (i.e., dolichoectasia). Peripheral causes include any irritation of the vagus and phrenic nerves, stimulation of the meningeal afferents by meningitis, and stimulation of the pharyngeal or laryngeal nerve by pharyngitis, peritonsillar abscess, goiter, cysts, or tumor of the neck. Stimulation of the thoracic branches can result from chest trauma, bronchial or mediastinal tumor, pulmonary edema, pleuritis, mediastinitis, esophagitis, dissection of the thoracic aorta, pneumonia, bronchitis, empyema, and direct surgical manipulation. Hiccups related to indirect nerve stimulation arise from stimulation of the afferent vagus nerve branches, for example by peptic ulcer, gastritis, intestinal obstructions, intestinal inflammatory diseases, disorders of the genitourinary apparatus, hepatitis, or surgical manipulation of the abdominal organs. Other possible causes include hiatal hernia and diaphragmatic inflammation secondary to a perihepatic or subphrenic abscess. Hiccups developing during or after general anesthesia are variably attributed to central nervous system suppression, hyperextension of the neck, glottal stimulation due to intubation, or gastric distention secondary to mask ventilation. Several toxic and pathologic metabolic states such as uremia, sepsis, and alcohol intoxication can cause hiccups. Psychogenic causes, accounting for up to 50% of the cases of persistent refractory hiccups, include stress, excitement, suicidal ingestion of toxic substances, and anorexia nervosa.

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gaseousness can be seen with air swallowing from gum chewing and eating quickly as well as consumption of foods that relax the lower esophageal sphincter (e.g., chocolate, fats, mints). Ingestion of lactose, fructose, sorbitol, undigested starches (e.g., bran) and carbonated beverages can all increase the risk of bloating and flatulence.

1 Symptomatic Care Pending Diagnosis

Pathophysiology

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The pathophysiologic regulation of nausea and vomiting is complex and incompletely understood. Multiple neurotransmitters are involved, including acetylcholine, dopamine, histamine, and serotonin. The therapeutic action of antiemetics is often based on blocking the action of these neurotransmitters. Neurologic regulation of nausea and vomiting involves the chemoreceptor triggers in the fourth ventricle, the nucleus tractus solitarius in the medulla, motor nuclei that control the vomiting reflex, and vagal afferent nerves from the GI tract. The sympathetic and parasympathetic nervous systems are involved in conjunction with the smooth muscle cells and the enteric brain within the wall of the stomach and intestine. The pathophysiology of dyspepsia is unclear, but probably has multiple causes. Delayed gastric motility can occur in up to 30% of patients with dyspepsia. Additionally, decreased gastric compliance can be seen in dyspeptic patients. Sensations of lower tract gaseousness result from of one of three different mechanisms: excess gas production, abnormal intestinal transit, and increased visceral sensitivity. Gas production caused by carbohydrate maldigestion, (e.g., lactose intolerance, poorly absorbed starches) results in bloating and a sensation of fullness. High-fiber diets, celiac disease, and small intestine bacterial overgrowth can increase gas production. Dysmotility associated with diabetes mellitus, scleroderma, amyloidosis, and endocrine disease may result in gastroparesis and chronic intestinal pseudoobstruction. Additionally, previous Nissen fundoplication, fat intolerance, and various familial conditions may cause dysmotility. Increased visceral sensitivity is thought to be a main cause of pain and fullness in patients with functional bowel disorders such as irritable bowel syndrome (IBS) and functional dyspepsia.

Prevention

Once the diagnosis has been established, appropriate treatment of the underlying cause of the symptoms can be instituted. When the cause of nausea and vomiting is related to medication, the dose can be adjusted or the medication changed as appropriate. Upper GI bloating and fullness is almost exclusively caused by excess air swallow and can be improved with altering behaviors such as gulping food and gum chewing. Lower GI symptoms can be prevented by avoiding problem foods such as milk products in patients with lactose intolerance.

Clinical Manifestations

Nausea and vomiting are extremely common and are associated with many conditions. Associated symptoms are helpful in sorting out causes. Many common historical associations are listed in Table 1. The diagnosis of dyspepsia is based mainly on clinical symptoms. The Rome III criteria are listed in the opening paragraph. Alarm symptoms that should raise suspicions for gastric cancer include unintended weight loss, persistent vomiting, progressive dysphasia, odynophagia, unexplained anemia, iron deficiency, hematemesis, palpable abdominal mass, lymphadenopathy, family history of gastric cancer, previous gastric surgery, or jaundice. Gaseousness usually presents with abdominal fullness and bloating. Pain associated with the fullness is often relieved with eructation or flatulence (see Table 1).

Diagnosis

The first step in the assessment of patients with abdominal complaints is complete history of the duration of symptoms, the frequency of episodes, work environment, recent travel, household member illness, association of symptoms with certain foods or beverages (i.e., pain relief or worsening with food), and

TABLE 1

Key Symptoms and Differential Vomiting, Dyspepsia, and Bloating

SYMPTOMS Abdominal Pain  N/V • RUQ • Epigastric • RLQ • LLQ • Pelvic

DIFFERENTIAL Organic etiologies

• Cholelithiasis, cholecystitis • Dyspepsia, pancreatitis, GERD, gastritis, MI

• Appendicitis • Diverticulitis • PID, ovarian torsion, ectopic pregnancy

Abdominal pain þ distention þ N/V

Bowel obstruction

Abdominal distention associated with foods (lactose, wheat based products, bran, legumes)

Lactose intolerance Celiac disease Carbohydrate malabsorption, Oligosaccharide fermentation (legumes)

Vomiting several hours after eating þ succussion splash þ N/V

Gastric obstruction Gastroparesis

Heartburn  N/V

GERD, dyspepsia

Early morning þ N/V

Pregnancy

Feculent vomiting þ N/V

Intestinal obstruction Gastrocolic fistula

Vertigo þ nystagmus þ N/V

Vestibular neuritis

Dental erosions, parotid gland enlargement, lanugo-like hair, callus on dorsal surface of hands

Bulimia

Positional N/V

Neurogenic

Abbreviations: GERD ¼ gastroesophageal reflux disease; LLQ ¼ left lower quadrant; MI ¼ myocardial infarction; N/V ¼ nausea and vomiting; PID ¼ pelvic inflammatory disease; RLQ ¼ right lower quadrant; RUQ ¼ right upper quadrant.

determination of the success or failure of what the patient has tried to alleviate the symptoms, all of which may offer diagnostic clues. Focused inquiries into surgeries, sexual activity, and other elements of a review of symptoms may be helpful. A complete review of medication usage, with particular attention to GIirritating medications such as NSAIDs and over-the-counter medications, illicit drugs, and herbal products is important. Physical examination and diagnostic work-up can help isolate the cause (Table 2). In patients with acute (48 h due to seizure risk

Disease-Specific Analgesics

Restless Legs Syndrome. Restless legs syndrome (RLS) is a condition with leg pain that can only be relieved with walking or movement. The disorder can be quite distressing and be difficult to treat. Restless legs syndrome responds better to dopamine agonists such as ropinirole (Requip), pramipexole (Mirapex), or carbidopa/levodopa (Sinemet),1,2 than to typical analgesics. Migraine Headaches. The medication group known as the triptans are available as numerous formulations. The prototype drug was sumatriptan (Imitrex), which is available as a subcutaneous injection of 6 mg, a nasal spray of 5 to 20 mg, or oral tablets of 25 to 100 mg. The sumatriptan dose may be repeated after 2 hours to a maximum daily oral dose of 200 mg. This relatively new class of medications is more effective and has fewer side effects and more rapid onset of action than other analgesics for treating migraine headaches. Numerous medications can be used preventatively. Gout. Gout is a severe inflammatory condition of joints. The great toe is the most common site involved. Colchicine (Colcrys) can have a dramatic effect in a relatively short period of time. The dosing has changed recently to: 0.6 mg tablet, 2 tablets initially then 1 tablet 1 hour later if necessary. The maximum dose is 1.8 mg per treatment dose per attack. Allopurinol (Zyloprim) may be used to prevent recurrences. Glaucoma. Closed-angle glaucoma can appear suddenly and is usually painful. Visual loss can progress quickly, but the discomfort often leads patients to seek medical attention before permanent damage occurs. The treatment of acute angle-closure glaucoma consists of urgent reduction of intraocular pressure (IOP), suppression of inflammation, and the reversal of angle closure. Once glaucoma is diagnosed, the initial intervention includes acetazolamide (Diamox), a topical b-blocker, and a topical steroid. Acetazolamide should be given as a stat dose of 500 mg IV followed by 500 mg PO. Ophthalmologic topical b-blockers including carteolol (Ocupress) and timolol (Timoptic) also aid in lowering intraocular pressure. Studies have not conclusively demonstrated superior protectiveness of one b-blocker over another. Both b-blockers and acetazolamide are thought to decrease production of aqueous humor and to enhance opening of the angle. An a-agonist can be added for a further decrease in intraocular pressure. 1

Not FDA approved for this indication. Not available in the United States. * Withdrawn from the U.S. market in 2010. 2

Cauda Equina Syndrome. Cauda equina syndrome is an acute emergency. It is a serious neurologic condition in which there is acute loss of function of the neurologic elements (nerve roots) of the spinal canal below the termination (conus) of the spinal cord. Symptoms include paraplegia, urinary and rectal sphincter weaknesses, sexual dysfunction, saddle anesthesia, bilateral leg pain, and bilateral absence of ankle reflexes. Pain may be wholly absent. The patient might complain only of lack of bladder control and of perineal anesthesia. Surgical decompression usually by laminectomy in less than 48 hours is critical. Temporal Arteritis. This somewhat common condition manifests with a headache, fever, jaw claudication, and tenderness over the temporal artery. The disease did has a smoldering course; however, it usually manifests with these symptoms. Blindness is a wellknown complication and is more likely to occur if the disease is not treated promptly with corticosteroids. The erythrocyte sedimentation rate is typically greater than 60 mm/hour. The disease is confirmed by biopsy of the temporal artery; however, treatment should begin at the time the disease is suspected. Prednisone1 20 mg twice daily for 2 weeks and then tapered to maintain a normal sedimentation rate for up to 2 years is one effective approach to management. Pain is the most common reason patients seek medical attention. Practitioners need to be competent in the diagnosis of pain syndromes and effective pain treatments. People react differently to pain. Management of discomfort requires incorporation of modalities that are effective as well as acceptable to the patient. Elimination of the pain completely is not a reasonable goal. Effectiveness of therapy must be reevaluated at regular intervals, and multiple modalities are often more effective than single-entity treatments. Even though there is considerable controversy regarding numerous pharmacologic and nonpharmacologic interventions, the practitioner needs to be aware of different possible therapies. When one treatment is less than optimally effective, additional interventions need to be prescribed. The placebo effect with all treatments is substantial and should not be discredited if the treatment is safe (causing no harm) and is perceived as effective by the patient.

Pain

There is no identified maximum dose for many narcotic medications. Exceptions include codeine, meperidine (Demerol), nalbuphine (Nubain), pentazocine (Darvon*), propoxyphene (Darvon-N*), and tramadol (Ultram). Side effects are usually the limiting factor. Current pain-management therapy recommends the use of single-entity formulations, especially for treating chronic pain. Care must be used when using combination medications, which often add acetaminophen or an NSAID to the opioid, because the additional ingredient can become toxic when higher doses are used. Toxicity has commonly been reported in patients taking multiple different analgesic medications containing similar adjuncts such as acetaminophen. The treatment of chronic pain often requires multiple medicines to achieve satisfactory pain control. Pseudo-addiction and pseudo-allergy to opioids are two problems that occur often enough to warrant special discussion. Pseudoaddiction occurs when the patient demonstrates drug-seeking behavior due to ineffective pain control. Concern about addiction is the most commonly cited reason for undertreatment of pain. Proper pain management requires monitoring and adjusting medications to achieve an optimal balance between pain control and side effects. Pseudo-allergy occurs when the patient reports pruritus, which is a side effect of the opiate, which causes histamine release. Codeine, morphine, and meperidine are the most common causative agents of pseudo-allergy. When the only symptom of allergy is pruritus, it would be reasonable to use an alternative narcotic before labeling the patient “allergic to narcotics.”

1

Not FDA approved for this indication.

References

British Pain Society. Spinal cord stimulation for the management of chronic pain: Recommendations for best clinical practice. PDF available at www. britishpainsociety.org/SCS_2005.pdf; [accessed 5.06.10]. Council of Acupuncture and Oriental Medicine Associates (CAOMA) . Foundation for Acupuncture Research: Acupuncture and electroacupuncture. Evidence-based treatment guidelines. Calistoga, CA: Council of Acupuncture and Oriental Medicine Associates; 2004. Ernst E. Chiropractic: a critical evaluation. J Pain Symptom Manage 2008;35(5): 544–62. Hartrick C, Van Hove I, Stegmann J-U, Oh C, Upmalis D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: A 10day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther 2009;31(2):1–12. Johnson M, Martinson M. Efficacy of electrical nerve stimulation for chronic musculoskeletal pain: A meta-analysis of randomized controlled trials. Pain 2006;130(1):157–65. Kaye AD, Kaye AM, Hegazi A, et al. Nutraceuticals: potential roles and potential risks for pain management. Pain Pract 2002;2(2):122–8. Larson AM, Polson J, Fontana RJ, et al. Acute Liver Failure Study Group: Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364–72. Morone NE, Greco CM, Weiner DK. Mindfulness meditation for the treatment of chronic low back pain in older adults: A randomized controlled pilot study. Pain 2008;134(3):310–9. Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database Syst Rev 2008;(3):CD003222. Ohio Hospice and Palliative Care Organization. Palliative Care Pocket Consultant. 3rd ed. Dubuque, IA: Kendall/Hunt; 2008.

31

PHARYNGITIS

TABLE 1

Pharyngitis: Distribution of Causative Organisms (All Age Groups)

Method of

Ruth Weber, MD, MSEd

CURRENT DIAGNOSIS • Patients prioritize symptom relief over microbiological cure. • Most pharyngitis is viral; microbiological confirmation is required for group A b-hemolytic streptococcus pharyngitis. • In adults, throat culture is not necessary if rapid antigen detection test is negative. • Stop presumptive antibiotic therapy if throat culture results are negative for group A b-hemolytic streptococcus.

1 Symptomatic Care Pending Diagnosis

CURRENT THERAPY

32

• Penicillin is the drug of choice for group A b-hemolytic streptococcus pharyngitis. A macrolide is indicated if the patient is allergic to penicillin. • Treatment is necessary for 10 days to eradicate group A b-hemolytic streptococcus from the pharynx. • Amoxicillin can be substituted for penicillin. Patients older than 12 years may be treated with once-daily amoxicillin (Moxatag). • Patients are not infectious after 24 hours of appropriate antibiotic treatment.

Epidemiology

Pharyngitis is common and has substantial medical and societal costs. “Sore throat” accounts for over 7 million outpatient visits by children annually. The estimated total cost of pharyngitis in children is $540 million per year. An estimated 30% of childhood pharyngitis is caused by group A b-hemolytic streptococcus (GABHS). In temperate climates, pharyngitis occurs in outbreaks during winter and early spring, predominantly involving children age 5 to 15 years of age. GABHS is uncommon in preschool-aged children and in adults. Group C b-hemolytic streptococcus pharyngitis occurs mainly in college students and young adults. Of other causes of pharyngitis (Table 1), gonococcal pharyngitis is most common in older adolescents and young adults. Transmission is by oral-genital contact. If gonococcal pharyngitis is diagnosed in a prepubertal child, sexual abuse must be considered.

PATHOGEN

PERCENTAGE OF POPULATION

Group A b-hemolytic streptococcus

15–30

Rhinovirus

20

Adenovirus

2–5

Coronavirus

2–5

Coxsackievirus

2–5

Group C b-hemolytic streptococcus

2–5

Herpes simplex virus

2–5

Influenza virus

2–5

Chlamydia trachomatis

10 ng/mL

Medullary

Calcitonin, CEA

CTof neck, thorax, 6–12 mo or when abdomen; calcitonin is consider PET newly elevated scan

Anaplastic None

Neck U/S

1–3 mo

11 The Endocrine System

Abbreviations: CEA ¼ carcinoembryonic antigen; CT ¼ computed tomography; PET ¼ positron emission tomography; Tg ¼ thyroglobulin; TSH ¼ thyroid stimulating hormone; U/S ¼ ultrasound; WDTC ¼ well-differentiated thyroid cancer.

724

and distant metastases, tumor size), which was later refined to the MACIS scoring system (metastases, age, completeness of resection, extrathyroidal invasion, tumor size). The DeGroot classification consists of class I (intrathyroidal), class II (cervical node metastases), class III (extrathyroidal extension), and class IV (distant metastases) groups. The AMES system (age, metastases, extrathyroidal invasion, primary tumor size) is easy to use, but does not accurately distinguish low-risk from high-risk patients with FTC. Arguably the most widely used is the TNM staging system (tumor size, nodal status, distant metastases). None of the scoring systems can be used to guide the extent of surgical resection because the only factors known preoperatively are age and sex. The rate of recurrence in low-risk patients with WDTC is about 10%, whereas in high-risk patients it is about 45%. Among the low-risk patients who have a recurrence, 33% to 50% die from their disease. Traditionally, radioactive iodine whole body scans (WBS) have been performed every 6 to 12 months to detect recurrent disease. However, the usefulness of serum thyroglobulin assays combined with routine neck ultrasound has decreased the need for frequent WBS. Serum thyroglobulin is a useful marker for follow-up of patients with WDTC, because most of these tumors synthesize thyroglobulin. After successful treatment, thyroglobulin levels should be undetectable. Thyroglobulin levels that are elevated more than 10 ng/mL in the absence of thyroglobulin antibodies indicate residual thyroid tissue or persistent or recurrent thyroid cancer. Further imaging studies are then used to localize the residual tissue or cancer. For medullary thyroid cancer, elevated serum calcitonin or CEA levels after thyroidectomy should prompt appropriate imaging studies to localize persistent or recurrent disease. Persistent and recurrent disease that is detectable with imaging should be resected if it can be done with minimal morbidity. There are no useful tumor markers for anaplastic thyroid cancer.

Summary

Thyroid cancer is increasing in frequency. The majority of thyroid cancers are slow growing and indolent, but a small minority can be aggressive and fatal. Thyroid cancer treatment depends on the characteristics of each histopathologic type. FNA biopsy can be useful in detecting the presence and type of thyroid cancer prior to the initiation of therapy. Thyroidectomy is the first step in the successful treatment of most thyroid cancers; however, the extent of surgery and subsequent adjuvant therapy varies with the subtype of thyroid cancer. Serial measurement of tumor markers coupled with neck imaging studies is useful in the long-term follow-up of patients treated for thyroid cancer.

References

Ball DW. Medullary thyroid cancer: Therapeutic targets and molecular markers. Curr Opin Oncol 2007;19:18–23. Chabre O, Piolat C, Dyon JF. Childhood progression of hereditary medullary thyroid cancer. N Engl J Med 2007;356:1583–4.

Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109–42. D’Avanzo A, Ituarte P, Treseler P, et al. Prognostic scoring systems in patients with follicular thyroid cancer: A comparison of different staging systems in predicting the patient outcome. Thyroid 2004;14:453–8. Fialkowski EA, Moley JF. Current approaches to medullary thyroid carcinoma, sporadic and familial. J Surg Oncol 2006;94:737–47. Kebebew E, Clark OH. Differentiated thyroid cancer: “Complete” rational approach. World J Surg 2000;24:942–51. Kim AW, Maxhimer JB, Quiros RM, et al. Surgical management of welldifferentiated thyroid cancer locally invasive to the respiratory tract. J Am Coll Surg 2005;201:619–27. Lang BH, Lo CY. Surgical options in undifferentiated thyroid carcinoma. World J Surg 2007;31:969–77. Mazzaferri EL, Robbins RJ, Spencer CA, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1433–41. Pacini F, DeGroot LJ. Thyroid neoplasia. In: DeGroot LJ, Jameson JL, editors. Endocrinology. 5th ed. Philadelphia: Saunders; 2006. pp. 2147–80. Phitayakorn R, McHenry CR. Follicular and Hu¨rthle cell carcinoma of the thyroid gland. Surg Oncol Clin N Am 2006;15:603–23. Sanders EM Jr, Livolsi VA, Brierley J, et al. An evidence-based review of poorly differentiated thyroid cancer. World J Surg 2007;31:934–45.

THYROIDITIS Method of

Anthony P. Weetman, MD, DSc

CURRENT DIAGNOSIS • Thyroiditis can be classified as acute, subacute, or chronic, with pain as a hallmark of the first two types. • Silent thyroiditis occurs after pregnancy or following drug treatment. • A combination of thyroid function testing and thyroid peroxidase antibody measurement, supplemented by erythrocyte sedimentation rate and thyroid radionuclide uptake is sufficient to establish a diagnosis in most cases. • Thyrotoxicosis in patients with thyroiditis is transient, and subsequent hypothyroidism should be anticipated.

CURRENT THERAPY • Antibiotics and subsequent surgery are generally required for acute bacterial thyroiditis. • Most patients with subacute thyroiditis can be managed with nonsteroidal antiinflammatory drugs; around one third require a short course of prednisolone. • Thyrotoxicosis following destructive thyroiditis is treated with propranolol (Inderal)1; antithyroid drugs are useless in this setting. • Levothyroxine (Synthroid, Levoxyl) remains the treatment of choice for chronic thyroiditis associated with hypothyroidism. 1

Not FDA approved for this indication.

Thyroiditis simply means inflammation of the thyroid gland, and it arises from a number of different causes. Clinically these are best classified by the tempo of inflammation: acute, subacute, or chronic. Mild to moderate focal thyroiditis, in which there is a patchy infiltration of the thyroid gland by lymphocytes, is so common (in 15% of all autopsy specimens) that it has little clinical significance; in only a small fraction of such patients does disease progress to a chronic thyroiditis and destruction of thyroid tissue. Similarly, a focal thyroiditis is often found adjacent to (or even within) benign or malignant neoplasms of thyroid.

Background

Acute (suppurative) thyroiditis is a rare condition caused by a suppurative infection of the thyroid through the bloodstream, lymphatics, trauma, a persistent thyroglossal duct, or most commonly, extension from nearby infection. The latter typically arises through the piriform sinus, an anomalous remnant of the fourth branchial pouch, usually on the left side. This is the main cause of acute thyroiditis in children and young adults; a long-standing goiter, degeneration in a carcinoma, and immunosuppression are additional risk factors. Virtually any bacterium can cause acute thyroiditis. The most common are Staphylococcus aureus, Streptococci species, Klebsiella pneumoniae, and Escherichia coli. In immunosuppressed patients, including those with AIDS, unusual organisms can invade the thyroid, including Aspergillus, Candida, and Coccidioides species and Pneumocystis jiroveci. In rare instances, tuberculosis can affect the thyroid, but the picture then is usually one of subacute thyroiditis. The dominant clinical features are pain in the thyroid radiating to the ear, tenderness and erythema over the gland, fever, dysphagia, respiratory symptoms, and malaise. Features of septicemia may be present, as may lymphadenopathy and a local thrombophlebitis. The differential diagnosis for thyroid pain includes subacute and, rarely, chronic thyroiditis, hemorrhage into a cyst, and lymphoma. Clinical features help in the diagnosis, and simple investigations usually confirm the clinical suspicion.

Treatment Treatment is with high-dose antibiotics selected on the basis of the microbiology results from fine-needle aspiration biopsy. Surgical drainage of any abscess is indicated when pus cannot be fully removed by aspiration. Complications of acute thyroiditis include tracheal obstruction, retropharyngeal abscess, mediastinitis, and internal jugular venous thrombosis. Any piriform sinus should be located (usually by barium swallow study 2 months after the acute episode) and excised to prevent a recurrence; a thyroid lobectomy is usually needed for this.

Subacute Thyroiditis Background

Subacute thyroiditis (de Quervain’s, viral, or granulomatous thyroiditis) has a variable incidence, depending on region. In North America the incidence is 5 cases per 100,000 population per year. It is possible that it is overlooked in areas of apparently low incidence. Three times more women are affected than men, with a median incidence around the age of 45 years, and HLA-B35 is a predisposing genetic factor. Many viruses have been implicated, especially coxsackievirus, influenza, measles, mumps, and Epstein-Barr virus. There is no need to attempt identification serologically. The main clinical features are a painful and tender goitrous thyroid with fluctuating thyroid hormone levels. The pain can be in one or both thyroid lobes. Occasionally, a nodular form can be detected on palpation. Patients usually have a phase of thyrotoxicosis (caused by release of stored hormone from the damaged gland) lasting up to 4 weeks, followed by a phase of hypothyroidism of 1 to 3 months and then recovery. Many patients describe a prodromal phase of systemic upset or upper respiratory tract infection. The diagnosis is confirmed by the high erythrocyte sedimentation rate (ESR) and low isotope uptake.

