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PRACTICAL STRATEGIES IN PEDIATRIC DIAGNOSIS AND THERAPY Second Edition Copyright © 2004, 1996, Elsevier Inc. All rights reserved.
ISBN: 0–7216–9131–5
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NOTICE Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the authors assumes any liability for any injury and/or damage to persons or property arising from this publication. First Edition copyrighted 1996.
Library of Congress Cataloging-in-Publication Data Practical strategies in pediatric diagnosis and therapy / [edited by] Robert M. Kliegman, Larry A. Greenbaum, Patricia S. Lye.—2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 0–7216–9131–5 1. Pediatrics—Decision making. 2. Pediatrics. I. Kliegman, Robert. II. Greenbaum, Larry A. III. Lye, Patricia S. [DNLM: 1. Pediatrics. WS 200 P895 2004] RJ47.P724 2004 618.92—dc22
Executive Publisher: Judith Fletcher Developmental Editors: Wendy Buckwalter Coffman/Dana Lamparello Senior Project Manager: Robin E. Davis Book Designer: Gene Harris
Printed in the United States of America.
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This book is dedicated to those master clinician-educators who have inspired us with their clinical wisdom, enthusiasm, empathy, and insight. At no time in the history of pediatrics have these adaptable master clinician-educators been needed more to inspire young students and residents and to provide encouragement and clinical guidance to the practicing pediatrician. In this light, we dedicate this edition to the memory of Dr. David A. Lewis, Associate Professor of Pediatrics, Director of Residency Training, Pediatric Cardiologist, and master clinician at the Children’s Hospital of Wisconsin. His teaching will be missed by us all.
Contributors
Uri S. Alon, MD Professor of Pediatrics, University of Missouri at Kansas City School of Medicine; Pediatric Nephrologist and Director, Bone and Mineral Disorders Clinic, Children’s Mercy Hospital, Kansas City, Missouri
R. Alexander Blackwood, MD, PhD Associate Professor of Pediatrics and Pediatric Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan Recurrent Infection
Acid-Base and Electrolyte Disturbances
Andrew Bleasel, MBBS, PhD Staff Specialist, Neurology and Neurophysiology, Westmead Hospital and Children’s Hospital at Westmead, Sydney, Australia
R. Stephen S. Amato, MD, PhD Clinical Professor of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts; Chief, Pediatrics Service and Director, Medical Genetics, Eastern Maine Medical Center, Bangor, Maine
Paroxysmal Disorders
Laurence A. Boxer, MD Henry and Mala Dorfman Family Professor in Pediatric Hematology/Oncology, University of Michigan Medical School; Director, Pediatric Hematology/Oncology, C. S. Mott Children’s Hospital, Ann Arbor, Michigan
Dysmorphology
Stephen C. Aronoff, MD Professor and Chair, Department of Pediatrics, Temple University School of Medicine; Temple University Children’s Medical Center, Philadelphia, Pennsylvania
Recurrent Infection
Ben H. Brouhard, MD Professor of Pediatrics and Associate Dean, Case Western Reserve University School of Medicine; Executive Vice President of Medical Affairs and Chief of Staff, MetroHealth System, Cleveland, Ohio
Fever of Unknown Origin
Jane P. Balint, MD Clinical Associate Professor, Ohio State University; Pediatric Gastroenterologist, Columbus Children’s Hospital, Columbus, Ohio
Hematuria
Jaundice
Gale R. Burstein, MD, MPH Medical Officer, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
Sharon Bartosh, MD Associate Professor of Pediatrics, University of Wisconsin School of Medicine; Chief, Division of Pediatric Nephrology, University of Wisconsin Children’s Hospital, Madison, Wisconsin
Sexually Transmitted Diseases
Vimal Chadha, MD Assistant Professor of Pediatrics, Virginia Commonwealth University School of Medicine; Chair, Section of Pediatric Nephrology, Virginia Commonwealth University Medical Center, Richmond, Virginia
Hypertension
Stuart Berger, MD Professor of Pediatrics, Medical College of Wisconsin; Medical Director, Herma Heart Center, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Acid-Base and Electrolyte Disturbances
John C. Chandler, MD Pediatric Surgeon, Children’s Hospital of the Greenville Hospital System, Greenville, South Carolina
Heart Failure
Abdominal Masses
Brian W. Berman, MD Professor of Pediatrics, Case Western Reserve University School of Medicine; Vice Chair for Community–Physician Affairs and Chief, Division of General Academic Pediatrics, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
Bruce H. Cohen, MD Staff, Section of