Treatment Mild cases do not require treatment except analgesics, usually nonsteroidal antiinflammatory drugs. Severe disease (around one third of cases) warrants treatment with prednisolone at a dose of 30 to 40 mg/day initially. Depending on the clinical response and sedimentation rate, this is gradually tapered after 1 to 2 weeks

so that steroids are stopped after 4 to 6 weeks. Patients’ thyroid function should be monitored closely (every 1 to 2 weeks). During a phase of symptomatic thyrotoxicosis, propranolol (Inderal),1 20 to 40 mg three to four times a day, is useful for controlling the symptoms. Antithyroid drugs (methimazole [Tapazole], propylthiouracil [PTU]) are not effective in this situation. Subsequent symptomatic hypothyroidism is treated with levothyroxine (Synthroid, Levothroid, Levoxyl) 50 to 100 mg/day, but this should be withdrawn after 6 to 8 weeks because the phase is typically transient. However, patients with preexisting thyroid abnormalities can develop permanent hypothyroidism after subacute thyroiditis (5%– 10% of cases), and therefore full recovery of thyroid function must be established by testing. Recurrences occur in around 5% of cases and are dealt with in the same way as the initial attack, although prolonging prednisolone treatment by 2 to 4 weeks may be useful.

Silent Thyroiditis

A similar pattern of subacute thyroid dysfunction without thyroid pain is called silent thyroiditis. This has an autoimmune etiology and occurs most distinctly 3 to 6 months after pregnancy in women with thyroid peroxidase antibodies before delivery. Treatment for thyroid dysfunction is again with propranolol for thyrotoxicosis and levothyroxine for the usually transient hypothyroidism; steroids are not needed. Thyroxine treatment is discontinued 1 year after delivery and the TSH is checked after 6 weeks to verify the patient is euthyroid. Postpartum thyroiditis is a risk factor for the development of future permanent hypothyroidism. Affected women should therefore be screened annually for this and should be warned that the disease may well recur in future pregnancies. The appropriateness of screening all pregnant women for thyroid peroxidase antibodies in the first trimester is not yet clear except in women with type 1 diabetes mellitus, who are at particular risk of developing postpartum thyroiditis. In such women, the presence of thyroid antibodies before delivery should lead to careful monitoring of postpartum thyroid function.

Chronic (Autoimmune) Thyroiditis Background

Hypothyroidism caused by autoimmunity affects approximately 1% of women and 0.1% of men. However, there is a much higher prevalence of subclinical autoimmune thyroiditis shown by the presence of sustained, elevated circulating thyroid-stimulating hormone (TSH) levels with normal free thyroxine levels, with or without accompanying thyroid peroxidase or thyroglobulin antibodies. This condition often comes to light during screening for nonspecific symptoms such as fatigue or weight gain. Some patients have a goiter of variable size that is usually hard and often irregular (bosselated); this is Hashimoto’s, or goitrous, thyroiditis. At the opposite end of the pathologic spectrum is atrophic thyroiditis or primary myxedema in which the thyroid is replaced by fibrous tissue and the only clinical sign of the destructive process is the development of hypothyroidism. These patients may have antibodies that block the TSH receptor, but these are neither frequent nor unique in atrophic thyroiditis.

Treatment Overt hypothyroidism resulting from chronic thyroiditis is treated with levothyroxine. There is no role normally for thyroid extract or for liothyronine (triiodothyronine, T3) supplementation (Thyrolar, liotrix) or substitution (Cytomel), inasmuch as levothyroxine is converted smoothly and physiologically to T3, whereas the short half-life of liothyronine leads to peaks and troughs of circulating T3. Several recent trials have failed to confirm initially promising results from the addition of triiodothyronine to levothyroxine, and such current formulations of treatment can 1

Not FDA approved for this indication.

Thyroiditis

Acute Thyroiditis

725

11 The Endocrine System 726

lead to excessive T3 levels, with the potential for adverse effects on bone and the heart. In otherwise healthy patients younger than 60 years with overt hypothyroidism, I start levothyroxine at 50 to 100 mg a day, but in those older than 60 years or with ischemic heart disease, the usual starting dose is 12.5 to 25 mg a day, increasing every 2 weeks by 25-mg increments. In all cases, the aim is to normalize the TSH level, although rarely this proves impossible in patients whose angina is worsened by thyroxine replacement. Propranolol1 or other b-blockers help minimize this adverse effect. If the TSH is maintained in the reference range, there are no adverse effects. I check TSH levels only 2 to 3 months after changing dose because it can take this length of time for symptoms and TSH levels to normalize. The same applies if the commercial preparation of levothyroxine is changed. Once the desired dose is achieved, TSH levels need to be checked only annually. It is unusual for patients to need more than 200 mg of levothyroxine a day. In my experience an elevated (and usually fluctuating) TSH level in patients taking higher doses usually indicates poor compliance, although malabsorption syndromes and certain drugs—such as colestipol (Colestid), cholestyramine sucralfate (Questran), ferrous sulfate (Feosol), aluminum hydroxide (Amphojel), phenytoin (Dilantin), activated charcoal (CharcoAid), rifampicin (rifampin, Rifadin), and hormone replacement therapy—can interfere with absorption or metabolism. There is controversy about the optimal management of subclinical hypothyroidism. The risk of progression to overt hypothyroidism is highest in patients with both an elevated TSH and positive thyroid antibodies, and in my view it is worth treating these patients and those whose TSH is higher than 10 mU/L with levothyroxine (usually 25–50 mg initially) from the outset. In those with an elevated TSH but no thyroid antibodies, one option is a 3-month trial of levothyroxine, and if any symptomatic improvement occurs, to continue with this. If there is no improvement or the patient chooses not to have treatment, an annual check of thyroid function should be arranged to deal with the risk of progression to overt hypothyroidism. The goiter of Hashimoto’s thyroiditis usually shrinks with levothyroxine. Surgery is only rarely needed to control the goiter. Any focal irregularity in the goiter raises the suspicion of malignancy; such hard nodules are sometimes found in Hashimoto’s thyroiditis and should be investigated, initially by aspiration biopsy. Pain suggests lymphoma, which is a rare complication of autoimmune thyroiditis. Very rarely is the thyroid tender in uncomplicated Hashimoto’s thyroiditis, and this may be associated with an elevated ESR. Corticosteroids may be used but are sometimes unhelpful, and surgery may be needed in extreme cases.

Drug-Induced Thyroiditis

Autoimmune thyroiditis can be precipitated by lithium, excess iodide, or recombinant cytokines such as interferon-a (IFN-a), interleukin-2, and granulocyte-macrophage colony-stimulating 1

Not FDA approved for this indication.

factor (GM-CSF). Such patients usually have thyroid peroxidase and other thyroid antibodies before treatment, and screening for these, as well as measuring serum TSH, should be undertaken before starting these drugs. Regular monitoring of TSH thereafter is also indicated. Thyroxine replacement should be given and adjusted to maintain a normal TSH level. Treatment with amiodarone (Cordarone), lithium, and IFN-a can be continued. Amiodarone can cause both hypothyroidism, readily managed by levothyroxine, and thyrotoxicosis, the latter resulting either from a destructive process or from excess iodide supply that precipitates hyperthyroidism. Amiodarone-induced thyrotoxicosis can be very difficult to manage and necessitates specialist advice. Corticosteroids, potassium perchlorate, antithyroid drugs, and even surgery might be needed to control the disease, whereas stopping amiodarone has no immediate impact because of the long half-life of the drug. A painful but transient thyroiditis can occur 1 to 2 weeks after radioiodine for hyperthyroidism. It responds to simple analgesics, or corticosteroids if severe.

Riedel’s Thyroiditis

Riedel’s thyroiditis is a rare condition of unknown etiology that is caused by fibrosis of the thyroid, leading to a woodlike, hard mass often extending outside the thyroid and involving any of the adjacent structures. There is an association with idiopathic fibrosis elsewhere (retroperitoneum, orbit, mediastinum, biliary tree, lung). The condition is often detected because of suspicion of thyroid malignancy. Aspiration biopsy typically yields no specimen, and diagnosis requires open biopsy. Thyroxine is useful only if there is hypothyroidism, and corticosteroids are ineffective. The condition runs an unpredictable course, with a slow progression in many cases, and surgery should be reserved only for patients with esophageal or tracheal compression. Tamoxifen (Soltamox)1 treatment 20 mg twice daily has been successful in individual cases; due to the rarity of the disease, there have been no controlled trials of treatment. 1

Not FDA approved for this indication.

References

Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118:706–14. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G. Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90:4946–54. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab 2003;88:2100–5. Fatourechi MM, Hay ID, McIver B, et al. Invasive Fibrous Thyroiditis (Riedel Thyroiditis): The Mayo Clinic Experience, 1976-2008. Thyroid 2011 May 13;10:483–6 [Epub ahead of print]. Nicholson WK, Robinson KA, Smallridge RC, et al. Prevalence of postpartum thyroid dysfunction: A quantitative review. Thyroid 2006;16:573–82. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–38. Weetman AP. The thyroid gland and disorders of thyroid function. In: Warrell DA, Cox TM, Firth JD, Benz EJ, editors. Oxford Textbook of Medicine, vol. 2. Oxford: Oxford University Press; 2003. pp. 209–24.

12

Metabolic Disorders

DIABETES MELLITUS IN ADULTS Method of

Anthony L. McCall, MD, PhD, and J. Terry Saunders, PhD

CURRENT DIAGNOSIS • Screening for diabetes should be done in high-risk populations, especially: • Those with prediabetes or the metabolic syndrome. • High-risk ethnic groups (e.g., Native American, Latino American, African American). • Gestational diabetes. • Patients might present with atypical symptoms. • Most diabetes is type 2 in adults, but type 1 does occur in adults, and delayed diagnosis is common. • Cardiovascular risk should be aggressively screened for and treated. • Complications should be documented and tracked. • Check fasting lipids. • Check renal function and albuminuria yearly. • Have a low threshold for stress testing, with imaging for all patients. • Refer for yearly eye examinations. • Check feet for sensation, deformity, and circulation at regular visits. • All patients should receive an educational assessment and training in self-management and self-monitoring of blood glucose. • Take a diet history; this is especially important for patients on insulin. • Get a baseline HbA1c and repeat 2 to 4 times per year (twice yearly if at glycemic goal).

CURRENT THERAPY • Diabetes requires nutrition and behavioral self-management counseling as well as drug therapy. • Repeatedly encourage healthy eating and an active lifestyle. • Prediabetes diagnosis represents an opportunity for behavioral and drug interventions. • Metformin (Glucophage) is usually the first drug therapy. • Don’t expect one drug to do the job for very poorly controlled glycemia, especially if >9%. • Dual defects (insulin resistance and secretion) should be addressed in most patients. • Very insulin resistant patients might need a dual insulin resistance strategy. • Therapy goals for both HbA1c and self-monitored blood glucose can be achieved in most patients.

• Cardiovascular risk reduction therapy is a very high priority— statins and BP control best. • When patients have not met goals on dual oral agent therapy, basal insulin is often the most appropriate choice, particularly when patients are not near glycemic goals. • For oral agent therapy, add don’t switch unless side effects require it. • When adding basal insulin, continue oral agent therapies. • Threatening patients with insulin therapy is counterproductive. • Follow the 3F rule: Fix the fasting glucose first, especially in patients with poor glycemic control. • Prompt recognition of the need for meal insulin is critical to achieve glycemic goals. • Balance meal and basal insulin; check post-meal BP.

Epidemiology

The Centers for Disease Control and Prevention (CDC) estimated that in 2010 the prevalence of diabetes in the United States was 25.8 million. Diabetes is diagnosed in 18.8 million persons and undiagnosed in 7.0 million. Type 2 diabetes mellitus (T2DM) is 90% to 95% of prevalent diabetes, and type 1 diabetes (T1DM) is about 5% to 10%. There are fewer persons with secondary or monogenic forms of diabetes, called maturity-onset diabetes of the young (MODY). About 79 million people above the age of 20 in the United States are thought to have prediabetes. The focus of this article is T2DM because it is the most prevalent form and is increasing rapidly in the United States and worldwide. A few comments are made on adult T1DM. This chapter emphasizes both lifestyle and pharmacologic treatments.

Diagnosis and Classification of Diabetes and Prediabetes Diagnosis

Most diabetes is diagnosed by random or fasting glucose (Table 1). Symptoms should be present if random glucose criteria are used, but surprisingly, many people with diabetes are relatively asymptomatic. In the elderly, cognitive changes can occur and atypical symptoms such as prostatism can appear. The American Diabetes Association (ADA) screening recommendations suggest screening every 3 years starting at age 45 for the general population, but they suggest earlier and more frequent screening in those with high risk. Recently, a case has been made for using elevated Alc as an adjunct combined with glucose measurement or as a sole criterion when >7% for screening and diagnosis of diabetes. Patients from diabetes-prone ethnic groups (e.g., Latin Americans, African Americans, Native Americans) or with a strong family history, polycystic ovary syndrome (PCOS), or gestational diabetes should have early and frequent screenings. High-risk persons include those with prediabetes (impaired glucose tolerance, impaired fasting glucose) or who meet the National Cholesterol Education Program (NCEP) criteria for the metabolic syndrome or its individual components (dyslipidemia, hypertension, central obesity, prediabetes). The metabolic syndrome as defined by the NCEP is criticized as flawed, but such critique does not reduce the importance of fully documenting and treating cardiometabolic

727

TABLE 1

Diagnosis and Classification of Diabetes and Prediabetes

DIAGNOSIS

GLUCOSE TEST

DIAGNOSTIC LEVEL

COMMENTS

Diabetes

Random

>200 mg/dL

Plus classic symptoms*

Diabetes

Fasting

>126 mg/dL

8-hour fast; need confirmation

Diabetes

Postglucose load (75 g in nonpregnant adults)

>200 mg/dL at 2 h

Need confirmation

Diabetes

HbA1c


6.5%

New

Prediabetes IFG

Fasting

>100 mg/dL

Decreased insulin secretion

Prediabetes IGT

Postglucose load (75 g)

140–199 mg/dL at 2 h

Increased insulin resistance

Prediabetes

HbA1c

5.7–6.4%

New

*Polyuria, polydipsla, unexplained weight loss. Abbreviations: IFG ¼ impaired fasting glucose; IGT ¼ impaired glucose tolerance.

risk components in those with or at risk for T2DM in a targeted manner (see Box 1). The metabolic syndrome concept is useful to teach patients and clinicians about these risks and the response of the overweight and sedentary to a healthier lifestyle.

12 Metabolic Disorders

Classification

728

The classification of diabetes into its two most prominent types (T1DM and T2DM) seems straightforward in theory but in practice is increasingly confusing as more Americans become overweight. Although T1DM patients are traditionally lean, many now are overweight and some have metabolic syndrome characteristics. About 80% to 90% of persons with T2DM are overweight or have metabolic syndrome characteristics, but some are leaner

Box 1

Summary of Goals for Treatment

Lifestyle Medical Nutrition Therapy (individualized) • Appropriate calories • Low saturated and trans fats • Moderate, consistent carbohydrates (whole grains, vegetables, fruits) • Healthy fats and proteins (decreased saturated and trans fats, increased monosaturated fat; reduced consumption of animal protein) Activity • Consistent, regular activity tailored to complications and safety (ECG or stress test may be needed before starting an exercise program) Glycemia • Best possible without frequent or severe hypoglycemia • HbA1c 60 years) is also atypical and more likely to be related to another psychiatric or medical illness rather than primary PD. The risk for development of PD has a genetic component. Evidence from twin and family studies suggests the heritability of PD is approximately 40%, with first-degree relatives of probands with PD at a sevenfold greater risk of also developing PD compared with the general population. This risk is substantially higher in families in which the proband had early-onset PD. Because genetic patterns do not fully explain the incidence of PD, a stress-diathesis model has been proposed in which environmental stressors are presumed to play a role in precipitating and maintaining the illness in at-risk individuals. Some studies have reported that up to 80% of individuals described the occurrence of a stressful life event in the year preceding the onset of PD, with most subjects believing a direct connection existed between the two events. Several other risk factors for PD have been identified. Anxiety sensitivity is a traitlike construct referencing an individual’s tendency to specifically fear the physiologic symptoms of anxiety (e.g., palpitations, shortness of breath, sweating) because of the concern that they represent indications of a harmful or negative consequence (e.g., “I am having a heart attack”). Elevated anxiety sensitivity is a risk factor for different anxiety disorders, including PD, as is the personality trait of neuroticism (i.e., tendency to readily experience negative emotions such as anger or anxiety). Other risk factors for PD include a history of heavy smoking in adolescence or a history of childhood abuse. Psychiatric comorbidity with PD is extremely common, with more than 83% reporting one or more lifetime comorbid conditions (NCS-R), although rates are even higher with a diagnosis of PD with agoraphobia. Other anxiety disorders were identified as the most frequent lifetime comorbidity, followed by mood disorders. Much attention has been focused on comorbidity with major depressive disorder (MDD) because 34.1% of individuals with PD report a lifetime history of MDD, and there is a higher risk for PD with agoraphobia (38.5%). In one third of cases, PD precedes

COGNITIVE SYMPTOMS • Fear of going crazy • Fear of dying • Fear of losing control • Perceptual abnormalities • Feeling detached from one’s body (i.e., depersonalization) • Feelings of unreality regarding objects outside one’s body (i.e., derealization) • Sense of impending doom • Feelings of paralyzing terror

MDD; the reverse occurs in another third; and in the final third, the two conditions may occur together. Comorbid depression is also associated with poorer outcomes in both conditions, including worse levels of disability, greater time to response, lower rates of remission, increased risk of substance abuse or additional comorbidity, and greater suicide risk. PD itself is associated with elevated risk of suicide attempts within the past year, independent of the presence of depression. A suspected diagnosis of PD should include a thorough suicide risk assessment.

Differential Diagnosis

A variety of medical and psychiatric illnesses may manifest with panic attacks or panic-like symptoms. Differentiating between these isolated panic attacks and PD poses a diagnostic challenge. Isolated panic attacks are discrete attacks that are not followed by persistent concerns about more attacks or avoidant behavior, nor are there any resultant changes in the patient’s overall level of functioning. Distinguishing PD from other disorders may be more difficult (Table 1). The frightening presence of chest pain, palpitations, or respiratory difficulties during a panic attack may be why individuals with PD present with somatic symptoms as their primary complaint. A complete history and thorough physical examination are key in ruling out the possibility of underlying medical illness, substance intoxication, or drug withdrawal. Simple laboratory investigations may be helpful in initially ruling out serious illness. For instance, a preliminary work-up that includes a complete blood cell count, basic chemistry panel, thyroid-stimulating hormone (TSH) determination, chest radiograph, electrocardiogram or Holter monitor, and urine toxicology screen can rule out a large number of the differential diagnoses. More complex investigations, such as electroencephalography, computed tomography, or assay of urinary catecholamines, may be performed based on specific indications from the clinical examination. Atypical symptoms, new-onset symptoms in older individuals, and accompanying physical signs may suggest an underlying medical cause. Although medical illness can mimic, precipitate, or exacerbate preexisting panic symptoms, PD may also aggravate perception of and vigilance about medical symptoms and may influence the outcome of physical illness. For instance, PD in patients with comorbid asthma has been associated with worse quality of life, increased use of respiratory medication, and increased hospitalization rates. The presence of comorbid PD is more frequently found in certain medical illnesses, such as respiratory disease, vestibular dysfunction, thyroid disorders (i.e., hypothyroidism and hyperthyroidism), cardiac disease, chronic pain, migraines, and irritable bowel syndrome. Panic attacks often form part of the presentation of psychiatric illnesses, particularly of other anxiety disorders and major depression. A careful history documenting the onset, course, possible triggers, and accompanying symptoms is vital in establishing the

Panic Disorder

Box 1

959

TABLE 1

DIAGNOSTIC FEATURE Psychiatric

16 Psychiatric Disorders

diagnosis. For instance, the presence of situationally specific panic attacks can suggest a specific phobia or may occur as part of posttraumatic stress disorder when individuals are exposed to reminders of traumatic events, whereas new-onset panic attacks and excessive worry in a 50-year-old patient with accompanying symptoms of disturbances in sleep and appetite and with psychomotor changes may suggest MDD. Although uncommon (U.S. lifetime prevalence estimated at 0.17%–0.8%), some individuals may be diagnosed with agoraphobia without ever meeting the criteria for PD; this diagnosis remains controversial in the psychiatric community.

Differential Diagnosis of Panic Attacks POSSIBLE DIAGNOSES Mood disorder (e.g., major depression, bipolar disorder) Other anxiety disorder (e.g., social anxiety disorder, specific phobia, posttraumatic stress disorder, generalized anxiety disorder, obsessive compulsive disorder) Agoraphobia without panic disorder Psychotic disorder Somatoform disorder Factitious disorder

Treatment

Cardiac

Angina or myocardial infarction Arrhythmia Mitral valve prolapse Labile hypertension Congestive heart failure

Endocrine

Adrenal dysfunction Thyroid disorder (i.e., hypothyroid or hyperthyroid) Hypoglycemia Hyperparathyroidism

Respiratory

Chronic obstructive pulmonary disease Asthma Pulmonary embolus

Neurologic

Seizure disorder (e.g., temporal lobe epilepsy) Pheochromocytoma Vestibular dysfunction

Substance intoxication

Excess caffeine use Psychostimulants (e.g., L-dopa, cocaine, amphetamines) Cannabis use

Substance withdrawal

Caffeine withdrawal Nicotine withdrawal Alcohol or sedative withdrawal Opioid withdrawal

960

Effective pharmacologic and psychotherapeutic strategies exist for the treatment of PD. Regardless of the modality chosen, aims of treatment include decreased frequency and eventual elimination of panic attacks, eradication of anticipatory anxiety and associated phobic avoidance, correction of faulty cognitions about panic, and return to optimal psychosocial function. Initial choice of treatment modality may depend on a number of factors, including patient and physician preference, severity of symptoms, presence of comorbidity, availability of a therapist, and cost. There is insufficient evidence to recommend one modality (psychotherapy versus medication) over another as a first-line intervention during the acute phase. Figure 1 provides a suggested algorithm for the acute treatment of PD.

Pharmacotherapy Table 2 summarizes common medications used in the treatment of PD. A meta-analysis showed that selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and benzodiazepines had similar tolerability and efficacy in the treatment of PD. However, there may be clinical rationale for the choice of one medication class over another. Because benzodiazepines have limited benefit for mood symptoms, have the potential to be abused, and may cause psychomotor side effects, antidepressants may be the preferred treatment for patients with psychiatric comorbidity (particularly depressive or anxious disorders), a history of past or

Panic disorder

Pharmacotherapy 1st line agent: SSRI or SNRI

CBT

Good response

Partial or no response

• Continue to monitor • Consider booster session if symptoms recur

• Reevaluate diagnosis • Consider undiagnosed comorbidity • Consider medication trial

Good response

No response*

Switch to alternate 1st line agent

Good response

*An adequate trial of medication is 4–6 weeks at therapeutic doses. †Inadequate response at this step merits trials of 3rd or 4th line agents such as monoamine oxidase inhibitor (e.g., phenelzine), mirtazapine or divalproex. Would also strongly recommend referral to specialty mental health clinic.

• Optimize dose • Monitor symptoms • Continue medication for ≥12 months

Partial response*

Consider augmentation with CBT

No response*

Consider 2nd line agent† • TCA or BZD

Consider augmentation with one of the following medications: • BZD • Olanzapine • Pindolol

Partial response*

Consider augmentation with CBT

Consider augmentation with one of the following medications: • BZD • Olanzapine • Pindolol

Figure 1. Suggested algorithm for the acute treatment of panic disorder. Abbreviations: BZD ¼ benzodiazepine; CBT ¼ cognitive-behavioral therapy; SNRI ¼ serotonin-norepinephrine reuptake inhibitor; SSRI ¼ selective serotonin reuptake inhibitor; TCA ¼ tricyclic antidepressant.

Common Medications Used to Treat Panic Disorder RECOMMENDED INITIAL DOSE (mg/d)

MEDICATION (TRADE NAME)

RECOMMENDED DOSE RANGE (mg/d)

Citalopram (Celexa)1

5–10

20–40

Escitalopram (Lexapro)1

5

10–20

5–10

20–60

Fluvoxamine (Luvox)

50

100–300

Paroxetine (Paxil)

5–10

20–60

Paroxetine (Paxil CR)

6.25

25–75

Sertraline (Zoloft)

25

50–200

Venlafaxine XR (Effexor XR)

37.5

75–225

Clomipramine (Anafranil)1

25

75–250

Imipramine (Tofranil)1

25

75–250

15

45–90{

Alprazolam (Xanax)

0.25 tid

2–4{

1

Lorazepam (Ativan)

0.25 tid

2–8{

Clonazepam (Klonopin)

0.25 bid

1–2{

Fluoxetine (Prozac) 1

Tricyclic Antidepressants

Monoamine Oxidase Inhibitors Phenelzine* (Nardil)1 Benzodiazepines

1

Not FDA approved for this indication. *Dietary restrictions required (low-tyramine diet); 2-week washout required before initiation and after termination of monoamine oxidase inhibitor trial. { Usually administered three times daily. { Total daily dosage is divided across 2 to 4 doses/day.

present substance abuse, older patients, or those with a history for a specific antidepressant agent. In contrast, benzodiazepines may be preferred in patients with severe physical symptoms of anxiety or with comorbid bipolar disorder or where there is an urgent need for onset of action. A temporary course of benzodiazepines may be prescribed at the time of SSRI initiation to provide some symptomatic relief while the SSRI takes effect and to alleviate potential SSRI side effects that mimic anxiety (e.g., nausea, dizziness, agitation). In some cases as-needed use of benzodiazepines may be helpful, such as in patients with rare panic symptoms that are otherwise not troublesome or for periodic breakthrough symptoms. However, using benzodiazepines on a regular schedule usually is preferred. Monotherapy with b-blockers or the partial 5-HT1A agonist, buspirone (BuSpar),1 has not shown efficacy for PD. If symptom remission and return to optimal psychosocial function are achieved, clinicians should maintain patients on the optimized dose of medication for a minimum of 12 months. At that time, the clinician may attempt a very slow taper off medication (to minimize discontinuation or withdrawal symptoms) with close monitoring for symptom recurrence. A reasonable taper schedule may be 25% decreases in dose every 4 to 8 weeks, with a more gradual taper for benzodiazepines (e.g., 10% decreases every 1 to 2 weeks).

Psychotherapy Among the psychotherapies available, cognitive-behavioral therapy (CBT) has the greatest evidence to support its use. Two schools of CBT for PD predominate (i.e., panic control treatment [PCT] and cognitive therapy for panic [CTP]), although many therapists 1

Not FDA approved for this indication.

use elements of both. PCT, developed by Barlow and Craske, consists of three key components. First, psychoeducation provides patients with an understanding of the pathophysiology underlying panic attacks. This allows patients to link physiologic system changes with the production of somatic symptoms (e.g., palpitations, dizziness) and accompanying anxious thoughts (e.g., “I am going to lose consciousness.”) and to understand how these factors may interact to reinforce each other. Second, cognitive restructuring teaches patients to identify erroneous beliefs about panic and to use logic and reasoning to correct distorted cognitions that overestimate the threat and consequences of panic attacks. Third, patients undergo interoceptive exposure—systematic, repeated exposure to feared internal cues (i.e., physical symptoms of panic)—which facilitates progressive desensitization and normalization of these sensations. Additional relaxation strategies, such as progressive muscle relaxation or deep breathing, which are useful for lowering general anxiety, may be used. When agoraphobia is also present, graded in vivo exposure of avoided situations may be incorporated into the treatment. CTP, developed by Clark, is based on the premise that recurrent panic attacks are common in individuals with a habitual tendency to misinterpret normal bodily sensations (e.g., dizziness) as signs of imminent, potentially harmful events (e.g., a stroke). A positive-feedback loop is created when these misperceptions result in intense anxiety, which reinforces the intensity of the physical symptoms and arousal until a panic attack results. Although more reliant on cognitive techniques to correct misappraisals of physical symptoms, CTP also emphasizes psychoeducation to explain the creation of the vicious cycle. Patients become more aware of the sequence of events leading to the panic attack through the explanation of the vicious cycle. As with PCT, patients are encouraged to logically examine the basis of their fears and realistically evaluate their likelihood. Patients are taught to develop alternative rational explanations for the symptoms. Over time, the strength of beliefs that perpetuate the cycle is weakened and may be eliminated. CTP may also involve the use of exposure-based behavioral experiments to reinforce corrective learning. PCT and CTP are time-limited interventions accomplished over 12 to 16 1-hour sessions. Periodic “booster” sessions, usually yearly, may be of benefit in cases of symptom recurrence.

Course and Prognosis

PD tends to follow a chronic course with a waxing and waning pattern. During periods of stress, the chance of recurrence or exacerbation is high. Follow-up studies of patients treated for PD suggest that at 4-year follow-up, about 30% of patients maintain remission, 40% to 50% continue to experience mild to moderate symptoms, and approximately 20% report persistent and more severe symptoms. Although CBT and pharmacotherapy appear to be relatively equivalent during the acute phase of treatment, some evidence suggests that CBT may prolong periods of remission in patients with PD but may not necessarily prevent recurrence. Among patients who were treated with CBT, 39% experienced a recurrence at 10 years, whereas among those treated with medications, the same proportion relapsed within 6 months. A meta-analysis did find an advantage for combined treatment (i.e., psychotherapy and pharmacotherapy) delivered in the acute phase over either psychotherapy or pharmacotherapy alone; however, after treatments were discontinued, no differences were observed between those who received combined treatment and those who received psychotherapy alone, although both groups did better than those on pharmacotherapy alone. It has been suggested that rather than the duration of treatment, the level of symptom severity at the time of treatment discontinuation is the key factor in reducing recurrence, highlighting the importance of aiming for symptomatic remission. A course of CBT provided before medication discontinuation may enhance the odds of longer-term remission. Among adults with PD, several negative prognostic factors have been identified: presence of comorbid depression, generalized

Panic Disorder

TABLE 2

961

anxiety, or personality disorder; longer duration of illness; greater levels of avoidance; low levels of social support; and more intense fears about social catastrophes after a panic attack (e.g., “People will laugh at me”). The presence of agoraphobia with PD has been associated with more severe symptoms, chronicity, and limited response to treatment.

References

16 Psychiatric Disorders

Barlow DH, Craske MG. Mastery of Your Anxiety and Panic. Albany, NY: Graywind Publications; 1989. Clark DM. A cognitive approach to panic. Behav Res Ther 1986;24:461–70. Furukawa TA, Watanabe N, Churchill R. Psychotherapy plus antidepressant for panic disorder with or without agoraphobia: Systematic review. Br J Psychiatry 2006;188:305–12. Grant BF, Hasin DS, Stinson FS, et al. The epidemiology of DSM-IV panic disorder and agoraphobia in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2006;67:363–74. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593–602. Kessler RC, Chiu WT, Jin R, et al. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2006;63:415–24. Manfro GG, Otto MW, McArdle ET, et al. Relationship of antecedent stressful life events to childhood and family history of anxiety and the course of panic disorder. J Affect Disord 1996;41:135–9. Mitte K. A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia. J Affect Disord 2005;88:27–45. Smoller JW, Gardner-Schuster E, Covino J. The genetic basis of panic and phobic anxiety disorders. Am J Med Genet C Semin Med Genet 2008;148:118–26. Stein MB, Goin MK, Pollack MH, et al. Practice guidelines for the treatment of patients with panic disorder, Washington, DC: American Psychiatric Publishing; 2009. Available at http://www.psychiatryonline.com/pracGuide/pracGuideTopic_9.aspx (accessed July 2009).

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SCHIZOPHRENIA Method of

Brian Miller, MD, MPH, and Peter Buckley, MD

CURRENT DIAGNOSIS • Three primary symptom domains: • Positive (i.e., hallucinations, delusions, and disorganized thought and behavior) • Negative (i.e., blunted affect, anhedonia, alogia, and avolition) • Cognitive (i.e., attention, language, memory, and processing speed) • Symptoms lasting for 1 month and continuous signs of illness for 6 months • Significant impairment of one or more major areas of functioning (work, interpersonal relations, or self-care) • Ensure that psychosis is not caused by a primary mood disorder, schizoaffective disorder, substance intoxication or withdrawal, or a general medical condition

CURRENT THERAPY • Antipsychotic medication, with monitoring for medication adherence and side effects • Adjunctive medications as needed, including antidepressants, mood stabilizers, benzodiazepines, b-blockers, and anticholinergics • Aggressive monitoring for and management of medical comorbidities, substance use disorders, and suicidality, including collaboration with a primary care physician • Psychosocial interventions

• Involvement of family and support system in care • Long-term treatment, including outpatient medication management and therapy, with inpatient care for acute crisis intervention or illness exacerbation Schizophrenia is a complex, chronic, and often severe psychiatric disorder that is a leading cause of disability worldwide. Although the literal translation of the word schizophrenia is “split mind,” patients with this disorder do not have a “split personality” or a multiple personality disorder. Schizophrenia is a psychotic disorder that interferes with a person’s thinking, mood, behavior, and interpersonal relations. Schizophrenia often has devastating, lifelong consequences for affected individuals and their families, and it is associated with an increased risk of premature mortality, including deaths from suicide and cardiovascular disease. In this chapter, the epidemiology and diagnosis of schizophrenia are reviewed. We then discuss pharmacologic and psychosocial treatments for schizophrenia in the context of a chronic disease model. The risks of medical and substance-use comorbidity and suicidality are also highlighted.

Epidemiology and Risk Factors

The cause of schizophrenia is not known, but it is thought to involve interactions between genetic (or epigenetic) and environmental factors, including developmental problems that occur during gestation. The lifetime prevalence of schizophrenia is approximately 1% and is equal for men and women. The usual age of onset is in the late teens or early 20s to late 30s, although schizophrenia can have onset before age 10 (early onset) or after age 45 (late onset). The age of onset is usually younger for men than women. Several lines of evidence support a genetic contribution to the risk of schizophrenia. There is a 40% lifetime risk of schizophrenia in a child of two parents with schizophrenia. Twin-twin concordance is 50% for monozygotic twins and 12% for dizygotic twins. A meta-analysis found “strong epidemiologic credibility” for four candidate genes: DRD1, DTNBP1, MTHFR, and TPH1, although numerous other genes have been implicated. There are likely multiple candidate genes that increase the risk of schizophrenia, each with a small effect size. Replicated environmental risk factors for schizophrenia include season of birth (i.e., winter), advanced paternal age, prenatal stress throughout gestation (e.g., famine and acute maternal stress in the first trimester, second-trimester influenza exposure, loss of the father in the second or third trimester), obstetric complications (e.g., gestational diabetes, low birth weight, asphyxia), severe childhood abuse, and cannabis use. It remains unclear whether some of these risk factors are causal or represent early manifestations of schizophrenia.

Diagnosis

There are three primary symptom domains in schizophrenia: positive, negative, and cognitive. Positive symptoms are abnormalities of thought content, including hallucinations (i.e., abnormal sensory perceptions in the absence of external stimuli) and delusions (i.e., fixed, false beliefs) and disorganized thinking and behavior. Hallucinations are most commonly auditory, but they can occur in any sensory modality. Negative symptoms include impairments in motivation (i.e., avolition), emotional expression (i.e., blunted affect), speech (i.e., alogia), and the ability to experience pleasure (i.e., anhedonia). Cognitive symptoms include impairments in attention, language, memory, processing speed, and executive function. The most commonly used diagnostic criteria for schizophrenia are derived from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). These criteria include the presence of two or more characteristic symptoms (i.e., delusions, hallucinations, disorganized speech, disorganized behavior, or negative symptoms) for a significant portion of time during a 1-month period, with continuous signs of the disturbance persisting for at least 6 months. During this period, there is

Treatment

There is no cure for schizophrenia. Although there is significant clinical heterogeneity within the disorder, schizophrenia is usually a chronic condition that requires long-term treatment. Comprehensive treatment involves outpatient medication management and therapy, psychosocial interventions, involvement of the family and other support system, inpatient care for acute crisis intervention or illness exacerbation, and collaboration with primary care physicians. Antipsychotic medications play an important role in the pharmacologic management of schizophrenia. First-generation antipsychotics have been in clinical use since the introduction of chlorpromazine (Thorazine) in the 1950s. These agents block the dopamine D2 receptor, and common side effects include extrapyramidal side effects (e.g., parkinsonism, dystonia). The secondgeneration antipsychotics (SGAs), in addition to D2 receptor blockade, are also serotonin 5-HT2 receptor antagonists. Although the risk of extrapyramidal side effects is lower with the use of SGAs than with first-generation antipsychotics, the SGAs are associated with a heightened risk of weight gain and the metabolic syndrome. Table 1 provides a more detailed description of antipsychotic medications. The Texas Medication Algorithm Project (TMAP) recommends a trial of a single (non-clozapine) SGA for newly diagnosed patients with schizophrenia or for patients never before treated with an SGA. However, neither the TMAP nor the American Psychiatric Association (APA) guidelines for the treatment of schizophrenia preferentially endorse a particular antipsychotic. Clozapine (Clozaril) is primarily used for treatment-refractory schizophrenia, usually defined as a lack of or partial response to an adequate trial of two or three antipsychotics. Adjunctive medications may play an important role in the pharmacologic treatment of some patients with schizophrenia. The drugs include antidepressants for depression and anxiety, mood stabilizers for depression or mood elevation, benzodiazepines for anxiety or agitation, b-blockers for akathisia, and anticholinergics for extrapyramidal side effects. Medication nonadherence is a major treatment issue for patients with schizophrenia at all phases of the illness. Reasons for nonadherence are complex and multifaceted but may include medication side effects, impaired insight into illness, psychopathology in all three symptom domains, lack of efficacy, and comorbid substance use. More than 70% of patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial discontinued medication within the first 18 months of treatment. Medication nonadherence leads to dramatically increased risk of illness relapse, hospitalization, and suicidal behavior, and it should be routinely assessed in clinical visits. The use of rapid-dissolving oral or long-acting injectable medications may improve adherence for some patients. Psychosocial interventions are a cornerstone of the comprehensive treatment of patients with schizophrenia, and when used in combination with medication, they are more effective than antipsychotics alone. Psychotherapy, including cognitive-behavioral therapy, supportive therapy, and group therapy, promotes improved

illness management and medication adherence. Involvement of the patient’s family or support system in care, including familybased therapies and psychoeducation, has increased medication adherence and decreased illness relapse rates. Psychosocial rehabilitation, which may include assertive community treatment, social skills training, vocational rehabilitation, and cognitive remediation, can help maximize patients’ psychosocial function. Although there is no typical patient with schizophrenia, the clinical course is often characterized by acute relapses of illness with interepisode absence or attenuation of symptoms. Many factors increase a patient’s risk of illness relapse, including medication nonadherence, psychosocial stressors, substance use, medical illnesses such as infections, and the natural history of the disorder itself. Hospitalization may be required for acute exacerbations of psychotic symptoms, including hallucinations, delusions, and impaired self-care. Hospitalization may also be required if patients represent an acute danger to themselves or others. The concept of the recovery model and recovery-oriented care is a movement that is transforming the delivery of mental health services. Integral to the recovery model are certified peer specialists (CPSs). CPSs are licensed professionals who have progressed in their own recovery from mental illness and work to assist patients with schizophrenia and other mental illness in regaining control over their own lives and over their own recovery process. CPSs provide peer support services, serve as consumer advocates, are a resource for psychoeducation, and offer the unique perspective of their individual experiences.

Comorbidity

Schizophrenia is associated with an increased risk of premature mortality, and cardiovascular disease is a leading cause of death in this patient population. Many factors contribute to this risk, including a high prevalence of smoking, poor health habits, poor health care, medication side effects, and perhaps the pathophysiology of the disorder itself. SGAs as a class are associated with weight gain and an increased risk of the metabolic syndrome. More than 40% of the 1460 patients in the CATIE schizophrenia trial met the criteria for the metabolic syndrome at baseline. Recommendations for monitoring of patients on SGAs, based on a consensus statement from the American Diabetes Association and the American Psychiatric Association, are described in Table 2. Primary care physicians play an important collaborative role with psychiatrists in the detection and management of metabolic disturbances in patients with schizophrenia to minimize the cardiovascular risks associated with these comorbidities. Patients with schizophrenia are at an increased risk for suicide, which is a leading cause of premature mortality. The prevalence of completed suicide attempts among patients with schizophrenia is about 10%, and suicide attempts occur with even greater frequency. Clinicians should routinely assess patients for suicidal ideation, and if present, explore risk factors for completed suicide, which include a suicidal plan and intent, previous suicide attempts, a family history of suicide, access to lethal means, social isolation, and comorbid substance use. Medications, psychotherapy, and hospitalization may be required. Comorbid substance-use disorders predominate among patients with schizophrenia; the estimated prevalence is 40% to 50%. Common substances of abuse include alcohol, marijuana, and cocaine. Patients with schizophrenia and comorbid substance use are at increased risk for medication nonadherence, illness relapse, hospitalization, suicidal and violent behavior, and an overall poor response to treatment. Up to 90% of patients with schizophrenia are tobacco users, which contributes to the increased risk of medical comorbidity. Clinicians are encouraged to routinely screen for and address substance use in their treatment plans.

Conclusions

Schizophrenia is a complex, heterogeneous, and chronic psychiatric disorder. Comprehensive treatment usually involves long-term medication management and therapy, education for patients and

Schizophrenia

significant impairment in one or more major areas of functioning, including work, interpersonal relations, and self-care. It must also be established that the disorder is not better accounted for by a primary mood disorder, schizoaffective disorder, substance intoxication or withdrawal, or another general medical condition. Delusions and hallucinations, although common, are not required for the diagnosis. Although cognitive symptoms are not required for the diagnosis, they are a significant cause of illness-related disability. A diagnosis of schizophrenia is most definitively made by interviewing the patient, obtaining collateral history from family and friends, and completing a medical work-up (i.e., physical examination with routine blood and urine tests). Also of note, the Psychoses Workgroup for DSM-V (anticipated release in May 2013) is considering the addition of prodromal or high-risk psychosis as a diagnostic category, echoing increased attention and efforts at early diagnosis.

963

TABLE 1

Antipsychotic Medications

AGENT

MECHANISM OF ACTION*

TYPICAL DOSING

SIDE EFFECTS{

SIDE EFFECTS{

COMMENTS

First Generation D2-antagonist

1.5–15 mg/d

EPS/TD Akathisia

NMS Hyperprolactinemia

PO, IM, IV, and longacting injection formulations

Aripiprazole (Abilify)

Partial D2-agonist and antagonist

10–30 mg/d

Weight gain (þ) Dyslipidemia (þ) Glucose dysregulation (þ)

Sedation EPS/TD Akathisia

PO, rapid-dissolving PO, and IM formulations

Asenapine (Saphris)

D2-antagonist/5-HT2 antagonist

10–20 mg/day

Weight gain (þ) Dyslipidemia (þ) Glucose dysregulation (þ)

Sedation EPS/TD Akathesia

Rapid-dissolving PO, and IM formulations

Clozapine (Clozaril)

D2-antagonist/5-HT2 antagonist

300–900 mg/d

Weight gain (þþþ) Dyslipidemia (þþþ) Glucose dysregulation (þþ) Agranulocytosis Sedation

Orthostatic hypotension Seizures Myocarditis EPS/TD

PO and rapiddissolving PO formulations

Iloperidone (Fanapt)

D2-antagonist/5-HT2 antagonist

12–24 mg/day

Weight gain (þþ) Dyslipidemia (þ) Glucose dysregulation (þ)

Dizziness Tachycardia Sedation EPS/TD

PO formulation

Lurasidone (Latuda)

D2-antagonist /5-HT2 antagonist

40–80 mg/day

Weight gain (þ) Dyslipidemia (þ) Glucose dysregulation (þ)

Sedation Akathisia Nausea EPS/TD

PO formulation

Olanzapine (Zyprexa)

D2-antagonist/5-HT2 antagonist

5–20 mg/d

Weight gain (þþþ) Dyslipidemia (þþþ) Glucose dysregulation (þþ)

Sedation EPS/TD

PO, rapid-dissolving PO, and IM formulations

Paliperidone (Invega)

D2-antagonist/5-HT2 antagonist

6–12 mg/d

Weight gain (þ) Dyslipidemia (þ) Glucose dysregulation (þ)

EPS/TD

PO formulation Active metabolite of risperidone (Risperdal)

Quetiapine (Seroquel)

D2-antagonist/5-HT2 antagonist

400–800 mg/d

Weight gain (þþ) Dyslipidemia (þ) Glucose dysregulation (þ)

Sedation EPS/TD Orthostatic hypotension

PO and ER formulations

Risperidone (Risperdal)

D2-antagonist/5-HT2 antagonist

2–6 mg/d

Weight gain (þþ) Dyslipidemia (þ) Glucose dysregulation (þ)

EPS/TD Hyperprolactinemia

PO, PO liquid, rapiddissolving PO, and long-acting injection formulations

Ziprasidone (Geodon)

D2-antagonist/5-HT2 antagonist

80–160 mg/d with food

Weight gain (þ) Dyslipidemia (þ) Glucose dysregulation (þ)

QTc prolongation EPS/TD

PO and IM formulations

Haloperidol (Haldol)

16 Psychiatric Disorders

Second Generation

964

*All first-generation and second-generation antipsychotics have an FDA black box warning for an “association with an increased risk of mortality in elderly patients treated for dementia-related psychosis.” All second-generation agents are D2 and 5-HT2 antagonists; however, many act on multiple receptors, including alpha-adrenergic, betaadrenergic, histaminergic, muscarinic cholinergic, D1, and 5-HT1 receptors. { EPS and TD are possible side effects with all antipsychotics, but they occur less frequently with second-generation than first-generation drugs. Abbreviations: D2 ¼ dopamine D2 receptor; EPS ¼ extrapyramidal side effects; ER, extended release; 5-HT2 ¼ serotonin 5-HT2 receptor; NMS ¼ neuroleptic malignant syndrome; TD ¼ tardive dyskinesia; þ ¼ mild or low risk; þþ ¼ moderate risk; þþþ ¼ severe risk.

TABLE 2

Monitoring Second-Generation Antipsychotics (Excluding Clozapine)

FEATURE

BASELINE

Personal and family history*

X

Pregnancy test{

X

Weight and body mass index

X

Waist circumference

X

4 WEEKS

8 WEEKS 12 WEEKS QUARTERLY ANNUALLY X

X X

X

X

X X

Blood pressure

X

X

X

Fasting glucose and HgbA1C

X

X

X

Fasting lipid panel

X

X

{

IF SYMPTOMS EVERY ARISE 5 YEARS OTHER

X

Electrocardiogram

X

X

Prolactin

X

X

Complete blood cell count with differential}

X

their families, and psychosocial interventions. Primary care physicians play an important collaborative role in the detection and management of medical comorbidities, substance-use disorders, and suicidality. Physicians, patients, and families are encouraged to become involved in the National Alliance on Mental Illness (NAMI; www.nami.org), which is a tremendous resource for help, support, education, and advocacy for patients with schizophrenia and other mental illness.

References

Allen NC, Bagade S, McQueen MB, et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: The SzGene database. Nat Genet 2008;40:827. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for Studies on Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry 2004;65:267.

American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 2nd edition. Am J Psychiatry 2004;161(Suppl):1717. Brown S. Excess mortality of schizophrenia. A meta-analysis. Br J Psychiatry 1997;171:502. Buchanan RW, Carpenter WT. Schizophrenia and other psychotic disorders. In: Sadock BJ, Sadock VA, editors. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. p. 1329–45. Green A. Schizophrenia and comorbid substance use disorder: Effects of antipsychotics. J Clin Psychiatry 2005;66:21. Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009;373:31. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209. McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the clinical antipsychotic trials of intervention effectiveness (CATIE). Schizophr Res 2005;80:19. Messias EL, Chen CY, Eaton WW. Epidemiology of schizophrenia: Review of findings and myths. Psychiatr Clin North Am 2007;30:323.

Schizophrenia

*Including obesity, diabetes, hypertension, and dyslipidemia. { In all women of childbearing age. { For patients taking ziprasidone (Geodon), which may prolong the QTc interval, and clozapine (Clozaril). } For patients taking clozapine (Clozaril). Complete blood cell count with a differential cell count is required at baseline, then weekly for 6 months, then every other week for 6 months, and then monthly thereafter. White blood cell count must be
3500/mm3, and absolute neutrophil count must be
2000/mm3 due to risk of agranulocytosis. More frequent assessments may be warranted based on clinical status.

965

17

Men’s Health

BENIGN PROSTATIC HYPERPLASIA Method of

Judd W. Moul, MD

Epidemiology

Benign prostatic hyperplasia (BPH) was generally a topic only of interest to urologists up to about 20 years ago, when several classes of medical therapy became available. Once widespread direct-toconsumer medical advertising hit the airwaves, the public’s lexicon included “BPH” and men and their families were being educated about it. When combined with the aging population, the obesity epidemic, and subsequent health consequences, we have a very important disease process. As other countries improve their standards of living, BPH has become one of the most common health conditions of the aging man worldwide. From a practical standpoint, BPH and its symptoms are very uncommon before the age of 40 years. By ages 60 years and 85 years, the histologic prevalence of BPH at autopsy is 50% and 90%, respectively. The symptoms of BPH are now referred to as lower urinary tract symptoms (LUTS). At age 70 years, about 40% of men report LUTS and by age 75 years, the incidence of LUTS increases to 50%. The diagnosis and treatment of BPH has always been in the realm of the specialty of urology, and this remains the case. However, as more medical therapies have been introduced and prostate-specific antigen (PSA) testing for prostate cancer has become commonplace, urologists are working more closely with internists, family physicians, generalists, and physician extenders to jointly manage these patients.

Pathophysiology

Even though BPH is common, we know very little about the true pathophysiology. However, we do know that men who were castrated before puberty do not develop BPH, and we also know that it is a progressive disease of aging. Before the 1980s, BPH was generally thought of as a static condition of a gradually growing prostate gland that caused progressive bladder outlet obstruction. In fact, it was common to use the “donut hole” analogy with patients, explaining to them that the prostate is like a donut surrounding the bladder neck and outlet. With aging and prostate growth, the donut hole gets smaller, causing progressive obstruction. In the era when transurethral resection of the prostate (TURP) was the only effective treatment, this simple static explanation was sufficient. However, from the 1980s onward, our understanding has advanced to recognize that BPH has both a static, obstructive and a dynamic component under neural control. The donut hole now has to have electrical wires attached to it with the ability to adjust the current. In addition, the contribution of the bladder to LUTS has been well recognized as a key contributor to the dynamic component of BPH and LUTS. The static growth and proliferation of the periurethral tissue into BPH is under androgenic stimulation. Specifically, the main male hormone testosterone is converted to the more active metabolite dihydrotestosterone by the enzyme 5a-reductase in the

prostatic stromal and epithelial cells of the prostate. 5a-Reductase occurs in two forms, type 1 and type 2. Only type 2 is present in the prostate and genitalia. This is critical for the understanding of one of the two main classes of medical therapy for BPH, the 5a-reductase inhibitors (5-ARIs). The dynamic component of BPH and LUTS is based on autonomic input to the smooth muscles in the lower urinary tract, including the bladder, prostate, and urethra. These areas have a large concentration of a1-adrenergic receptors that when stimulated by various stressors cause increasing smooth muscle tone. This increased smooth muscle tone leads to increased urethral resistance and contributes to the bladder outlet obstructive symptoms of BPH. This physiology leads to the basis for the other main class of drugs to treat BPH, the a1-adrenergic blockers.

Symptoms

Lower urinary tract symptoms (LUTS) include urinary frequency, decreased force and caliber of the urinary stream, hesitancy, straining, urgency, and nocturia. The severity can range from the stoic man who refuses to acknowledge any symptoms to the man in frank urinary retention. Most urologists now use a standardized patient-self-administered questionnaire, such as the International Prostate Symptom Score (IPSS) (Figure 1). This is very useful to elicit symptoms and bother in a typical male population with suboptimal health-seeking behavior. It is now very common for men to be referred to urology for a collection of age-related issues including elevated PSA, LUTS, BPH, or erectile dysfunction. Commonly, the PSA or the erectile dysfunction brings the patient to the attention of the health care system for the first time in years and may be the first opportunity to influence men on healthy living and health maintenance as they enter middle or older vulnerable ages. Recognizing this, all health care providers should keep this in mind and try to perform a broader men’s health assessment while the patient is captive.

Diagnosis

The diagnosis of BPH is generally made based on symptoms or the IPSS standardized patient-self-administered questionnaire combined with a digital rectal examination, PSA blood test, urinalysis, and, in some cases, a cystoscopy. The differential diagnosis can include urinary tract infection (UTI), prostatitis, urinary stones in the lower urinary tract, urethral stricture disease, neurogenic or overactive bladder, prostate or bladder cancer, and even congestive heart failure. Some common medications, such as over-thecounter cold medicines containing a-adrenergic agents, can exacerbate LUTS and can even put a man into acute urinary retention if he has underlying BPH. A properly performed digital rectal examination is critical to master in the diagnosis of BPH. Because the posterior prostate gland is located adjacent to the rectum and about 3 to 5 cm internal to the anus, the experienced clinician can gain valuable information. I prefer the patient to bend over the examining table with toes pointed slightly inward, the knees bent slightly forward and the forehead and arms resting on the table. The examiner uses a liberally lubricated gloved index finger to palpate the posterior side of the prostate for size estimate and for any induration or

967

International Prostate Symptom Score (I-PSS) Patient Name:

Date of birth:

17 Men’s Health

In the past month:

Not at all

Less than 1 in 5 times

Less than half the time

About half the time

More than half the time

Almost always

1. Incomplete emptying How often have you had the sensation of not emptying your bladder?

0

1

2

3

4

5

2. Frequency How often have you had to urinate less than every two hours?

0

1

2

3

4

5

3. Intermittency How often have you found you stopped and started again several times when you urinated?

0

1

2

3

4

5

4. Urgency How often have you found it difficult to postpone urination?

0

1

2

3

4

5

5. Weak stream How often have you had a weak urinary stream?

0

1

2

3

4

5

6. Straining How often have you had to strain to start urination?

0

1

2

3

4

5

None

1 Time

2 Times

3 Times

4 Times

5 Times

0

1

2

3

4

5

7. Nocturia How many times did you typically get up at night to urinate?

Your score

Total I-PSS score Score

968

Date completed

1–7: Mild

Quality of life due to urinary symptoms If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?

8–19: Moderate

20–35: Severe

Delighted

Pleased

Mostly satisfied

Mixed

0

1

2

3

Mostly Unhappy dissatisfied

4

5

Terrible

6

Figure 1. International Prostate Symptom Score (IPSS) questionnaire. (Available from the Urological Sciences Research Foundation at http://www.usrf. org/questionnaires/AUA_SymptomScore.html [accessed July 26, 2010].)

nodularity that might indicate the presence of prostate cancer. In this case, referral to an urologist is mandatory. The size of the prostate is measured either by estimating the weight in grams or the volume in cubic centimeters. Models have been developed to teach clinicians how to gauge size and consistency. In general, a normal size prostate is 20 to 25 g (or cm3) in middle-aged men. A size of 25 to 30, 30 to 50, and greater than 50 g (or cm3) is a general guide to mild, moderate, and severe BPH. However, size does not necessarily correlate to symptoms, and both symptom score and size estimate should be reported. The size gauges the histologic condition and the symptoms indicate the LUTS and the bother index, which are both important for individualized treatment. The laboratory assessment should include a urinalysis to rule out hematuria. Like an abnormal digital rectal examination, a urinalysis that shows persistent red blood cells should prompt referral to a urologist for cystoscopic and upper urinary tract assessment.

A urinalysis suggesting urinary tract infection should be followed up with a urine culture. If the patient presents in acute or chronic urinary retention and especially if there is a high postvoid or postcatheter residual bladder volume, a serum creatinine and blood urea nitrogen should be obtained. Severe BPH sometimes causes hydronephrosis and renal insufficiency, and rarely it causes renal failure. In-office bladder ultrasound scanners are very useful to quickly assess residual urine. Contemporary diagnosis of BPH involves obtaining a PSA result. The latest guidelines from the American Urological Association (http://www.auanet.org) regarding the use of PSA testing are very helpful. Although the traditional upper limit of normal for PSA testing has been 4.0 ng/mL, recent guidelines base more on changes in PSA levels over time, considering that most men with BPH will have prior PSA results. In the specific setting of using PSA to help manage BPH, the best data come from the PLESS trial (Proscar Long-Term Efficacy and Safety Study), where a PSA of

Treatment

Treatment of BPH is always individualized to the patient and involves evaluation of symptoms and bother along with objective findings from examination and laboratory results. Current treatments range from periodic monitoring without treatment to treatment of extreme cases with open enucleative surgery.

Active Surveillance and Watchful Waiting For many men, especially those with lower symptom scores and little bother, annual monitoring with digital rectal examination, PSA, urinalysis and symptom assessment is all that is required. Many men are happy to be reassured that they do not have clinically significant prostate cancer and are glad to hear that no immediate treatment is necessary.

Complementary and Alternative Medicine The use of complementary and alternative medicine supplements is very common and physicians should ask patients about their use just as they ask about prescription medications. There are now many “prostate” and “men’s health” supplements containing a variety of chemicals that include zinc, saw palmetto, vitamin E,1 vitamin D,1 and selenium, among others. Aside from a few European clinical trials of saw palmetto, the use of supplements to help BPH is speculative. One challenge is quality assurance of dose and ingredients of these agents that are not FDA-regulated. Although not for BPH, the NIH-funded SELECT trial (Selenium and Vitamin E Cancer Prevention Trial) to determine whether vitamin E or selenium, or both, would prevent prostate cancer is illustrative. Neither supplement had any effect on prostate cancer (or BPH to my knowledge). With the lack of robust trial data for the plethora of supplements, the evidence-based medicine answer to patients is clear.

Medical Therapy a-Blocker Medications

The use of a-adrenergic blocking oral agents to treat BPH has been commonplace since the 1980s. These agents are directed at the dynamic component of BPH and LUTS by relaxing the smooth muscle tissue in the bladder neck and prostate. In simple terms, they relax the bladder outlet, resulting in better urinary flow. Initial agents, such as prazosin (Minipress),1 were not selective blockers and were also used to treat hypertension. Furthermore, these early agents were not long-acting and had to be taken multiple times per day, which severely limited their practical clinical utility. The next generation in the class were doxazosin (Cardura) and terazosin (Hytrin), which were longer-acting agents only dosed once a day. However, they were not selective and also lowered blood pressure, so titration was necessary. The third and current generation agents are selective blockers that treat BPH but do not lower blood pressure when used at recommended doses. The two in this class are tamsulosin (Flomax) and alfuzosin (Uroxatral). In general, clinicians use a-blockers in men with smaller prostate glands (
30-35 g or cm3), in younger men, and in patients where rapid effect is needed. Side effects of this class include headache, dizziness, asthenia, drowsiness, and retrograde ejaculation. Alfuzosin is reported to have the lowest rate of retrograde ejaculation. a-Blockers lower urinary tract muscular relaxation properties and are also now employed for ureteral urinary calculi (kidney stones) to facilitate spontaneous passage. a-Blockers are often used to treat prostatitis as well. In this setting, the agents can relieve dysfunctional voiding that contributes to some cases of prostatitis. 1

Not FDA approved for this indication.

5a-Reductase Inhibitors The 5a-reductase inhibitors have been available since the early 1990s. Finasteride (Proscar) was the first agent in this class (5 mg/daily) and is a type 1 inhibitor. Dutasteride (Avodart; 0.5 mg/daily) is a type 1 and type 2 inhibitor and was approved in 2002. Both drugs prevent the conversion of testosterone to the more active metabolite dihydrotestosterone in the prostate. This inhibition results in involution of BPH tissue and prostate shrinkage. On average, most men achieve 20% to 40% reduction in prostate size after at least 6 months of use. In general, these agents are most effective in men with prostate glands more than 30 g (or cm3). Both drugs lower PSA levels by about 50% after 6 months of use. This is critical to take into account when screening for prostate cancer. If the PSA level does not fall by one half and the patient has been compliant with medication, the patient should be referred to a urologist for a work-up. In follow-up of men, PSA is generally doubled in assessing risk for prostate cancer. However, the use of PSA velocity or doubling-time and other prostate cancer screening tools are still valid as long as the effect on PSA is appreciated. There are two key clinical trials that are important. The MTOPS trial (Medical Therapy of Prostate Symptoms) showed that the combination of an a-blocker (doxazosin) and a 5a-reductase inhibitor (finasteride) was more effective than either alone or placebo in treatment of BPH and LUTS. The PCPT (Prostate Cancer Prevention Trial) showed that finasteride1 lowered the rate of prostate cancer by 25% over placebo in a large 7-year study. Recently, the REDUCE trial (Reduction by Dutasteride of Prostate Cancer Events) confirmed the prostate chemoprevention benefit of this class of drugs showing, that dutasteride1 also lowered the rate of prostate cancer by 23% over placebo. In 2010 the FDA ruled that dutasteride would not be approved for prostate cancer prevention, citing safety concerns in this prevention setting. Urologists also use 5a-reductase inhibitors to treat chronic hematuria due to an enlarged prostate and sometimes prescribe these agents before transurethral resection of the prostate (TURP) to lessen surgical bleeding.

Minimally Invasive Procedures Since the 1980s, a series of transurethral procedures have been evaluated to shrink or non-obstruct the prostate using heat, pressure, or direct pharmacotherapy. Balloon dilation of the prostate was the first to come and go as it was proved not to be durable. Then came microwave energy delivered either transurethrally (transurethral microwave thermotherapy [TUMT]) or via the rectum using transrectal ultrasound guidance. The microwaves create heat in the prostate gland, which can shrink the prostate and improve BPH and LUTS symptoms and flow rates. A number of these therapies are FDA approved; however, their popularity has waned a bit because long-term follow up is lacking and results are thought not to be as durable as the gold standard TURP. Heat energy to the prostate can also be delivered via radiofrequency energy in the form of the transurethral needle ablation (TUNA) procedure. A transurethral cystoscope-like device deploys several radiofrequency needles into the prostate to deliver the heat and shrinkage or cavitation effect. Clinical trials were also conducted with transurethral ethanol injection into the prostate to cause shrinkage; however, this therapy has yet to be FDA approved. High-intensity focused ultrasound (HIFU) is also used in some countries to treat prostate cancer, but it is not approved in the United States to treat cancer or BPH as of 2010.

Surgical Therapy Surgical therapy for BPH was the mainstay of treatment until about 1990, when medical and minimally invasive treatments came on the scene. Currently, surgical therapy, mostly consisting of TURP, is generally reserved for men who fail medical or minimally invasive therapy or men who present with advanced or complicated BPH. The classic indications to proceed directly to TURP 1

Not FDA approved for this indication.

Benign Prostatic Hyperplasia

0 to 1.3 ng/mL, 1.4 to 3.2 ng/mL, and greater than 3.2 ng/mL was associated with small, medium, and large prostate glands (assuming prostate cancer has been ruled out) and predicted therapeutic response to finasteride (Proscar) (see later section).

969

include bladder calculi, severe BPH causing renal insufficiency, or urinary retention in cases of severe BPH. It is also reasonable to proceed to TURP in the man who does not desire medical therapy. A TURP has become safer in the era of improved fiberoptic and endoscopic equipment now employed by urologists. This new generation of equipment allows improved visualization during the operation, especially when combined with microchip endoscopic cameras and large flat-screen technology available in modern endoscopic suites. The removal of prostate tissue has traditionally been accomplished using resectoscopes equipped with electrocautery. Today, this tissue removal can also be accomplished using laser technology, including the Green-Light laser system of tissue vaporization and other lasers that employ laser enucleation of tissue. A variation of TURP is the transurethral incision of the prostate (TUIP). In this operation, the laser or resectoscope is used to make longitudinal cuts or incisions along the course of the prostate urethra from the bladder neck out to the apex of the prostate. This effective treatment can be used in men with smaller prostate glands who have significant LUTS. Finally, for men with severe BPH and gland sizes 80 to 100 g/mL or more, open prostatectomy is still a valuable and highly effective surgical treatment. A small suprapubic incision is used to remove the prostate adenoma. As with radical prostatectomy used for prostate cancer, open prostatectomy for BPH should be performed by urologic surgeons who are experienced in this area.

17 Men’s Health

References

970

Burnett AL, Wein AJ. Benign prostatic hyperplasia in primary care: What you need to know. J Urol 2006;175(3 Pt 2):S19–24. Donnell RF. Minimally invasive therapy of lower urinary tract symptoms. Urol Clin North Am 2009;36(4):497–509. Emberton M, Zinner N, Michel MC, et al. Managing the progression of lower urinary tract symptoms/benign prostatic hyperplasia: Therapeutic options for the man at risk. BJU Int 2007;100(2):249–53. Harkaway RC, Issa MM. Medical and minimally invasive therapies for the treatment of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis 2006;9(3):204–14. Hoffman RM, Monga M, Elliot SP, et al. Microwave thermotherapy for benign prostatic hyperplasia. Cochrane Database Syst Rev 2007;(4):CD004135. Neal RH, Keister D. What’s best for your patient with BPH? J Fam Pract 2009;58 (5):241–7. Roehrborn CG. BPH progression: Concept and key learning from MTOPS, ALTESS, COMBAT, and ALF-ONE. BJU Int 2008;101(Suppl 3):17–21. Roehrborn CG. Pathology of benign prostatic hyperplasia. Int J Impot Res 2008; (Suppl 3):S11–18.

Laboratory Tests and Ultrasonography • Perform a urethral swab for white blood cell count, gonococcal and chlamydial infection, and DNA testing. • Urine should be collected for culture and analysis. • Consider ultrasonography of the scrotum to rule out torsion.

CURRENT THERAPY • For men 18 to 35 years who have sexually transmitted diseases or are at risk for them, empiric therapy includes ceftriaxone (Rocephin) 250 mg IM once (can substitute cefixime (Suprax) 400 mg PO once) plus doxycycline (Vibramycin) 100 mg bid for 10 days or azithromycin (Zithromax) 1 g PO for one dose. • For men older than 35 years in whom the suspected cause is coliform bacteria and not gonococcal or chlamydial infection, therapy includes ofloxacin (Floxin) 300 mg bid for 10 days or levofloxacin (Levaquin) 500 mg qd for 10 days. Treat for 21 days if prostatitis is suspected. • Children and infants should be treated for urinary tract infection and should have a urologic work-up for anatomic abnormality. • All patients should take antiinflammatory medications and pain medications, should decrease their activity, and should wear supportive undergarments. • Follow-up includes reevaluation if treatment fails to improve over 2 to 3 days. Consider rare causes, including viral infection, tuberculosis, autoimmune disease, and abscess. • If cultures are obtained (urethral or urinary), results should be followed and antibiotic adjusted (if necessary) to optimize coverage. • Patient and sexual partner should be educated (if indicated) to prevent future incidents. Epididymitis by definition is inflammation of the epididymis and can be classified by the cause of inflammation. Epididymitis can be infectious (bacterial or nonbacterial) or noninfectious. One can further separate epididymitis into acute (lasting less than 6 weeks) or chronic (lasting more than 3 months).

Anatomy and Physiology EPIDIDYMITIS Method of

David M. Quillen, MD

CURRENT DIAGNOSIS History • In men 18 to 35 years, risk factors include unprotected sexual activity and anal intercourse. Signs and symptoms include gradual onset of unilateral pain and dysuria or urethra discharge. • In men older than 35 years, causes can include urologic abnormality or infection resulting from prostatitis, surgery, catheterization, and urinary tract infection. Other causes are heavy lifting, bicycle riding, and direct trauma. • In children or infants, look for a urinary tract infection and genital or urinary abnormality. Physical Examination • Unilateral pain and swelling • Urethral discharge • Structural abnormality • Normal cremasteric reflex (decreases possibility of torsion)

The epididymis is a narrow, tightly coiled tube connecting the testicle to the vas deferens. The epididymis has three basic functions: transit, storage, and maturation of sperm.

Definition and Classification

There are three types of epididymitis: bacterial, nonbacterial infectious, and nonbacterial noninfectious epididymitis. Bacterial epididymitis generally manifests with a gradual occurrence of pain and swelling of the epididymis associated with inflammation. It can be secondary to urinary tract infection, usually in older men and occasionally in infants. Bacterial epididymitis can occur secondary to a sexually transmitted disease, most commonly chlamydia. Nonbacterial infectious epididymitis is uncommon. The infectious agent can be viral, fungal, or parasitic. Nonbacterial noninfectious epididymitis can result from an autoimmune cause, can be associated with a known syndrome, such as Behc¸et’s disease, or can be induced by medication, such as amiodarone. It can be related to trauma, including from exercise, direct trauma, or sexual activity. Epididymitis that does not result from one of these causes is considered idiopathic.

Definition

Chronic epididymitis is defined as a 3-months or longer history of symptoms of discomfort or pain in the scrotum, testicle, or epididymis that are localized to one or both epididymides on clinical examination.

Epidemiology

Epididymitis can effect men of all ages, but it is most common among men between the ages of 18 and 35 years. Based upon the National Ambulatory Medical Care Survey of 2002, there are around 600,000 cases a year. Different patient populations have different risk factors. The most common cause across all patient populations is a sexually transmitted chlamydia infection usually in 18- to 35-year-old men. Coliform bacteria can also be sexually transmitted cause when associated with anal intercourse in homosexual men. In young children or infants, bladder infections and coliform bacteria are usually the cause. In older men, hypertrophy of the prostate, prostatitis, surgery, catheterization, and bladder infections are common causes. Subacute infections (less-acute pain, few voiding symptoms) are generally associated with sexual activity (without sexually transmitted diseases), heavy physical activity, or bicycle or motorcycle riding. Uncommon and rare causes of epididymitis include medications (amiodarone [Cordarone]), viral infections, fungal infections, and autoimmune disease.

Diagnosis

Patients with epididymitis generally present with a gradual increase in scrotal pain and discomfort that is usually unilateral to start. Frequently painful urination and lower abdominal pain are often present. A normal cremasteric reflex is present, and pain relief can occur with testicular elevation (Prehn sign). Symptoms generally increase gradually with noninfectious causes than with infectious ones. The physical examination usually localizes the tenderness to the epididymis and often demonstrates testicular pain. The spermatic cord is also commonly tender and swollen. Very early on in the presentation, only the tail of the epididymis may be tender, but the inflammation can quickly spread to the rest of the epididymis, to the testicle, and to the other epididymis and testicle. Both acute infectious and acute noninfectious epididymitis present in much the same way as do acute infectious and acute noninfectious orchitis. Orchitis typically manifests with acute pain, testicular swelling, and a normal cremasteric reflex. Orchitis is much less common than epididymitis, but it should be included in the differential. Testicular torsion manifests abruptly, with more-severe pain than either epididymitis or orchitis. It is almost always unilateral, and the cremasteric reflex is abnormal. Testicular torsion is a medical emergency and needs quick surgical consultation if considered. Unfortunately, occasionally acute bacterial epididymitis or orchitis can manifest with similar symptoms. Patients with chronic epididymitis and epididymalgia usually present with a long-standing history of pain (waxing and waning or constant) localized to the epididymis and by definition for at least 3 months. Chronic orchitis manifests similarly, and both can have a significant impact on the patient’s quality of life. Common laboratory tests can include a urethral smear (Gram stain and culture, DNA probe for Neisseria gonorrhoeae or Chlamydia trachomatis) and a midstream urine specimen for analysis

and culture. When epididymitis is diagnosed in an infant or young boy, the child should be further evaluated with abdominopelvic ultrasound to assess urinary tract abnormality and should have a urology referral or urologic work-up. Imaging with ultrasound is often an important tool to confirm the diagnosis and help eliminate the possibility of testicular torsion. On ultrasound, epididymitis is characterized by an enlargement and thickening of epididymis with an increase in blood flow on color Doppler. Orchitis is characterized by normal epididymis, testicular mass, or swollen testicles with hypoechoic and hypervascular areas. Testicular torsion is characterized by normal-appearing testes, but with decreased blood flow on one side.

Treatment

The Centers for Disease Control and Prevention (CDC) recommends in young men at risk for chlamydia or gonorrhea empiric treatment after obtaining cultures and DNA probe. Ceftriaxone (Rocephin) 250 mg intramuscular injection or cefixime (Suprax) 400 mg orally once and 10 days of oral doxycycline (Vibramycin) are first-line treatment. Azithromycin [Zithromax] 1 g orally once is an acceptable alternative for doxycycline. The one-dose quinolone regimen for gonorrhea is no longer recommended owing to widespread resistance. For older men, empiric treatment with levofloxacin (Levaquin) 500 mg once daily or ofloxacin (Floxin) 300 mg twice daily for 10 days and obtaining urine cultures is acceptable. If prostatitis is suspected, treatment with either levofloxacin or ofloxacin should be extended to 21 days.

References

Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep 2007;56(14):332–6. Centers for Disease Control and Prevention, Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55 (RR-11):1–94. Lee JC, Bhatt S, Dogra VS. Imaging of the epididymis. Ultrasound Q 2008;24 (1):3–16. Nickel JC. Chronic epididymitis: A practical approach to understanding and managing a difficult urologic enigma. Rev Urol 2003;5(4):209–15. Trojian TH, Lishnak TS, Heiman D. Epididymitis and orchitis: an overview. Am Fam Physician 2009;79(7):583–7. Yagil Y, Naroditsky I, Milhem J, et al. Role of Doppler ultrasonography in the triage of acute scrotum in the emergency department. J Ultrasound Med 2010;29 (1):11–21.

ERECTILE DYSFUNCTION Method of

Luciano Kolodny, MD

CURRENT DIAGNOSIS • The risk factors for ED include tobacco, alcohol, and drug use, as well as DM, hypertension, hyperlipidemia, and prostate disease. • ED is widely prevalent, and incidence sharply increases with age. • ED is a cardiovascular sentinel event, and its occurrence warrants a cardiac workup. • The workup of ED should include checking testosterone levels, prolactin, glucose, and lipid levels. • First-line therapies include the use of PDE5 inhibitors such as sildenafil citrate (Viagra), vardenafil (Levitra), and tadalafil (Cialis). Abbreviations: DM ¼ diabetes mellitus; ED ¼ erectile dysfunction; PDE5 ¼ phosphodiesterase 5.

Erectile Dysfunction

In inflammatory chronic epididymitis, the patient has pain and discomfort associated with abnormal swelling and induration. The types are infective (e.g., chlamydia, gonorrhea), postinfective (e.g., after acute bacterial epididymitis), granulomatous (e.g., tuberculosis), drug-induced (e.g., amiodarone), associated with a known syndrome (e.g., Behc¸et’s disease), or idiopathic (no identifiable etiology for inflammation). In obstructive chronic epididymitis, the patient has pain or discomfort associated with congenital, acquired, or iatrogenic obstruction of epididymis or vas deferens, such as congenital obstruction or surgical scarring after vasectomy. Chronic epididymalgia is pain or discomfort in a normal-feeling epididymis associated with no identifiable etiology. The epididymis is normal but it tender on palpation.

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CURRENT THERAPY • PDE5 inhibitors Sildenafil citrate (Viagra) 25–100 mg Vardenafil (Levitra) 10–20 mg Tadalafil (Cialis) 10–20 mg • Alprostadil (PGE1) intracavernosal injections (Caverject) 20 mg Intraurethral application (MUSE) 1-mg pellet • Papaverine injections1 30–60 mg • Agents not yet approved for use by the FDA: Apomorphine (Uprima)1 3, 4, 6 mg Phentolamine (oral)1 40, 60, 80 mg Abbreviations: MUSE ¼ medicated urethral system for erection; PDE5 ¼ phosphodiesterase 5; PGE1 ¼ prostaglandin E1. 1 Not FDA approved for this indication.

The term erectile dysfunction (ED) is relatively new, having replaced impotence approximately a decade ago. ED is defined as the “inability of the male to attain or maintain an erection sufficient for satisfactory sexual intercourse.” ED affects millions of men worldwide with implications that go far beyond sexual activity alone. ED is now recognized as a sentinel event in cardiovascular disease, diabetes mellitus (DM), and depression. It can also be damaging to interpersonal relationships and self-esteem.

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Epidemiology

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The Massachusetts Male Aging Study is one of the pivotal studies on the prevalence of ED. Between 1987 and 1989, men between the ages of 40 and 70 years received questionnaires inquiring about several aspects of their sexual health. Of the 1790 men who received the questionnaires, 1290 responded. They revealed that 52% of them had some degree of dysfunction, 17% with minimal, 25% with moderate, and almost 10% with complete absence of erectile function. It also showed the extremely detrimental link between coronary artery disease (CAD), DM, and ED. A few years later another group used the same patient database and followed up on these subjects. The risk of ED was 26 cases per 1000 men annually, which increased with age, lower education, DM, heart disease, and hypertension.

Physiology of Erection

The penile erection requires intact vascular, neuronal, and hormonal systems. The intricate details of this process are beyond the scope of this article, but in summary, after any sensorial

stimulation, which can be visual, tactile, auditory, or olfactory, nitric oxide (NO) and other neurotransmitters are released at the cavernous nerve terminals. The endothelial cells then release vasoactive relaxing factors, which lead to vasodilatation of the penile blood vessels and increased blood flow. As blood flow increases, compression of the subtunical venular plexuses will substantially decrease venous outflow and finally cause the penis to change from flaccid to erect (Figure 1). NO is the principal neurotransmitter involved in penile erection, but other vasoactive substances such as vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide (CGRP), substance P, and serotonin also play roles. High levels of intrapenile NO facilitate the relaxation of intracavernosal trabeculae, thereby maximizing blood flow and penile erection. Nonadrenergic, noncholinergic neurons have been found to release NO, leading to increased production of cyclic guanosine monophosphate (cGMP). Through a series of reactions, cGMP will lead to relaxation of the smooth muscle, directly impacting the ability to go from a flaccid to an erect penile state. The return from erect to flaccid requires the hydrolysis of cGMP to guanosine monophosphate (GMP) by phosphodiesterase 5 (PDE5) (see Figure 1).

Testosterone and Erectile Function

Testosterone provides intrapenile nitrous oxide synthase (NOS), which has an important role in enhancing the production of NO, subsequent local vasodilatation, and penile erection. There is no correlation between serum testosterone levels and the degree of ED. However, hypogonadal men may experience significantly reduced libido. Hypogonadism is associated with decreased selfesteem, depression, osteoporosis, insulin resistance, increased fat mass, decreased lean body mass, and cognitive dysfunction.

Pathophysiology of Erectile Dysfunction

ED can be classified as psychogenic, organic (hormonal, vascular, drug-induced, or neurogenic), or mixed psychogenic and organic. Up to 80% of ED cases have an organic origin. The most common cause of ED is vascular disease (Box 1). Atherosclerosis is the most common cause of vasculogenic ED, whereas endothelial damage is the most common mechanism. Aging is a well-known risk factor for ED, and it is hypothesized that there are alterations in the levels of NO that occur as a consequence of the aging endothelium. Additionally, chronic illness, depression, and lack of a sexual partner are all prevalent in this age population.

NO synthesis Arginine

NO

Cavernous nerve cell

Guanylate cyclase Smooth muscle cell

GTP GMP

cGMP

Enhanced smooth muscle relaxation

Type V-PDE

Type V-PDE inhibitor

Enhanced erection

Figure 1. The biochemical process involved in erections and the mechanism of action of sildenafil citrate (Viagra). The cavernous nerves (S2-S4) innervate the penis and release NO. NO stimulates the production of cGMP in the smooth muscle cells of the penis. cGMP is directly responsible for increasing smooth muscle relaxation, which leads to increased arterial inflow and an erection. When cGMP is metabolized by PDE5, the penis undergoes detumescence. Sildenafil citrate (Viagra) inhibits PDE5 and increases the available cGMP, thereby leading to an enhanced erection. cGMP ¼ cyclic guanosine monophosphate; NO ¼ nitric oxide; PDE5 ¼ phosphodiesterase 5.

Classification of Erectile Dysfunction

Endocrine • Hypogonadism • Hyperprolactinemia Drug Induced • b-Blockers • Calcium channel blockers • Alcohol • Nicotine • Antiandrogens • Cocaine • Heroin • Marijuana • Cimetidine • Metoclopramide • Antidepressant medications • Antipsychotic medications Vascular • Coronary artery disease • Peripheral vascular disease • Hypertension • Diabetes mellitus Psychogenic • Depression • Performance anxiety Neurogenic • Spinal cord injury • Neuropathy (diabetic, hypertensive) • Cerebrovascular disease • Radical prostatectomy • Pelvic surgery Multifactorial • Aging • End-stage renal disease • Pelvic trauma (neurogenic and vasculogenic) • Diabetes mellitus (neurogenic, vasculogenic, drug induced) Chronic tobacco use is a major risk factor for the development of vasculogenic ED because of its effects on the vascular endothelium. Additionally, blood nicotine levels rise after smoking, which increases sympathetic tone in the penis and leads to nicotineinduced, smooth-muscle contraction in the cavernosal body. Chronic smoking also leads to decreased penile NOS activity and neuronal NOS content. DM is a major risk factor for ED. In the Massachusetts Male Aging Study, the diabetic subset had a threefold increased prevalence of ED compared with nondiabetic subjects (28% versus 9.6%). In the same study, the overall incidence rate of ED was 26 cases per 1000 man-years in nondiabetics and 50 cases per 1000 man-years in the diabetic population. The pathogenesis of ED in the diabetic patient is related to accelerated atherosclerosis, alterations in the corporal erectile tissue, and neuropathy. Hypertension is another major risk factor for ED. Whether ED in patients with hypertension is related to the disease itself or to the use of antihypertensive medications has been debated for years. In a study looking at 104 subjects, the differences in incidence or severity of ED were minor between distinct types of antihypertensive medications or the number of agents being used simultaneously. This favors the concept that antihypertensive agents as well as the disease itself contribute to the appearance of ED. There are, however, classes of antihypertensive medications that are notorious for their negative impact on erectile function such as thiazides and b-blockers. The only b-blocker not associated with significant incidence of ED is carvedilol (Coreg). Hyperlipidemia is another etiologic factor for ED. It is believed to contribute to ED by its relationship to endothelial dysfunction.

One study showed that decreasing total cholesterol to less than 200 mg/dL by using atorvastatin (Lipitor) led to significant improvement of ED as measured by the International Index of Erectile Function (IIEF). A number of clinical studies with PDE5 inhibitors have shown significant improvement of erectile function in men with ED and hyperlipidemia. ED may be a sentinel manifestation of vascular disorders. In a study of 980 subjects seeking ED advice, 18% were suffering from undiagnosed hypertension, 16% had DM, 5% had ischemic heart disease, 15% had benign prostatic hyperplasia, 4% had prostate cancer, and 1% had depression. ED can itself be an independent marker for CAD. In addition, the extent of CAD correlates with the prevalence of ED. Cardiovascular risk reduction alleviates ED in patients with type 2 DM. In a study in which patients received interventions to improve hemoglobin A1C, blood pressure, and total cholesterol, there was significant improvement in the International Index of Erectile Function-5 (IIEF-5), suggesting that improved glycemic control in men with diabetes may lead to an improvement in ED. A study by Thompson revealed significant trends regarding the association of ED and subsequent cardiovascular disease in a retrospective analysis of data from 9457 men. A study published in 2009 looked at the association between ED and the long-term risk of CAD. Results showed that when ED occurred in a younger man, it was associated with a marked increase in the risk of future cardiac events, whereas in older men it appeared to be of little prognostic significance.

Quantification of the Severity of Erectile Dysfunction and Improvement

There are several tools designed to assess the severity of ED, as well as to measure the efficacy of different treatments. We discuss three different measures, the IIEF, the Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ) (Box 2).

Patient History When assessing sexual dysfunction, it is important to inquire about a number of issues: 1. Differentiate between decreased libido and ED: assess whether the patient has one or both 2. Tobacco use: type, amount, duration 3. Alcohol intake 4. History of depression or anxiety disorder 5. Presence of social/relationship stressors 6. Ability to have erections while masturbating versus when with partner 7. List of all prescription, over-the-counter, and herbal medications 8. Knowledge of whether nocturnal erections are present 9. History of drug use: marijuana, cocaine, other recreational drugs 10. History of genitourinary trauma 11. History of prostatic disease, or possible related symptoms 12. History of hypertension, hyperlipidemia, CAD, peripheral vascular disease, cerebrovascular disease 13. History of DM 14. History of spinal cord injury 15. History of penile plaques: possible Peyronie’s disease 16. Frequency of intercourse or attempted intercourse 17. Ability to ejaculate

Physical Examination The physical examination should include a careful testicular examination to assess testicular size, asymmetries, presence of hernias, or varicoceles. Additionally, a digital rectal examination to assess the prostatic size, consistency, and presence of nodules is warranted. Penile inspection and palpation should be performed, with special attention to possible fibrotic plaques. Palpation and auscultation of femoral arteries for possible bruits is another important part of the examination.

Erectile Dysfunction

Box 1

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Box 2

Tools Used to Quantify Erectile Dysfunction Severity

Tools used in the quantification of the severity of erectile dysfunction (ED) include the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ).

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International Index of Erectile Function The IIEF is a standardized questionnaire designed to measure ED and detect treatment-related changes. It is a 15-item questionnaire addressing five different domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. The IIEF is the most frequently used efficacy measurement employed in ED drug trials. Using a scale from 1 (never/almost never) to 5 (almost always/always), men grade each domain. It is very sensitive and specific, and has been validated in 20 languages to assess treatment-related changes in sexual function. The questions 1–5 and 15 are used to quantify erectile dysfunction severity and are as follows: 1. How often were you able to get an erection during sexual activity? 2. When you had erections with sexual stimulation, how often were your erections hard enough for penetration? 3. When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? 4. During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? 5. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse? 15. How do you rate your confidence that you could get and keep an erection?

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And it is scored as follows: 26–30 22–25 17–21 11–16
10

Normal ED Mild ED Mild to moderate ED Moderate ED Severe ED

Sexual Encounter Profile SEP is a five-question survey provided to patients with ED in clinical studies of oral therapies. The survey is completed after each sexual attempt. The questions are as follows: 1. Were you able to achieve at least some erection? 2. Were you able to insert your penis into your partner’s vagina? 3. Did your erection last long enough to have successful intercourse? 4. Were you satisfied with the hardness of your erection? 5. Were you satisfied with the overall sexual experience? Answers to questions 2 and 3 are the ones most often used in the literature. Global Assessment Questions GAQ is usually administered at the end of the treatment period during efficacy studies. Question 1: Has the treatment taken during the study improved your erections? Question 2: If yes, has the treatment improved your ability to engage in sexual activity? This is very subjective, and its responses tend to be valued less than SEP and IIEF.

Laboratory Studies Laboratory workup on a patient with ED should include total and bioavailable testosterone levels drawn in the morning, prolactin, prostate-specific antigen, fasting glucose, and fasting lipid panel. Further studies may be warranted depending on the results of the aforementioned.

Management of Erectile Dysfunction

The landscape of ED was revolutionized with the introduction of sildenafil citrate (Viagra), the first oral medication for the treatment of this condition. Since then, oral agents have become the preferred mode of treatments by patients in surveys worldwide. There are three oral agents that inhibit PDE5 currently on the market: 1. Sildenafil citrate (Viagra) 2. Vardenafil (Levitra) 3. Tadalafil (Cialis) All three drugs work by inhibiting PDE5, which maintains intracavernosal levels of cGMP, subsequently producing vasodilatation and penile erection (see Figure 1).

Sildenafil Citrate (Viagra) Sildenafil citrate (Viagra) is an orally active, potent, and selective inhibitor of cGMP-specific PDE5. The predominant phosphodiesterase isoform in the penile tissue is type 5. The selectivity of sildenafil citrate (Viagra) for PDE5 is approximately 4000-fold greater than its selectivity for phosphodiesterase 3 (PDE3), the isoform involved in the control of cardiac contractility. Sildenafil citrate (Viagra) is absorbed rapidly after oral administration, with an absolute bioavailability of 40%. The time of maximal (T-max) plasma after oral dosing in the fasting state is between 30 and 120 minutes. A high-fat meal increases the time to peak plasma concentration by 60 minutes and reduces the peak plasma concentration by 29%. The half-life of the drug is from 3 to 5 hours. Sildenafil citrate (Viagra) is metabolized by hepatic microsomal cytochrome P450 isoenzyme 3A4 for the most part. Cytochrome P450 3A4 inhibitors, cimetidine (Tagamet), erythromycin, ketoconazole (Nizoral), and protease inhibitors may retard the metabolism of sildenafil citrate (Viagra). The recommended dose is from 25 to 100 mg as needed approximately 1 hour before sexual activity. In some individuals, the onset of activity may be seen as early as 11 to 19 minutes, but this is not the norm. The usual starting dose is 50 mg. The maximum recommended dose is 100 mg, and the maximum dosing frequency is once daily. A starting dose of 25 mg can be considered for patients older than age 65 years as well as for patients with severe hepatic cirrhosis or severe renal impairment. There are more than two dozen, randomized, double-blind, placebo-controlled studies involving this agent. It produces positive results regardless of the etiology of ED. It has been studied in patients with DM, CAD, postcoronary artery bypass graft (post-CABG), spinal cord injury, depression, hypertension, prostate cancer post-prostatectomy, benign prostate enlargement post-transurethral resection of the prostate (TURP), patients on hemodialysis, as well as recipients of renal transplants. Results vary according to the underlying condition causing ED in the first place, ranging from 50% to 85%. The most common side effects of sildenafil citrate (Viagra) include vasodilatory effects such as headaches, flushing, and nasal congestion caused by hyperemia of the nasal mucosa, as well as dyspepsia. Up to 30% of patients may get at least one side effect. Another side effect that presents on occasion is blurred or bluegreen vision because of inhibition of phosphodiesterase 6 (PDE6) in the retina. It is absolutely contraindicated in men taking long-acting or short-acting nitrate drugs, and men taking any form of nitrates should be informed about the dangerous interaction. Do not prescribe sildenafil citrate (Viagra) to patients with unstable CAD who need nitrates. Assess the need for ordering treadmill testing in select patients. Initial monitoring of blood pressure (BP) after the administration of sildenafil citrate (Viagra) may be indicated in men with complicated congestive heart failure (CHF). a-Blockers should not be used in combination with sildenafil citrate (Viagra) because of possible orthostatic hypotension.

Vardenafil (Levitra) Vardenafil (Levitra) is a highly potent inhibitor of PDE5. It was approved for use in the United States in late 2003. It is a more selective PDE5 inhibitor than sildenafil citrate (Viagra). The

Tadalafil (Cialis) The third oral agent of this class is tadalafil (Cialis). It has a halflife of 17.5 hours, with two thirds of patients experiencing clinical benefits of this drug up to 36 hours after its use. The clinical onset of action occurs in less than 1 hour. There is no interaction between food and alcohol on the absorption of the drug. There have been numerous phase II and III studies in Europe, Canada, and the United States using doses of 2, 5, 10, and 25 mg of the drug in comparison with placebo. The average success rates on these studies averaged 17% for placebo, 51% for the 2-mg dose, and 80% for the other doses, as well as up to 88% on the 25-mg dose in one study. In one study looking at 216 subjects with type 2 DM, improved erections were reported in 56% to 64% of the patients. A recent article looking at all the previously published patient data showed that among 2102 men studied in 11 randomized placebo-controlled trials lasting 12 weeks, each mean improvement in IIEF at 20 mg of tadalafil (Cialis) was 8.6. Mean positive Sexual Encounter Profile Diary Question 3 (SEP3) response was 68% versus 31% in placebo groups. Mean GAQ was 84% versus 33% in placebo group. In a multicenter, randomized, double-blind, crossover study looking at 181 men who received either sildenafil citrate (Viagra) or tadalafil (Cialis), 73% (132) preferred tadalafil (Cialis) at 20 mg instead of sildenafil citrate (Viagra) at 50 or 100 mg. The most clinically effective dose of tadalafil (Cialis) is 20 mg. It should be taken at least 30 minutes before intercourse. It may be used with caution in patients using a-blocking agents. Nitrates are absolutely contraindicated for use in patients taking tadalafil (Cialis). The most common side effects include headaches, dyspepsia, back pain, rhinitis, and flushing. There are no visual side effects reported. Tadalafil has most recently been studied for use on a daily basis, with doses ranging from 2.5 to 5 mg, and showed favorable results.

Use of PDE5 Inhibitors and Cardiovascular Safety The safety and efficacy of the three currently available PDE5 inhibitors (sildenafil, tadalafil, vardenafil) have been evaluated extensively in patients with ED and concomitant CVD, hypertension, hyperlipidemia, or diabetes, with or without additional risk factors. Overall, these studies have shown similar efficacy for the three agents, resulting in significant improvement of erectile function in patients with any of these comorbid conditions, and there was no evidence of cardiovascular risk from using any of these agents. However, because ED is known to be a harbinger of cardiovascular events in some men, the presence of ED should prompt investigation and intervention for cardiovascular risk factors.

Apomorphine (Uprima)1

Apomorphine (Uprima)1 is a potent emetic that acts on central dopaminergic receptors. The stimulation of central dopaminergic receptors transmits excitatory signals down the spinal cord to the sacral parasympathetic nucleus, stimulating activity of the sacral nerves supplying the penis. It has been used successfully in up to 67% of patients when administered through a sublingual preparation. Subcutaneous injections2 of apomorphine (Uprima)1 produce almost a 100% erectile response, but nausea and vomiting are limiting factors to this mode of administration. The most common side effects are headache, nausea, and dizziness. Rare syncopal episodes have been reported.

Phentolamine (Regitine)

Phentolamine (Regitine) is an a1- and a2-adrenergic receptor antagonist. The sympathetic system via the release of noradrenaline (NA) is the primary determinant of cavernosal smooth muscle contraction and detumescence. A relative predominance of NA-induced contraction over NO-induced smooth muscle relaxation may contribute to ED. In large phase III studies, 55% to 59% of patients receiving 40 and 80 mg were able to achieve vaginal penetration. Adverse effects include nasal congestion (10%), headaches (3% to 5%), dizziness (3% to 5%), tachycardia (3%), and nausea.

Trazodone (Desyrel)1

Trazodone (Desyrel)1 is a serotonin reuptake inhibiting agent. Its action in ED is believed to be the result of central serotonergic and peripheral a-adrenolytic activity. The efficacy of trazodone is poorly demonstrated; however, it may have a place in those with performance anxiety. Side effects include drowsiness, insomnia, headaches, and weight loss.

Dietary Supplements and Erectile Dysfunction

Yohimbine1 is an a2-adrenoreceptor antagonist with short duration of action. It is administered orally, and it is thought to have a central effect at adrenergic receptors in brain centers associated with libido and penile erection. A meta-analysis of seven studies established that it is superior to placebo, although results can be very erratic. Side effects include palpitations, tremors, and anxiety. Yohimbine should not be recommended as part of the management of ED. A study with 60 patients who had failed papaverine1 injections (50 mg or less) were treated with an extract of Ginkgo biloba, 60 mg for 12 to 18 months. After 6 months, 50% of the patients reported improvement in erectile function. A placebo-controlled randomized trial using 240 mg of Ginkgo biloba extract daily for 24 weeks in patients with vasculogenic ED did not demonstrate significant differences between the groups. 1 L-Arginine is an amino acid that is the precursor to NO. Three small studies are looking at this drug. There are encouraging results in one study. 1

Not FDA approved for this indication. Not available in the United States.

2

Erectile Dysfunction

absorption of vardenafil (Levitra) is delayed by a fatty content of more than 30% in a meal. However, that does not seem to affect its effectiveness in different trials. The half-life of vardenafil (Levitra) is 4.4 to 4.8 hours, and the clinical effectiveness may be as long as 12 hours. The time for maximum plasma concentration is between 42 and 54 minutes. The first trial using the agent included 580 patients, excluding patients with spinal cord injury, radical prostatectomy, hypogonadism, thyrotoxicosis, or DM. The successful rates of intercourse were 71% to 75% on patients taking 5 or 10 mg at a time. Those taking 20 mg had a success rate of 80%. The placebo groups had an average success rate of 30%. Vardenafil (Levitra) has been tested in patients with type 2 DM; 452 patients were enrolled in a double-blind, placebo-controlled trial. The success rate in the vardenafil (Levitra) group ranged from 57% to 72%. In a different study involving 736 subjects including men with DM and stable CAD, the success rates were 28% for the placebo group, 65% for those taking 5 mg, 80% for those taking 10 mg, and 85% for the 20-mg group. Patients who were unresponsive to sildenafil citrate (Viagra) at a dose of 100 mg on several attempts were given vardenafil (Levitra) in doses of 10 and 20 mg (proved in trial). Vardenafil (Levitra) produced statistically and clinically significant results compared with placebo in men who were historically unresponsive to sildenafil citrate (Viagra). The dose that offers the best clinical results is 20 mg. It should not be taken more than once every 24 hours. Safety studies have shown no deleterious effects with long-term daily use of this drug for up to 12 months. The most common side effects include headaches (10% to 21%), flushing (5% to 13%), rhinitis (9% to 17%), and dyspepsia (1% to 6%) because vardenafil (Levitra) does not inhibit PDE6. Unlike sildenafil citrate (Viagra), it does not produce problems of blurred vision or blue-green visual disturbances. The same warning regarding the use of nitrates as sildenafil citrate (Viagra) applies to vardenafil (Levitra). Patients taking vardenafil (Levitra) may use a-blocking agents with caution.

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Zinc is found in high concentrations in seminal fluid. Anecdotal reports of improvement in ED.

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Alprostadil (Prostaglandin E1, Caverject, Medicated Urethral System for Erection)

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Prostaglandin E1 (PGE1) exerts a number of pharmacologic effects including systemic vasodilatation, inhibitory actions on platelet aggregation, and relaxation of smooth muscle. PGE1 binds to PGE receptors and causes a relaxation response mediated by cyclic adenosine monophosphate (cAMP). It can be administered intracavernosally or intraurethrally. It has been used in combination with papaverine,1 and the combination was superior to PGE1 alone. The intracavernosal administration seems to be more effective than transurethral (medicated urethral system for erection [MUSE]). MUSE should be administered in 1-mg doses, applied intraurethrally. Responses to intracavernosal injections (Caverject) as high as 80% may be expected in patients with organic ED with a dose of 20 mg, and much lower to MUSE (35% to 43%). Injections are given with 27- to 30-gauge needles. The administration of PGE1 is usually relegated as an alternative in patients who have contraindications to the use of phosphodiesterase 5 (PDE5) inhibitors. The possible side effects include penile fibrosis, priapism, urethral bleeding, hypotension, or syncopal episodes. Papaverine1 is a nonspecific phosphodiesterase inhibitor that increases cAMP and cGMP levels in penile erectile tissue. It produces smooth muscle relaxation and vasodilatation. It decreases the resistance to arterial inflow and increases the resistance to venous outflow. It is highly effective in psychogenic and neurogenic ED but not vasculogenic. It has been commonly used in combination with phentolamine (Regitine). Major side effects include priapism, corporeal fibrosis, and possible elevation of liver transaminases. Moxisylyte chlorohydrate2 is an a-blocking agent. In a study where 156 subjects received either alprostadil or moxisylyte in a dose-escalating fashion, alprostadil had much better success rates (46% versus 81%). Chlorpromazine (Thorazine)1 is useful when given in combination with alprostadil or papaverine. It has a-blocking properties, and it is cheaper than phentolamine (Regitine). Decreased concentration of vasoactive intestinal polypeptide (VIP)* has been reported in the penile tissue of men with ED. VIP is believed to play a role in the erectile process. It is ineffective when administered alone but can be quite effective in combination with phentolamine (Regitine). In a small study of 52 subjects with organic ED, 100% of them achieved an erection sufficient for intercourse. Further studies into the effectiveness of VIP may be needed.

Penile Prostheses This surgical approach used to be quite common before the advent of oral agents. The use of prostheses is still a suitable alternative for those who are unresponsive to less invasive treatments. Prostheses can be classified as rod, one-piece inflatable, twopiece inflatable, and three-piece inflatable. Postsurgical infections and malfunctions are the most common complications. Patients are usually satisfied with the results of prosthetic placement.

Vacuum Constrictive Device Vacuum constrictive device is a plastic cylinder that is placed over the penis and connected to a pump that creates a partial vacuum. After achieving penile rigidity, a band is placed around the base of 1

Not FDA approved for this indication. Not available in the United States. * Investigational drug in the United States. 2

the penis to maintain the erection. This is a safe, noninvasive, and effective method of treating ED. It requires an understanding partner and the quality of the erection is not ideal, but patients are usually satisfied.

Testosterone Patients who have low testosterone levels may benefit substantially from replacement. Men may expect significant improvements in libido, self-esteem, and overall energy levels. Additionally, testosterone is necessary for NO generation in the penile tissue. The different testosterone preparations include injections such as testosterone enanthate (Delatestryl), cypionate (DepoTestosterone) given as an intramuscular (IM) injection in doses of 100 to 200 mg, every 2 weeks on average. They also include transdermal testosterone patches (Androderm and Testoderm, 5 mg/d) or transdermal gel (AndroGel 5-g packets, one daily; or Testim 1% testosterone gel, one packet daily). Testosterone gel preparations provide physiologic replacement of testosterone and are preferred more than depot IM injections.

References

Archer SL. Potassium channels and erectile dysfunction. Vascul Pharmacol 2002;38:61–71. Burchardt M, Burchardt T, Baer L, et al. Hypertension is associated with severe erectile dysfunction. J Urol 2000;164(10):1188–91. Carson CC, Rajfer J, Eardley I, et al. The efficacy and safety of tadalafil: An update. BJU Int 2004;93:1276–81. Crowe SM, Streetman DS. Vardenafil treatment for erectile dysfunction. Ann Pharmacother 2004;38:77–85. Donatucci CF, Wong DG, Giuliano F, et al. Efficacy and safety of tadalafil once daily: Considerations for the practical application of a daily dosing option. Curr Med Res Opin 2008;24(12):3383–92. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 1994;151(1):54–61. Inman BA, St. Sauver JL, Jacobson DJ, et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009;84(2):108–13. Jackson G, Betteridge J, Dean J, et al. A systematic approach to erectile dysfunction in the cardiovascular patient: A consensus statement—Update 2002. Int J Clin Pract 2002;56(9):663–71. Jaynat D, Shepherd MD. Evaluation and treatment of erectile dysfunction in men with diabetes mellitus. Mayo Clin Proc 2002;77(3):276–82. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men ages 40 to 69 years old: Longitudinal results from the Massachusetts Male Aging Study. J Urol 2000;163(2):460–3. Khatana SAM, Taveira TH, Miner MM, et al. Does cardiovascular risk reduction alleviate erectile dysfunction in men with type II diabetes mellitus? Int J Impotence Res 2008;20:501–6. Kirby M, Jackson G, Betteridge J, et al. Is erectile dysfunction a marker for cardiovascular disease? Int J Clin Pract 2002;55(9):614–8. Lue TF. Drug therapy: Erectile dysfunction. N Engl J Med 2000;342(24):1802–13. Michelakis E, Tymchak W, Archer S. Sildenafil: From the bench to the bedside. CMAJ 2000;163(9):1171–5. Nehra A. Erectile dysfunction and cardiovascular disease: Efficacy and safety of phosphodiesterase type 5 inhibitors in men with both conditions. Mayo Clin Proc 2009;84(2):139–48. NIH Consensus Development Panel on Impotence. Impotence (NIH Consensus Conference). JAMA 1993;270(1):83–90. Padma-Nathan H. Intra-urethral and topical agents in the management of erectile dysfunction. In: Carson III CC, Kirby RS, Goldstein I, editors. Textbook of Erectile Dysfunction. Oxford: Isis Medical Media; 1999. p. 323–6. Rhoden EL, Teloken C, Mafessoni R, et al. Is there any relation between serum levels of testosterone and the severity of erectile dysfunction? Int J Impot Res 2002;14:167–71. Shokeir AA, Alserafi MA, Mutabagani H. Intracavernosal versus intraurethral alprostadil: A prospective randomized study. BJU Int 1999;83:812–5. Spahn M, Manning M, Juenemann KP. Intracavernosal therapy. In: Carson III CC, Kirby RS, Goldstein I, editors. Textbook of Erectile Dysfunction. Oxford: Isis Medical Media; 1999. p. 345–53. Sullivan ME, Thompson CS, Dashwood MR, et al. Nitric oxide and penile erection: Is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999;43:658–65. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294(23):2996–3002.

Method of

Louis Kuritzky, MD

CURRENT DIAGNOSIS • A diagnosis of acute prostatitis is usually made on a clinical basis when typical lower urinary tract symptoms such as dysuria and frequency are coupled with the corroborative physical findings of a tender, boggy prostate and urinalysis revealing pyuria. If the presentation is less typical, the literature suggests that the diagnosis may be missed. • Chronic prostatitis is a little-understood malady with diverse presentations ranging from chronic pelvic pain syndromes to intermittent flares of lower urinary tract symptoms. Although the pathophysiology that allows lower urinary tract symptoms to persist and recur is obscure, some pharmacologic interventions have been shown to provide symptomatic relief. • The inflammatory changes seen in bacterial prostatitis typically involve the anatomic central zone of the prostate, giving credence to the likely ascending urethral origin of most prostatitis episodes.

Definitions

A classification scheme developed by the National Institutes of Health (NIH) is the most widely recognized, and it is also included in the most recent British National Guidelines for the Management of Prostatitis. This categorization recognizes three main clinical entities: acute bacterial prostatitis, chronic bacterial prostatitis, and chronic prostatitis and chronic pelvic pain syndrome.

Acute Prostatitis Presentation

Men with acute prostatitis usually present with signs of genitourinary inflammation and systemic toxicity. Lower urinary tract symptoms (LUTS), most commonly dysuria, frequency, and urgency, are prominent. Patients often report aching pain in the genitorectal area, which can manifest as perineal, penile, or even low back pain. Bacteremia can produce a toxic state with fever and generalized malaise. Gentle examination of the prostate generally reveals a gland that is markedly tender but unusually pliable owing to inflammatory swelling. Vigorous prostate palpation should be avoided lest additional load of prostatic bacteria be delivered to the bloodstream.

Diagnosis Acute onset of LUTS with signs of systemic toxicity should prompt urinalysis and genitourinary examination. The presence by urinalysis of pyuria and bacteriuria, coupled with distinct prostatic tenderness and bogginess, should be sufficient to arrive at a provisional diagnosis of acute bacterial prostatitis.

Differential Diagnosis Dysuria, frequency, and urgency mimic simple cystitis, but systemic symptoms, especially fever, should be absent from either urethritis or cystitis. Although upper urinary tract infection (e.g., pyelonephritis) might have some similar symptoms, localization of pain in pyelonephritis is distinctly different. Urethritis can cause dysuria and—if incomplete bladder emptying ensues—frequency, but because it is most likely initiated secondary to a sexually transmitted infection (especially gonorrhea or chlamydia), history of a new sexual partner is typical. Urethritis and associated prostatic tenderness should not be associated with systemic symptoms. Overactive bladder causes frequency and urgency, but it is not associated with pain, and the symptoms are not acute in onset. A kidney stone is usually unilateral, and it causes prominent hematuria and colicky rather than constant pain. Pain

is the most prominent and acute feature of kidney stone, and it might be better described as a second tier complaint in prostatitis.

Laboratory Evaluation Standard urinalysis is fundamental to the diagnosis. Absence of pyuria should generate reconsideration of the diagnosis. Because of bacteremia associated with acute bacterial prostatitis, both urine and blood cultures should be obtained.

Treatment The most common organism that causes acute prostatitis is Escherichia coli, but other gram-negative species (e.g., Proteus, Klebsiella, Pseudomonas) are sometimes responsible. Less commonly, Enterococcus species, Staphylococcus aureus (usually following instrumentation or catheterization), or even Bacteroides species can cause acute prostatitis. Presumptive treatment for acute prostatitis should provide coverage for these organisms. Hence, it is reasonable to initiate treatment with a broad-spectrum cephalosporin (e.g., cefuroxime [Zinacef], cefotaxime [Claforan], ceftriaxone [Rocephin]) or a quinolone plus gentamicin (Garamycin) pending results of urine and blood cultures. Although oral quinolones provide effective coverage for the majority of organisms causing acute bacterial prostatitis, the toxic state of many men with acute prostatitis as well as risk from bacteremia suggest that intravenous antibiotics be administered on an inpatient basis. When a confirmed pathogen and its sensitivity are defined, specific oral treatment can be initiated when evidence of toxicity (e.g., fever, elevated white blood cell count) is resolved. Once acute toxicity is resolved, a long-term regimen of an oral quinolone is suggested, unless specific organisms or sensitivities preclude it. Regimens include 4 weeks of either ciprofloxacin (Cipro) 500 mg twice daily or ofloxacin (Floxin) 200 mg twice daily. For patients intolerant of quinolones, the combination of trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily or even trimethoprim (Proloprim) 200 mg twice daily3 alone for 28 days are reasonable alternatives. Not all antibiotics penetrate into the prostate with equal efficacy, and it has been suggested that pharmacologic permeability of the blood-prostate barrier is greatest during acute inflammation, becoming progressively less as inflammation resolves. Nonetheless, experience has suggested that penetration of quinolone antibiotics is substantial even as infection dissipates.

Partner Treatment Prostatitis is not generally considered a sexually transmitted infection. There is no need for partner treatment.

Follow-up Most patients with acute prostatitis do well, though a substantial minority go on to have chronic or recurrent episodes. Once the patient has recovered, many experts suggest evaluation of the genitourinary tract, seeking abnormalities that might lend themselves to bacterial colonization, such as urethral stricture, bladder diverticulum, prostate stones, or urinary obstruction. In only a small percentage of patients, however, is a definitive pathogenetic defect that leads to acute bacterial prostatitis identified.

Nonresponders Infrequently, acute prostatitis does not respond with prompt relief of symptoms and defervescence. Assuming that an antibiotic has been chosen to appropriately match organism sensitivity, clinicians should seek consultation from colleagues with special knowledge of male genitourinary health or infectious disease, because secondary pathology involving the genitourinary tract may be involved. For instance, prostatic abscess, identifiable by transrectal ultrasound or CT of the prostate, can manifest as acute bacterial prostatitis but be refractory to antibiotic intervention unless the abscess itself is surgically drained. 3

Exceeds dosage recommended by the manufacturer.

Prostatitis

PROSTATITIS

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Chronic Bacterial Prostatitis

Although some patients enjoy freedom from future episodes of prostatitis after an acute episode, many go on to have chronic recurrences. Fortunately, the intensity of recurrences is much less than an initial acute attack, and because patients learn to recognize signs of recurrence early and intervene with antibiotics, hospitalizations for second episodes of acute bacterial prostatitis are uncommon. Unfortunately, the constellation of symptoms associated with chronic prostatitis is diverse and includes both the typical LUTS symptoms seen with acute attacks (frequency, urgency, and dysuria) and additional symptoms such as perineal pain and ejaculatory pain. The precipitant of recurrent symptoms after widely varying intervals is unknown. It appears that not all organisms responsible for acute bacterial prostatitis have the same proclivity to produce chronic bacterial prostatitis; the majority of cases are caused by E. coli, S. aureus, or Enterococcus faecalis, with other causative organisms being distinctly less common.

17 Men’s Health

Presentation

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Because of prior episodes of prostatitis, recurrences are usually readily recognized by both the clinician and patient. There is, however, a fairly broad diversity in presentation, ranging from typical symptoms of urinary tract infection to vague pelvic pain. In between recurrences, patients are most often asymptomatic. However, mild LUTS can become chronic, and I have seen men who date the onset of erectile dysfunction to establishment of a pattern of chronic prostatitis. Similarly, I have seen men complaining of ejaculatory pain, new-onset urinary frequency, or urgency as symptoms of recurrence during the course of chronic bacterial prostatitis. Such symptoms usually promptly remit with antibiotic treatment (see later). Patients with chronic bacterial prostatitis are not generally systemically ill or toxic, so that blood cultures are rarely necessary. Occasionally, a recurrence of bacterial prostatitis is as acute and systemically toxic as the initial case, in which circumstance it is appropriate to approach the management in a similar fashion as for acute bacterial prostatitis.

ofloxacin 200 mg twice daily. No particular advantage for one quinolone over another has been demonstrated. Because patients with chronic bacterial prostatitis might need to receive multiple courses of antibiotics over time, it is suggested that clinicians advise patients about the tendinopathy uncommonly induced by quinolones. For patients intolerant to quinolones, minocycline (Minocin)1 100 mg twice daily for 28 days or trimethoprim1 (200 mg twice daily3 for 28 days are reasonable alternatives. Such long courses of antibiotics are intended to eradicate the prostatic nidus of infection. If, however, recurrences are very frequent, some patients prefer to take shorter courses of antibiotics, which often resolve symptoms equally effectively. I suggest that if, after an initial recurrence has been treated for 28 days, another recurrence appears, brief antibiotic trials be offered (3-7 days), rather than expose the patient to unnecessarily protracted courses. Prostatic irritability manifesting as urinary frequency and dysuria may be modulated by use of a-blockers. Although not indicated as primary therapy, for persons with substantial residual LUTS (especially frequency and urgency), a-blocker treatment is worth considering. All a-blockers (alfuzosin [Uroxatral]),1 doxazosin [Cardura],1 prazosin [Minipress],1 silodosin [Rapiflo],1 terazosin [Hytrin],1 tamsulosin [Flomax],1) are considered essentially equivalent for efficacy in relieving prostatic symptoms. Because of associated symptoms of hypotension, and the need to titrate the first-generation a-blockers, I suggest preferential consideration of second-generation agents such as alfuzosin, silodosin, or tamsulosin.

Follow-up If an evaluation of the genitourinary tract has not been done, recurrences suggest that it be done. Nonetheless, in my experience, an etiologic source for prostatitis is rarely found. It is suggested that all patients with chronic bacterial prostatitis receive at least a one-time urology consultation, if available.

Chronic Prostatitis & Chronic Pelvic Pain Syndrome Presentation

Diagnosis Initial evaluation should include rectal examination and urinalysis. The prostate may be enlarged or tender, but it lacks the dramatic sensitivity to palpation seen in acute bacterial prostatitis. When pyuria is present with typical symptoms, suspicion for a recurrence of prostatitis should be strong. Some clinicians prefer to confirm localization of infection to the prostate (as opposed to kidneys, bladder, or urethra), by performing the four-glass urine test. The theory of this test is that by measuring different consecutive urine specimens, a comparison of bacterial counts can support localization of the infected tissue. In the four-glass test, the patient is asked to provide a small amount of urine, and then stop urinating (glass 1). Glass 1 colony counts are thought to reflect proportionately greater urethral content than other subsequent specimens. Glass 2 is obtained from midstream urine, and is thought to reflect bladder concentrations of bacteria more than urethral. Glass 3 is obtained after prostatic massage to induce prostatic secretions. Glass 4 is obtained by urinating immediately after prostatic massage. Higher bacterial counts in glass 4 than glass 1 or glass 2 corroborate contribution of prostatic fluid to the increased colonies, and hence likely prostatitis. The clinical utility of this methodology is uncertain, because most patients are treated similarly regardless of results, and differential colony counts are not always straightforward and convincing. Nonetheless, in challenging cases this method may be helpful.

Treatment As in acute bacterial prostatitis, provisional treatment should be guided by the knowledge of typical pathogens (E. coli, S. aureus, E. faecalis), and revised once confirmation of pathogen and sensitivity are obtained. Because patients are generally not toxic, oral antibiotics are appropriate, such as 4 weeks of a quinolone: ciprofloxacin 500 mg twice daily, levofloxacin 500 mg once daily, or

Chronic pelvic pain syndrome can include one or more of genitourinary and musculoskeletal symptoms including abdominal pain, perineal aching, penile pain, back pain (very low), ejaculatory pain, LUTS, and testicular pain. The cause(s) of chronic prostatitis & chronic pelvic pain syndrome remain obscure, although abnormalities in neuromuscular function, autoimmune dysfunction, and infection are but a few of the suggested contributors. Symptoms are not acute, and they can occur individually or in combination. Symptoms can be constant or can wax and wane.

Diagnosis and Differential Diagnosis There is no specific laboratory test to confirm chronic prostatitis & chronic pelvic pain syndrome. Rather, the diagnosis is suggested by prototypical symptoms combined with an absence of confirmatory findings such as normal urinalysis, normal—albeit sometimes tender—prostate examination, and normal urine culture. The critical part of evaluation is to exclude other important pathology. Hence a prostate-specific antigen (PSA) test to rule out prostate cancer, urine cytology to rule out bladder cancer, urocystometry to look for abnormal neuromuscular function of the bladder, and transrectal ultrasonography to seek anatomic abnormalities of the genitourinary system, abscess, or cyst are considerations. Because of the potential depth of evaluation needed, urologic referral is usually required. Exhaustive investigations have sought potential urinary tract pathogens without consistent success, including Chlamydia, Mycoplasma, and Ureaplasma species. Pyuria is not a reliable sign. Because the symptom profile of chronic prostatitis & chronic pelvic pain syndrome is consonant with other categories of prostatitis, it is likely that many men who carry a diagnosis of 1

Not FDA approved for this indication. Exceeds dosage recommended by the manufacturer.

3

prostatitis instead have chronic prostatitis & chronic pelvic pain syndrome. Some experts suggest that chronic prostatitis & chronic pelvic pain syndrome is actually more common than acute bacterial prostatitis and chronic bacterial prostatitis combined.

Although the symptom burden may be substantial, patients should be reassured about the absence of any progressive pathologic process. Indeed, symptoms spontaneously improve or even resolve in as many as one third of sufferers in long-term observational studies.

Treatment

1

Not FDA approved for this indication.

References

Clinical Effectiveness Group. United Kingdom national guideline on the management of prostatitis, London: British Association for Sexual Health and HIV (BASHH); 2008. Available at http://www.guideline.gov/summary/summary.aspx?ss¼15& doc_id¼14278&nbr¼7154; [accessed July 26, 2010]. Nickel JC, Downey JA, Nickel KR, Clark JM. Prostatitis-like symptoms: One year later. Br J Urol Int 2002;90:678–81. Pontari M: Chronic prostatitis/chronic pelvic pain syndrome. UpToDate (subscription only). Propert KJ, McNaughton Collins M, et al. A prospective study of symptoms and quality of life in men with chronic prostatitis/chronic pelvic pain syndrome: The National Institutes of Health chronic prostatitis cohort study. J Urol 2006;175:619–23. Scofield S, Kaplan SA. Voiding dysfunction in men: Pathophysiology and risk factors. Int J Impot Res 2008;20(Suppl 3):S2–10.

Prostatitis

There is no definitive treatment. Symptomatic treatment trials are appropriate. For instance, a-blockers might provide symptom relief from typical LUTS symptoms. If urgency is a primary complaint, antimuscarinic agents might be useful, such as darifenacin (Enablex),1 fesoterodine (Toviaz),1 oxybutynin (Ditropan),1 solifenacin (Vesicare),1 tolterodine (Detro)],1 or trospium (Sanctura).1 Some data suggest modest symptom improvement with nonsteroidal antiinflammatory drugs (NSAIDs). However, long-term use of NSAIDs has been associated with substantial gastrointestinal toxicity, renal toxicity, increased risk of cardiovascular disease, and retention of sodium, potassium, and water.

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Women’s Health

ABNORMAL UTERINE BLEEDING Method of

Beth W. Rackow, MD, and Aydin Arici, MD

CURRENT DIAGNOSIS Detailed medical and menstrual history Thorough physical and gynecologic examination Pregnancy test for all reproductive-age women Determination of ovulatory status based on menstrual history Laboratory evaluation: complete blood count, endocrine studies, coagulation profile • Endometrial sampling if high risk for hyperplasia or cancer • Imaging studies to evaluate anatomy • • • • •

CURRENT THERAPY • Progestins Cyclic or intermittent use Prolonged therapy Progestin-releasing intrauterine device (IUD) (Mirena)1 • Estrogens1 Intermittent use High-dose course for acute heavy bleeding • Estrogen-progestin contraceptives1 Cyclic use High-dose course with taper for heavy bleeding • Other therapies Nonsteroidal antiinflammatory drugs1 Tranexamic acid (Lysteda) Gonadotropin-releasing hormone agonists • Surgical options Endometrial ablation Myomectomy Uterine artery embolization Hysterectomy 1

Not FDA approved for this indication.

Abnormal uterine bleeding is a common disorder among reproductive-age women. Although abnormal bleeding involves a broad differential diagnosis, approximately 33–50% of women with abnormal bleeding are found to have a systemic disorder that affects the hypothalamic-pituitary-ovarian axis and hence makes them anovulatory. Normal menstrual bleeding predictably occurs at the end of an ovulatory cycle because of estrogen and progesterone withdrawal; the bleeding lasts up to 7 days, with a cycle interval of 24 to 35 days. Abnormal bleeding may present with altered

intervals between menstrual cycles or changes in volume or duration of menstrual blood flow. Evaluation of the woman with abnormal uterine bleeding must consider a broad differential diagnosis that includes a complication of pregnancy, cervical and uterine pathology (polyps, leiomyomas, adenomyosis, malignancies, chronic endometritis, congenital anomalies), infectious etiologies (sexually transmitted infections, vaginitis), endocrinopathies (thyroid or androgen disorders, hyperprolactinemia), medications (exogenous hormonal therapy, anticoagulants, antibiotics, glucocorticoids, tamoxifen [Nolvadex], herbal supplements), bleeding diathesis, systemic illness (liver or renal disease), and genital trauma or foreign bodies. A thorough menstrual history is essential and should include details about past and present length of intermenstrual intervals, regularity of menses, volume and duration of bleeding, onset of abnormal bleeding, factors associated with change in bleeding (postcoital, contraceptive method, postpartum, new medical diagnosis, change in weight), and associated symptoms such as premenstrual symptoms, dysmenorrhea, dyspareunia, pelvic pain, hirsutism, or galactorrhea. A complete medical history, list of medications, and review of systems help identify any systemic illness or medication effect contributing to the abnormal bleeding. The physical exam should include careful inspection of the external genitalia, vagina, and cervix and a bimanual exam to palpate the uterus and adnexa to assess size, contour, and tenderness. Laboratory evaluation provides further information. A negative pregnancy test (preferably quantitative) rules out bleeding because of a pregnancy complication. A complete blood count evaluates for anemia and thrombocytopenia, and is important with prolonged or heavy bleeding. Endocrine testing may include serum thyroid stimulating hormone, prolactin, testosterone levels, and further evaluation as indicated. Coagulation studies (prothrombin, partial thromboplastin, bleeding time), von Willebrand disease, and platelet testing should be considered in adolescents, women with unexplained menorrhagia, and those with a personal or family history concerning for a bleeding disorder. In the setting of a systemic disorder such as chronic liver or renal disease, appropriate testing should be performed. An endometrial biopsy should be performed in women at high risk for hyperplasia and cancer based on age (35 years and older) and duration of unopposed estrogen exposure. Young women (less than 35 years old) with chronic anovulation, thus prolonged estrogen exposure, should also undergo endometrial biopsy because they can develop endometrial hyperplasia and cancer. If the biopsy reveals secretory endometrium, and not proliferative endometrium, this suggests that ovulation has occurred. A Pap smear, cervical cultures, and wet mount should also be performed as indicated. A history of regular menstrual cycles with an increasing volume or duration of bleeding, or intermenstrual bleeding, is suggestive of an anatomic cause of abnormal bleeding. Transvaginal ultrasonography provides detailed assessment of the uterus and endometrium. Pathology such as leiomyomas and polyps can be identified, and size and location determined. Although an endometrial biopsy may not be necessary if the endometrium is thin (less than 5 mm), clinical suspicion of endometrial pathology takes precedence. Sonohysterography (or saline-infusion sonography) involves

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ultrasonographic assessment of the uterus and endometrium while sterile saline distends the uterine cavity. This procedure has high sensitivity and specificity for detecting uterine and endometrial pathology and is comparable to hysteroscopy. Hysteroscopy can simultaneously diagnose and treat intrauterine pathology, but involves an invasive procedure. During assessment of uterine anatomy, it is important to recognize when anatomic abnormalities, such as leiomyomas, are present but not contributing to the bleeding.

18 Women’s Health

Anovulatory Uterine Bleeding

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A menstrual history that reveals irregular, infrequent, unpredictable bleeding, a varying amount and duration of bleeding, and no reliable premenstrual symptoms is often sufficient to diagnose anovulatory bleeding. Considered a systemic disorder, anovulatory bleeding occurs because of a variety of endocrinologic, neurochemical or pharmacologic processes. Estrogen breakthrough is the most common scenario: persistently high estrogen levels stimulate overgrowth of an endometrium that is fragile without the stabilizing, growth-limiting effects of progesterone, and focal areas of the endometrium breakdown, bleed, and subsequently heal because of estrogen effect. Therefore, synchronous and complete endometrial shedding does not occur. This pattern of bleeding is common in women with polycystic ovary syndrome, in postmenarchal adolescents, and in perimenopausal women. Other conditions associated with anovulation include thyroid disorders, hyperprolactinemia, androgen disorders, psychological or physical stress, eating disorders, dramatic weight changes, and insulin resistance. Management of anovulatory bleeding involves treating both the cause of anovulation and the abnormal bleeding. Progestins are the foundation of this medical therapy. Cyclic courses of progestin stabilize the estrogen-stimulated endometrium and result in withdrawal bleeding after the progestin course. Medications used for a 10- to 14-day course each month include medroxyprogesterone acetate (Provera), 10 mg, and norethindrone acetate (Aygestin), 5 mg. If bleeding does not occur after progestin withdrawal, the woman may also be hypoestrogenic, and further evaluation is indicated. Estrogen-progestin contraceptives effectively cause regular withdrawal bleeding and may decrease the volume of bleeding and also provide contraception. Combined contraceptives are available in pill, patch, and vaginal ring preparations. Medroxyprogesterone acetate (Depo-Provera),1 150 mg intramuscularly every 3 months, can also be used to manage anovulatory bleeding, especially if women cannot take combined contraceptives. This therapy may cause irregular bleeding in the first few months, but 50% of women report amenorrhea by 12 months of use. Treatment of prolonged heavy anovulatory bleeding can be achieved with either lowdose monophasic combined contraceptives,1 one pill twice daily for 5 to 7 days until the bleeding slows or stops, followed by routine daily use if desired, or with a higher-dose course of progestin therapy. Once the heavy bleeding is controlled, further evaluation is warranted. Estrogen therapy is indicated for the treatment of abnormal bleeding with a thinned endometrium due to low estrogen levels or prolonged bleeding. This can be accomplished with conjugated estrogens (Premarin),1 1.25 mg, or micronized estradiol (Estrace),1 2 mg daily for 7 to 10 days. Similarly, estrogen (a 7- to 10-day course) can be used to treat progestin breakthrough bleeding in the setting of long-acting progestin therapy (medroxyprogesterone acetate [Depo-Provera]).

Ovulatory Uterine Bleeding

Heavy or prolonged bleeding may occur during ovulatory cycles, and often no specific etiology is identified; local defects in endometrial hemostasis are implicated. A number of medical and surgical therapies are effective in this situation. Nonsteroidal 1

Not FDA approved for this indication.

antiinflammatory drugs (NSAIDs), such as ibuprofen (Motrin),1 naproxen (Aleve),1 or mefenamic acid (Ponstel),1 decrease menstrual blood loss by inhibiting prostaglandin synthesis, and thus altering the balance of factors required for endometrial hemostasis. NSAIDs may decrease blood loss by 20% to 40%, and should be initiated just prior to the onset of menses and continued for 3 to 5 days. Similarly, combined contraceptives can reduce menstrual flow by 40% to 60%. Another option is the levonorgestrelreleasing intrauterine system (Mirena)1; the local progestin effect on the endometrium is profound and can reduce menstrual blood loss by 75% to 90% in women with heavy bleeding. Gonadotropin-releasing hormone agonists produce a hypoestrogenic state and thus cause amenorrhea as well as shrinkage of myomas, if present. This therapy is best reserved for short-term management of heavy bleeding and severe anemia prior to a surgical procedure because of its cost and significant side effects such as menopausal symptoms and bone demineralization. The only FDA-approved nonhormonal treatment for heavy menstrual bleeding (menorrhagia) is tranexamic acid (Lysteda), an antifibrinolytic agent; two 650-mg tablets are taken three times daily for up to 5 days per month during menses. Intermenstrual bleeding can also occur during ovulatory cycles. This abnormal bleeding can be caused by anatomic abnormalities, infection, or the preovulatory decline in estrogen. Conjugated estrogens (Premarin),1 1.25 mg, or micronized estradiol (Estrace), 2 mg for 2 to 3 days midcycle or 7 to 10 days for persistent break-through bleeding, may be effective. For women who fail medical therapy or for those who do not desire future fertility, surgical management is appropriate. The definitive procedure is hysterectomy, but this surgery carries a significant risk of complications and involves longer recovery time. Endometrial ablation by hysteroscopic, thermal, or cryosurgical techniques is a less invasive procedure for the management of abnormal bleeding, and should be reserved for women who do not desire future fertility. These techniques can result in significantly reduced bleeding and dysmenorrhea, and even amenorrhea, but approximately 20% of women require additional procedures. Women with menorrhagia attributed to uterine myomas can be managed with myomectomy (hysteroscopic, laparoscopic, or abdominal procedures as indicated) or uterine artery embolization. Currently, pregnancy is not recommended after the latter option because few data are available on postprocedure pregnancy outcomes.

Uterine Hemorrhage

Acute heavy bleeding requires high-dose estrogen therapy. Women who need inpatient management should receive conjugated estrogens (Premarin), 25 mg intravenously every 4 hours for 24 hours or until the bleeding decreases. A Foley catheter balloon (30 cc) can be placed in the uterine cavity to tamponade the bleeding. Additionally, dilation and curettage can be performed to help stop acute uterine hemorrhage. If stable for outpatient management, women can receive conjugated estrogens (Premarin),1 1.25 mg, or micronized estradiol (Estrace),1 2 mg every 4 to 6 hours for 24 hours, and when the bleeding is controlled, the dose is tapered to once daily for 7 to 10 days. Another effective regimen uses highdose combination contraceptives1 (3 to 4 pills daily) until the bleeding is decreased, followed by a taper to 1 pill daily for several weeks. Estrogen therapy should be followed by progestins or combined contraceptives to stabilize the estrogen-stimulated endometrium. When evaluating a woman with abnormal uterine bleeding, a thorough history and evaluation are essential to help narrow the differential diagnosis. A number of medical and surgical treatments are available for the management of abnormal uterine bleeding, but the range of options may be limited by a woman’s fertility plans. 1

Not FDA approved for this indication.

References

American College of Obstetricians and Gynecologists. Management of anovulatory bleeding. ACOG Practice Bulletin, no. 14, March 2000. Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993;269:1823–8. Berek JS, Benign diseases of the female reproductive tract. In: Berek JS, editor. Novak’s Gynecology. Philadelphia: Lippincott Williams & Wilkins; 2002. pp. 351–73. Bonnar J, Sheppard BL. Treatment of menorrhagia during menstruation: Randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid. BMJ 1996;313:579–82. Dickersin K, Munro MG, Clark M, et al. Hysterectomy compared with endometrial ablation for dysfunctional uterine bleeding: A randomized controlled trial. Obstet Gynecol 2007;110:1279–89. Farquhar CM, Lethaby A, Sowter M, et al. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999;181:525–9. Kouides PA, Conard J, Peyvandi F, et al. Hemostasis and menstruation: Appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril 2005;84:1345–51. Munro MG. Dysfunctional uterine bleeding: Advances in diagnosis and treatment. Curr Opin Obstet Gynecol 2001;13:475–89. Munro MG. Medical management of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:287–304. Shwayder JM. Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:219–34. Speroff L, Fritz M. Dysfunctional uterine bleeding. In: Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Lippincott Williams & Wilkins; 2005. pp. 548–71. Wallach EE, Vlahos NF. Uterine myomas: An overview of development, clinical features and management. Obstet Gynecol 2004;104:393–406.

AMENORRHEA Method of

Vickie Martin, MD, and Robert L. Reid, MD

Definition

Amenorrhea may be defined as the absence of menstruation for 3 or more months in women with past menses (secondary amenorrhea) or the absence of menarche by the age of 16 years in girls who have never menstruated (primary amenorrhea). Infrequent menstruation, termed oligomenorrhea, may have similar causes and also warrants investigation.

Menstrual Cycle

A clear working knowledge of the menstrual cycle and its physiology is mandatory for the clinician in these circumstances. Menstruation normally results when a cascade of hormonal signals from the hypothalamus (gonadotropin-releasing hormone [GnRH]) to cause pituitary release of luteinizing hormone (LH) and folliclestimulating hormone (FSH). These in turn stimulate the development of an egg-containing ovarian follicle. Estrogen from this follicle results in steady growth of the endometrial lining over a 2-week period (follicular phase). When ovulation occurs, the follicle (now called the corpus luteum) develops the ability to produce a second hormone, progesterone. The secretion of estrogen and progesterone for the next 2-week period causes the endometrial lining to become lush (decidualized) in preparation for implantation of a pregnancy. If pregnancy fails to occur, the corpus luteum undergoes a spontaneous demise, the endometrium no longer has adequate hormonal support to survive, and the tissue is sloughed synchronously over the next 5 to 7 days as menstrual flow. The final steps of this process require a means of egress for blood, implying a normal uterus with a patent cervix and vagina (the outflow tract).

CURRENT DIAGNOSIS • Always consider the possibility of pregnancy in any woman presenting with secondary amenorrhea. • Secondary amenorrhea is most commonly the result of some significant lifestyle change (weight gain or loss, stress, excessive exercise) or illness (with marked weight loss) in the preceding 6 months. • Obesity and features of androgen excess are most often related to polycystic ovary syndrome (PCOS). • Because constitutional delay of puberty is found in only one third of girls presenting with delayed menarche, an investigation should be initiated at the time of presentation rather than waiting until the girl is 16 years old (meeting the definitional criteria). • Primary amenorrhea, particularly with the absence of other features of pubertal development (breasts and pubic and axillary hair) suggests ovarian failure. • When amenorrhea due to ovarian failure (high FSH) occurs before age 35 years, a karyotype is indicated. If Y chromosome material is identified on karyotype, gonadectomy is required to reduce the risk of malignancy in the gonadal tissues. Amenorrhea, simply put, is the absence of menses. It can be classified as either primary (when a woman of reproductive age has never had menstruation) or secondary (when amenorrhea occurs after menstruation has been established). There are normal situations in which amenorrhea is expected (physiologic amenorrhea): during pregnancy, during lactation, and at the onset of menopause. Approximately 5% of reproductive-age women experience amenorrhea at times other than these, which warrants investigation. Women with amenorrhea often present with significant apprehension and anxiety. Thus, an appropriate but timely workup and diagnosis are required. The clinician must have a systematic approach for evaluating such women to ensure that important causes of amenorrhea are identified. As always, a detailed history, a targeted physical examination, and selective use of simple diagnostic tests are required.

Different classification systems have been employed. One system defines the type of amenorrhea based on the level of FSH in circulation. For example, high FSH levels indicate that the hypothalamus and pituitary are fully functioning but that the ovary is not responding (similar to menopause). The gonadotropin (FSH) levels are high and the ovary (gonad) is not functioning, which is termed hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism refers to the situation where FSH levels are very low due to some central disturbance of hypothalamic or pituitary function. The problem with this classification is that normal FSH levels are often low and the distinction between hypogonadotropic and eugonadotropic causes of amenorrhea can be difficult. A simple way to consider causes of amenorrhea is to divide the processes that regulate menstruation (the hypothalamic-pituitaryovarian axis [HPO axis]) into compartments (Figure 1) and then consider possible contributory factors for disruption of normal processes at each of these levels. Always consider the possibility that amenorrhea may be due to unexpected pregnancy before moving on to a full investigation.

Hypothalamic Compartment The hypothalamus integrates a wide variety of signals from the brain and is ultimately responsible for turning on or off the hormonal cascade necessary for triggering ovulatory and menstrual function. In adolescents, the development of breasts (thelarche) between ages 8 and 10 years is usually the first sign that the HPO axis has turned on and first menstruation (menarche) typically follows within 3 to 5 years. All girls with primary amenorrhea by age 14 years, particularly if 5 or more years have passed since the first evidence of pubertal development, warrant careful investigation, because girls with primary amenorrhea on the basis of constitutional delay cannot readily be differentiated on clinical history from the two thirds of patients with primary amenorrhea who have irreversible causes of reproductive failure.

Constitutional Delay One third of young women presenting with primary amenorrhea have constitutional delay of puberty, meaning that they are undergoing a normal sequence of pubertal development at a rate that

Amenorrhea

Etiology

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Hypothalamus

Pituitary

Ovaries

Outflow tract

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Figure 1. The four compartments to consider when evaluating amenorrhea.

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falls 2.5 standard deviations behind the mean. Girls with constitutional delay often present between ages 13 and 16 with primary amenorrhea and only early signs of breast development. Investigation reveals low to low-normal levels of gonadotropins and an otherwise negative workup.

Congenital Causes A variety of unusual congenital conditions result in hypogonadotropic hypogonadism and primary amenorrhea. These conditions may be caused by deficiency of GnRH production or by abnormalities of the GnRH receptor. A Kallman’s-like syndrome has been identified in some affected women who present with anosmia and a complete lack of pubertal development.

Acquired Causes Acquired diseases can lead the hypothalamus to shut down the reproductive hormonal cascade, resulting in amenorrhea, which may be primary or secondary, depending on when they develop. Nutritional deprivation (including eating disorders), excessive caloric demand due to participation in demanding sports, and extreme psychological stress are common reasons for delayed activation of reproductive processes by the hypothalamus. Less commonly, systemic illnesses, including malabsorption states, active autoimmune diseases, and rare hypoxemic states related to congenital heart malformations or severe anemias (sickle cell disease), can lead to amenorrhea.

Pituitary Compartment Lesions of the pituitary stalk that interrupt normal delivery of GnRH to the pituitary include those resulting from head trauma, rare stalk tumors such as craniopharyngiomas, or from the surgery to remove these. Pituitary causes of amenorrhea are almost always due to oversecretion of prolactin. Hyperprolactinemia resulting in amenorrhea, if associated with central retro-orbital headache and bitemporal hemianopia, can result from a prolactin-producing tumor. Other causes of hyperprolactinemia originate outside the pituitary. For example, primary hypothyroidism, breast or chest wall lesions (or piercings) in the T4-6 dermatome, renal failure, and a variety of medications have all been linked to hyperprolactinemia. Medications that can cause hyperprolactinemia include dopamine receptor antagonists (phenothiazines, butyrophenones,

thioxanthenes, risperidone, metoclopramide, sulpiride,2 pimozide), dopamine-depleting agents (e.g., methyldopa, reserpine), H2blockers (cimetidine), opiates, and cocaine. Rarely, other pituitary conditions result in amenorrhea. In empty sella syndrome, radiologic examination reveals an apparently empty sella due to pituitary regression from some vascular or other insult. Other conditions include Sheehan syndrome (postpartum pituitary necrosis), pituitary apoplexy (massive pituitary infarction), and radiation-induced hypopituitarism. In each of these situations, amenorrhea is usually part of a larger picture of endocrine disruption.

Ovarian Compartment Depletion of eggs from the ovary before or after puberty results in primary or secondary amenorrhea, respectively. FSH levels are markedly elevated in these cases, as the hypothalamus and pituitary try to elicit follicular development from the unresponsive ovary. Destruction of oocytes by any of several environmental insults, including ionizing radiation, various chemotherapeutic (especially alkylating) agents, and certain viral infections can accelerate follicular atresia. Primary amenorrhea in a woman with evidence of gonadal failure should elicit a search for a chromosomal abnormality. It is known that two intact X chromosomes are needed for maintenance of ovarian function. A variety of X chromosome structural abnormalities have been identified in women with premature ovarian failure, including complete absence of one X chromosome (Turner’s syndrome). Elevated FSH occurs in association with a normal karyotype. These women have normal 46,XY or 46,XX karyotypes without the phenotypic abnormalities of Turner’s syndrome. Those with a Y chromosome should have their gonads removed because of the potential for malignant transformation. Several rare inherited enzymatic defects also may be associated with premature ovarian failure. These include partial deficiencies in four enzymes in the steroidogenic pathway—17a-hydroxylase, 17,20-desmolase, 20,22-desmolase, and aromatase—and galactosemia. Premature ovarian failure may be associated with a number of autoimmune disorders. Most commonly associated with thyroiditis, ovarian failure also occurs in women with polyglandular failure, including hypoparathyroidism, hypoadrenalism, and mucocutaneous candidiasis. Though it is not exclusively an ovarian disorder, it is useful to consider polycystic ovary syndrome (PCOS) in the ovarian compartment for the purpose of completeness in considering possible diagnoses. PCOS is one of the most common causes of secondary amenorrhea. Typically, women suffering from this condition are overweight (although one third have normal body weight) and have clinical features of hyperandrogenism (acne and hirsutism), hyperinsulinism (acanthosis nigricans), and hyperestrogenism (watery cervical mucus). Months of amenorrhea may be punctuated by episodes of heavy and prolonged menstrual bleeding as an estrogenthickened endometrium sheds irregularly over several weeks.

Outflow Tract Compartment Congenital abnormalities of development of the reproductive outflow tract can cause amenorrhea. Complete absence of a uterus can be due to isolated mu¨llerian agenesis or it can manifest in phenotypic females with a 46,XY karyotype who have complete androgen insensitivity. Developmental abnormalities can include cervical atresia, tranverse vaginal septum, and imperforate hymen. These latter abnormalities may be associated with cyclic menstrual pain in the absence of bleeding (cryptomenorrhea). Similarly, monthly cramps can occur with cervical stenosis following trachelectomy or conization. Uterine synechiae due to a vigorous curettage in the face of a postpartum or postabortion endometritis can 2

Not available in the United States.

result in obliteration of the uterine cavity and secondary amenorrhea with or without monthly menstrual-like cramps.

patient). Visualization of the cervix in most circumstances is sufficient to rule out an outflow compartment problem.

Other Causes

Investigations Initial Investigations

Pregnancy must always be considered in a sexually active female patient presenting with secondary amenorrhea. Hormonal suppression of the endometrium can be accomplished with a variety of medications. The progestin component of the cyclic oral contraceptive gradually results in a thinner and thinner endometrium, which can ultimately result in pill-withdrawal amenorrhea. Other medications, including danazol, medroxyprogesterone, and longacting GnRH agonists can result in amenorrhea.

Diagnosis A search for clues as to the etiology should start with a personal developmental history in the amenorrheic teen and with a menstrual and reproductive history in the older amenorrheic woman. Events in the 3 to 6 months preceding the onset of amenorrhea are often critical. Rapid weight gain or loss or a marked change in energy expenditure through exercise may be important. Systems review should examine possible disruption to any of the compartments (Box 1). Inquiry about general health, risk of pregnancy, and use of medication (including illicit drugs) is important.

Physical Examination Height, weight, and body mass index (BMI) should be determined. Body habitus often provides an important clue to which patients are amenorrheic due to excessive physical or nutritional stress (eating disorder or malnutrition). In primary amenorrhea, examination for the stage of breast and pubic hair development (Tanner staging) can indicate whether there has been delay or disruption to the entire process of pubertal development. Restriction of later visual fields to examination by confrontation, the presence of galactorrhea, or evidence of recent scars or lesions in the region of the breast (such as zoster) can implicate hyperprolactinemia. The thyroid gland should be palpated and features of hypothyroidism sought. A lower abdominal mass may be due to pregnancy, hematocolpos or hematometra. The gynecologic examination should be tailored to the patient. The external genitalia should be evaluated for pubic hair, acanthosis nigricans, and clitoral size. The hymen should be visualized; an imperforate hymen usually shows a bluish central bulge. Estrogenization of the tissues (presence of leukorrhea, thickened mucosa, or watery cervical mucus) can be assessed with speculum examination (choosing a speculum size appropriate to the sexual maturity of the

A Compartmental Approach to Systems Review

Hypothalamic Compartment • Changes in temperature regulation, sleep, appetite, thirst • Headache or visual field defects Pituitary Compartment • Central retro-orbital headache, bitemporal hemianopia • Galactorrhea • Features of hypothyroidism • Medications affecting prolactin Ovary Compartment • Hot flushes • Insomnia • Night sweats • Vaginal dryness Outflow Compartment • Cyclic cramps • Possibility of pregnancy • Recent gynecologic procedures (dilation and curettage, cervical laser or conization)

A low normal FSH in the presence of a normal outflow tract should elicit a more detailed search for hypothalamic disruptors (such as nutritional, physical, or psychological stress). In a patient who has low FSH in conjunction with an elevated PRL and who is not taking medications known to increase PRL and whose TSH is normal, lesions of the hypothalamus or pituitary should be excluded with CT or MRI. An elevated FSH indicates ovarian failure and should elicit a search for possible explanations such as past surgery, exposure to radiation or chemotherapy, or genetic causes. With an elevated FSH, a karyotype is usually indicated unless there is some obvious cause for loss of ovarian function. If the karyotype reveals any Y chromosome material, then, at the appropriate age, referral to a gynecologist is necessary for counseling and gonadectomy to reduce the risk of gonadoblastoma and dysgerminoma. Evidence of outflow tract obstruction on pelvic examination or the possibility of cervical stenosis (cyclic dysmenorrhea without bleeding after a cervical surgical procedure such as a loop excision, cone biopsy, or trachelectomy) or Asherman’s syndrome (obliteration of the endometrial cavity following a postpregnancy or postabortion dilation and curettage) merits referral to a gynecologist for further assessment and management. Secondary amenorrhea related to weight gain or obesity, particularly when associated with features of acne and hirsutism, suggests the polycystic ovary syndrome. Management depends on whether the patient is seeking menstrual cycle regulation and relief from hirsutism (cyclic progestational therapy or an oral contraceptive plus an anti-androgen) or pregnancy (weight loss and fertility medication such as clomiphene citrate [Clomid]).

References

Rebar RW. Evaluation of amenorrhea, anovulation and abnormal bleeding. March 26, 2006. Available at http://endotext.org/female/female4/female-frame4.htm [accessed June 15, 2007]. Reid RL. Amenorrhea. In: Copeland L, Jarrell J, McGregor J, editors. Textbook of Gynecology. 2nd ed. Philadelphia: WB Saunders; 1997. pp. 365–90. Reindollar R, Lalwani S. Abnormalities of female pubertal development. Novermber 21, 2002. Available at http://endotext.org/female/female2/femaleframe2.htm [accessed June 15, 2007].

BREAST DISEASE Method of

Jana Lewis, MD, and Patrick Borgen, MD Benign diseases of the breast historically are subdivided into proliferative and nonproliferative lesions (Table 1). In a study by Dupont and Page, patients with breast biopsies yielding nonproliferative lesions had no increased risk for subsequent breast cancer. In contrast, proliferative lesions were associated with a minimal to a fivefold increased risk for breast cancer. In clinical practice, of the proliferative lesions, only atypical epithelial lesions increase breast cancer risk significantly. Appropriate treatment and counseling of patients depend on the risk for breast cancer associated with these benign diseases.

Breast Disease

Follow-up Investigations

History

Box 1

Initial investigation for any patient with amenorrhea or oligomenorrhea includes follicle-stimulating hormone (FSH), prolactin (PRL), thyroid stimulating hormone (TSH), and a sensitive pregnancy test if pregnancy is a possibility. Ultrasonography can be helpful when an internal examination cannot be performed. When a congenital anomaly is considered, magnetic resonance imaging (MRI) can provide more definitive information.

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TABLE 1

Breast Cysts and Fibrocystic Breast Disease

Benign Diseases of the Breast INCREASE IN BREAST CANCER RISK

LESION Nonproliferative Lesions Mild hyperplasia without atypia

None

Squamous or apocrine metaplasia

None

Duct ectasia

None

Mastitis

None

Cysts

None

Proliferative Lesions Fibroadenoma

None

Moderate or florid hyperplasia

Minimal

Microglandular adenosis

Minimal

Sclerosing adenosis

Minimal

Papilloma

Minimal

Atypical ductal hyperplasia

4-fold to 5-fold

Atypical lobular hyperplasia

5.8-fold

Copyright #1985 Massachusetts Medical Society. All rights reserved.

18 Women’s Health

Nonproliferative Lesions

Nonproliferative lesions include mild hyperplasia without atypia, squamous or apocrine metaplasia, duct ectasia, mastitis, and fibrocystitc disease. In the study of 3303 patients by Dupont and Page, only 2.2% of patients with nonproliferative lesions had breast cancer following a benign breast biopsy with a mean follow-up time of 17 years.

Fibrocystic breast disease is a benign process in which generalized microcystic formation with stromal proliferation leads to increased breast nodularity. Cysts within the breast are most common in perimenopausal women 50 to 59 years of age, but may present in premenopausal women as well. Postmenopausal women on hormone replacement therapy may develop cysts in their breasts. Benign cysts are often tender and fluctuate in size with the menstrual cycle. Cysts may be detected either on physical examination as a palpable, smooth, mobile nodule or by breast ultrasound. They may appear as a solitary nodule or in a cluster. Ultrasonographic appearance of simple benign cysts is that of an anechoic, round or oval, well-circumscribed mass with posterior enhancement. If the mass meets all four criteria, the accuracy of ultrasound is close to 100% for the diagnosis of a simple benign cyst. Cysts that appear complex, with internal echoes, thick septations, and irregular walls are suspicious for breast carcinoma and should be examined surgically or with an ultrasound-guided biopsy. Confirmation of the diagnosis can be made by fine-needle aspiration (FNA) of the cystic fluid. Bloody fluid may be an indication for a biopsy. In a study of 6782 cyst aspirates, Ciatto and colleagues found that cytologic examination identified atypical cells in 1677 specimens. Of these specimens, only 0.3% of these cases had clinically and radiologically negative intracystic papillomas. Cytologic examination was positive in only 0.1% of these cases. Thus fluid from cyst aspirations is not routinely sent for cytologic examination. Figure 1 describes the management of suspected cysts.

Mastitis and Duct Ectasia Mastitis is divided into lactational and nonlactational. Lactational mastitis can occur from the reflux of bacteria into the breast during breast-feeding. The causative bacteria are usually gram-positive cocci. Patients should be treated with antibiotics with the Figure 1. Algorithm for the management of suspected cysts.

Suspected cyst

Directed ultrasound (mammogram if none done within the past year and patient is >40 yo)

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Suspicious cyst with solid component

Biopsy

Definitive for simple cyst

Equivocal for simple cyst

Aspirate

Bloody

Routine follow-up

Non-bloody

Mass does not resolve

Mass resolves

Follow-up in 6–8 weeks

Proliferative Benign Breast Diseases

Proliferative breast diseases include moderate or florid hyperplasia, microglandular and sclerosing adenosis, papilloma, fibroadenoma, atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH). All proliferative lesions have an increased risk for subsequent breast cancer after biopsy except for fibroadenoma. This risk is 1.9 times higher in the presense of proliferative disease without atypia and increases to 5.3 times higher with atypia. Patients with moderate or florid hyperplasia, sclerosing adenosis, and solitary papilloma without atypia carry a minimal increase in risk for developing breast cancer over the general population. These patients are not classified as high risk. However, the risk for subsequent breast cancer is increased by fourfold to fivefold in the presence of atypia. ALH carries a higher risk than ADH, with a relative risk as high as 5.8. This increased risk applies to the contralateral breast as well because subsequent breast carcinomas are evenly divided between both breasts.

Proliferative Lesions with No Increased Risk for Subsequent Cancer: Fibroadenoma Fibroadenomas are the most common breast tumor in women, as well as the most common benign tumor found in young women (less than 30 years of age with a peak incidence at 21 to 25 years of age). They are characteristically detected on physical examination as well-circumscribed, rubbery, highly mobile, palpable masses. On mammograms, these lesions may appear as a wellcircumscribed mass. Involution of fibroadenomas in the elderly can lead to hyalinization and dense popcorn-like calcification on mammograms. Fibroadenomas pose no increased risk for breast cancer and do not mandate surgical removal unless desired by the patient. Pregnancy can increase the size of these lesions; thus it may be reasonable to remove them prior to a planned pregnancy. Removal may facilitate follow-up, given the inability to follow breast masses adequately during pregnancy. Other types of fibroadenomas include juvenile and giant fibroadenomas. Juvenile fibroadenomas occur in adolescent women and can grow larger than 5 cm in diameter. These lesions are not malignant; given their large size, however, surgical excision may be needed to prevent asymmetry of the breasts. Giant fibroadenomas are large fibroadenomas found in the lactating breast or in the breasts of pregnant patients. These lesions may regress in size once hormonal stimulation subsides. Lesions that remain large can be excised surgically. Fibroadenomas and phyllodes tumors may be linked. Any rapidly enlarging fibroadenoma should be considered for surgical excision to rule out phyllodes tumor because it is difficult clinically to differentiate the two.

Proliferative Lesions with Minimal Increased Risk for Subsequent Breast Cancer Multiple Peripheral Papillomas Multiple peripheral papillomas are lesions that occur in the peripheral ducts. They most commonly present as a mass but may also present with nipple discharge. Complete excisional removal may be considered to rule out a papillary carcinoma of the breast. In the era of larger-gauge biopsy devices it is easier to classify a lesion as a benign intraductal papilloma, which may be observed.

Sclerosing and Microglandular Adenosis Sclerosing adenosis occurs as result of the proliferation of stromal tissue along with small terminal ductules. Often these lesions are picked up incidentally, but they may also present as microcalcifications on mammogram or as a mass (termed adenosis tumor). Sclerosing adenosis may be confused with a tubular carcinoma.

Proliferative Lesions with a Fourfold to Fivefold Risk for Subsequent Breast Cancer: Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia ADH and ALH are very similar to their in situ counterparts. These lesions are termed atypical hyperplasia because they lack some of the microscopic features of in situ disease. The distinction between atypical hyperplasia and carcinoma in situ may be difficult to discern. In a study by Rosai, five expert breast cancer pathologists reviewed 17 cases of ductal or lobular lesions. In no case did all five agree on a diagnosis. Four of the five were able to agree on a diagnosis in three cases (18%). In one third of the patients, the diagnosis ran the gamut from hyperplasia without atypia to carcinoma in situ. Despite such difficulty, the diagnosis of atypical hyperplasia is on the rise as mammographic screening becomes more routine. Atypical hyperplasia, which is detected secondary to microcalcifications or by serendipity, carries the highest risk for subsequent breast carcinoma among all proliferative lesions of the breast, with a fourfold to fivefold increased risk over the general population. ALH carries a higher risk than ADH, with a relative risk as high as 5.8. This risk applies to the contralateral breast as well as the ipsilateral breast. Surgical excision of atypical hyperplasia on a core biopsy is recommended because 20% of patients are found to have breast cancer at time of surgical excision for atypical hyperplasia. It is not necessary to achieve negative margins for these lesions.

Other Benign Breast Lesions: Fat Necrosis, Hamartoma, Mondor’s Disease, Radial Scars, and Pseudoangiomatous Stromal Hyperplasia Other benign lesions of the breast include fat necrosis, hamartoma, Mondor’s disease, radial scars, and pseudoangiomatous stromal hyperplasia (PASH). Trauma to the breast may lead to fat necrosis and can be mistaken for carcinomas on clinical examination. Fat necrosis lesions present clinically as painless, irregular masses with or without associated skin changes such as skin thickening. These lesions can be normal or may have rim calcifications on mammograms. No further treatment is needed when a core biopsy definitively makes the diagnosis of fat necrosis. Hamartomas are benign lesions that are often picked up on a mammogram. The fatty composition of the mass makes these lesions clinically occult. They can be mistaken for fibroadenomas on mammograms. Hamartomas can be left alone without histologic confirmation if diagnosed definitively on a mammogram. Mondor’s disease is a thrombophlebitis of the superficial breast veins that presents as a palpable tender cord leading to the axilla. In a study of 63 cases, 8 patients (25%) had an underlying malignancy; thus a mammogram should be done to rule out the presence of breast carcinoma. Radial scars are benign lesions whose etiology is unknown. They are often mistaken for breast carcinoma on mammograms because of their stellate appearance. Radial scars may also mimic breast carcinoma histologically. Staining for myoepithelial cells can help distinguish between invasive carcinoma and a radial scar. Radial scars carry a 1.5-fold increase in risk for subsequent breast carcinoma, so these lesions should be considered markers of future disease. First described in 1986, PASH is a benign proliferative lesion that may present as an incidental finding or a mobile breast mass. It can occur in all ages and also in men. On a mammogram, PASH appears as a round noncalcified mass. Histologically, PASH may be mistaken for low-grade angiosarcoma. Unlike angiosarcoma, however, there should be no evidence of mitosis or cytologic atypia in PASH specimens. The role of hormones in the pathogenesis of

Breast Disease

appropriate coverage and can continue to nurse or pump the breast to prevent engorgement. Nursing mothers can continue to breast-feed because the infant is not at risk for infection. Nonlactational (periductal) mastitis can be caused by duct ectasia, which occurs when the milk ducts become congested with secretions and debris, resulting in a periductal inflammation. These patients may present with greenish nipple discharge, nipple retraction, and subareolar noncyclical pain. The treatment of nonlactational mastitis includes broad-spectrum antibiotics to cover for gram-positive cocci and skin anaerobes. Total duct excision and eversion of the nipple may be necessary to treat recurrent periductal mastitis.

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PASH is controversial. Although these lesions tend to occur in young patients or in elderly patients on hormone therapy, most cases tend to be negative for estrogen receptors. The treatment for symptomatic PASH is complete surgical excision. Approximately 7% of cases recur despite adequate treatment.

Risk Factors for Breast Cancer

An estimated 80% of women in whom breast cancer develops have no documented risk factors or determinants. Risk factors cannot be changed, whereas risk determinants can be altered to decrease a person’s risk for subsequent breast cancer. Common risk factors include a familial history of breast cancer, personal breast biopsy history, menarche before 12 years of age, menopause after 55 years of age, increasing age, geographical location, and mutations of the BRCA1 or BRCA2 genes. The risk determinants for breast cancer include reproductive factors such as nulliparity and first pregnancy after the age of 30 years and previous radiation exposure. Previous radiation therapy for lymphoma, especially during adolescence, elevates a woman’s risk for subsequent breast cancer.

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BRCA Gene Mutations

988

BRCA1 and BRCA2 (breast cancer susceptibility gene) are tumor suppressor genes that normally ensure DNA stability and prevent uncontrolled cell growth. Mutations in these genes may lead to the development of hereditary breast and/or ovarian cancer in affected individuals, and less commonly to other cancers such as pancreatic, uterine, and colon. It is estimated that these inherited mutations account for 3% to 5% of all breast cancers and 10 to 15% of all ovarian cancers among white women in the United States. Men with a mutated BRCA2 gene also have an increased risk for breast cancer. The likelihood that a breast and/or ovarian cancer is associated with a BRCA mutations is increased in families with history of multiple cases of breast cancer, cases of both breast and ovarian cancer, one or more family members with two primary cancers, or an Ashkenazi Jewish background. Roughly 10% of women in the general population will develop breast cancer sometime in their life, compared to 60% to 80% of women with a harmful BRCA mutation. For ovarian cancer, 1.4% of unaffected women will develop the disease, while 15% to 40% of affected women will. To test for BRCA1 and BRCA2 mutations, a DNA sample (blood is currently required for full-length gene sequencing) is needed. There are currently no universally agreed-upon criteria for screening patients with a suspected BRCA mutation, and each case should be assessed individually. Genetic counseling is recommended before and after the workup. Options for further management after a positive BRCA test include close surveillance, prophylactic (risk reducing) surgery, and chemoprevention. A discussion between physician and patient should include all options and be adjusted to the patient’s needs.

Screening Techniques

Screening for breast cancer includes mammography, ultrasound, breast self-examination (BSE), and physical examination by a physician. Multiple studies, such as the Gothenburg and Malmo¨ trials, show a reduction in breast cancer mortality from 30% to 40% in patients 40 to 49 years of age who undergo screening mammograms. A meta-analysis of six randomized trials revealed a 30% reduction in breast cancer mortality in patients 50 to 69 years of age. The sensitivity of mammograms depends on the patient’s age and ranges from 53% to 81% in women 40 to 49 years of age to 73% to 81% in patients 50 years of age or older. An estimated 10% to 15% of breast cancer cases are not detectable on screening mammography, thus emphasizing the importance of physical breast examination by a physician and BSE that include both visual inspection and manual examination of the breast. On inspection, signs of breast malignancy include skin or nipple retraction or discoloration, nipple discharge/crusting, or peau d’orange edema of the breast. On palpation, any asymmetric mass of the breast or axilla may be regarded as a potential malignancy that deserves further evaluation.

Screening for a woman with an average risk for developing breast cancer should start with routine BSEs at 18 years of age, yearly physical examinations, and initiation of annual mammography at 40 years of age in accordance with the American Cancer Society’s recommendations. In November 2009, the U.S. Preventative Services Task Force (USPSTF) updated their own breast-cancer screening recommendations by recommending that screening mammograms begin at age 50 instead of the previous recommended age 40, and that biannual screening is sufficient. They also advised against teaching BSEs, stating that BSEs do not reduce the risk of death from breast cancer. Further evaluation of the analysis and opinion statement of the USPSTF lead all concerned parties (including the United States Senate, the American Cancer Society, the American College of Surgeons and the American Society of Clinical Oncology) to reject the USPTF guideline changes. In patients who have a very high risk for breast cancer development, such as BRCA carriers, screening should start 10 years earlier than the age of onset of an affected relative or at the age of 35. Krieger screened 1909 patients (including 358 BRCA mutation carriers) who had more than a 15% lifetime risk for developing breast cancer. These patients had a biannual breast examination as well as annual mammogram and breast magnetic resonance imaging (MRI). In this population, mammograms had a sensitivity of 33% with a specificity of 95%. Breast MRI had significantly higher rates of sensitivity and specificity at 80% and 90%, respectively. Given these findings, breast MRI should be a part of the screening examination for these high-risk patients. Moreover, MRI is recommended as a standard screening test in BRCA heterozygotes. Patients with a history of mantle radiation for lymphoma should start annual screening at 25 years of age and biannual screening 10 years after receiving radiation therapy.

Workup of a Breast Mass

Dominant Palpable Mass The workup of a dominant palpable breast mass depends on the patient’s menopausal status and age, and on the degree of suspicion. It is reasonable to follow a premenopausal patient with a nonsuspicious mass over one menstrual cycle and then reexamine her. Suspicious lesions present as a hard, nontender, irregular mass or as a mass in a high-risk patient. Palpable masses in postmenopausal patients may also warrant a workup. In general, certain benign lesions on core biopsy should be excised, including lobular carcinoma in situ (LCIS), ADH, radial scars, sclerosing papillary lesions, columnar cell hyperplasia with atypia, and symptomatic PASH (Figure 2). Patients with a high-risk proliferative lesion should have close follow-up after surgery including physical examinations. Negative findings on a mammogram do not preclude the diagnosis of cancer because 10% of cancers are occult mammographically. This number drops to 3% when a lesion is occult both mammographically and ultrasonographically. An alternative to core biopsies in younger women is the use of the triple test: a physical examination in conjunction with breast imaging (mammogram or ultrasound) and FNA. When all three components indicate the mass is benign, the negative predictive value approaches 100%.

Masses Revealed on Screening Mammograms The American College of Radiology’s classification lexicon, the Breast Imaging Reporting and Data System (BI-RADS), is used in breast imaging to universally characterize lesions found on mammography (Table 2). BI-RADS 0 means the assessment is incomplete and repeat workup is needed. BI-RADS 1 indicates a normal mammogram. Mammograms with BI-RADS 2 signify benign findings. Patients with BI-RADS 3 have a 1% to 2% risk for malignancy and should have short-term follow-up with another mammogram in 6 months. BI-RADS 4 indicates the presence of suspicious lesions with a 20% to 40% probability of a malignant lesion. BI-RADS 5 is highly suggestive of cancer with a greater than 95% chance of harboring an underlying malignant lesion.

Dominant breast mass

Menopausal status

Premenopausal

Postmenopausal

Suspicious?

Mammogram +/– U/S Yes

No

Core biopsy Can observe over 1 cycle and re-examine; if persist treat as suspicious

Age

>25

7 mm Clinically visible lesions limited to the cervix or preclinical cancers greater than stage IA Clinically visible lesion 4 cm in greatest dimension Clinically visible lesion >4 cm in greatest dimension

Stage II II IIA IIA1 IIA2 IIB

Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina Without parametrial invasion Clinically visible lesion 4 cm in greatest dimension Clinically visible lesion >4 cm in greatest dimension With obvious parametrial invasion

Stage III III IIIA IIIB

The tumor extends to the pelvic wall and/ or involves lower third of the vagina and/ or causes hydronephrosis or nonfunctioning kidney Tumor involves lower third of the vagina, with no extension to the pelvic wall Extension to the pelvic wall and/ or hydronephrosis or nonfunctioning kidney

Stage IV IV IVA IVB

The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum; a bullous edema, as such, does not permit a case to be allotted as stage IV Spread of the growth to adjacent organs Spread to distant organs

18 Women’s Health

Adapted from Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105(2):103-104. Erratum in Int J Gynaecol Obstet 2010;108(2):176.

996

radiotherapy planning and evaluation of metabolic response to therapy. A 3-month post-therapy PET scan is highly predictive of longterm survival outcome.

Treatment

Multiple factors including tumor stage, size, histologic features (lymphovascular space invasion [LVSI], nonsquamous components, and depth of cervical stromal invasion), and evidence of lymph node metastasis influence the choice of treatment for cervical cancer. Patients with stage IA1 cervical cancer have undergone a cone biopsy and pathology demonstrates 3 mm of invasion or less, less than 7 mm width, no LVSI, and negative margins. Patients with this extent of disease can safely be treated with a less-radical hysterectomy, an extrafascial hysterectomy. Pelvic lymphadenectomy is not recommended owing to the low risk of pelvic node metastasis (less than 1%). In patients who desire to retain fertility, a cone biopsy may be considered. Wright and colleagues reported on 1409 women from the SEER database who were younger than 40 years and had stage IA1 cancer. The 5-year survival was 98% among 568 who underwent cone biopsy alone versus 99% among 841 who underwent hysterectomy. Patients with stage IA2 to IB1 are generally treated with radical hysterectomy; in patients who are not candidates for surgery owing to comorbidities, radiation therapy is used. In patients with highrisk criteria after surgery—positive surgical margin, parametrial involvement, and positive pelvic nodes—cisplatin-based1 chemoradiation, based on a positive randomized trial, is recommended. Those with intermediate risk factors including tumor size, cervical stromal invasion, and lymphovascular invasion had an improved progression-free survival with adjuvant radiation. Radical trachelectomy—laparoscopic, vaginal or open—in conjunction with lymphadenectomy is a reasonable alternative treatment for select young patients with stage IA2 and IB1 who desire 1

Not FDA approved for this indication.

to maintain their childbearing capacity. The criteria used for patient selection include early-stage cervical cancer with a lesion less than 2 cm, no lymphovascular invasion, and no lymph node metastasis. Reports comparing radical trachelectomies with matched controls identified increased complications (25% versus 3%) and overall less-radical dissection. Treatment of stage IB2 cancer of the cervix varies depending on the bulkiness and shape of the lesion. Surgery and chemoradiation therapy have advantages and disadvantages. Finan and colleagues reported that up 72% of patients with stage IB2 disease who were treated with surgery received adjuvant radiation owing to highrisk factors identified in pathologic evaluation of specimens. In a randomized Gynecologic Oncology Group trial, 94% of patients with IB2 cervical cancer who underwent radical hysterectomy had high or intermediate risk factors warranting adjuvant radiation. In 1999 the National Cancer Institute (NCI) initiated a clinical alert recommending that concurrent cisplatin-based1 chemotherapy be given with radiotherapy to women with cervical cancer based on five randomized studies, and this established a new standard of care (Table 3). It is estimated that approximately 35% of patients with invasive cervical cancer will have recurrent or persistent disease, with most recurrences occurring in the first 2 years following primary therapy. Recurrence can be expected in 10% to 20% of patients treated with radical hysterectomy in contrast to 30% to 50% treated for more-advanced disease primarily with radiation plus concurrent chemotherapy. The site of the recurrence can direct further treatment. Patients with central pelvic recurrences after surgery are candidates for curative radiation; after primary treatment with radiation therapy patients may be candidates for curative radical surgery (exenteration). Prognosis is more favorable for patients undergoing exenteration when there is a small (less than 3 cm) central recurrence, no sidewall involvement, and longer than 2 years of disease-free interval. Those with small recurrences limited to the 1

Not FDA approved for this indication.

TABLE 3

Randomized Trials of Cisplatin-based Chemoradiation SURVIVAL TREATMENT

STAGE

TYPE

PERCENTAGE

SIGNIFICANCE

Gynecology Oncology Group 85 RT/5-FU1 infusion/bolus cisplatin1 RT/oral HU1

IIB-IVA

3 y PFS

67% 57%

P ¼ 0.033

IA2-IIA

Est. 4-y

63% 80%

P ¼ 0.003

IIB-IVA

DFS

40% 67%

P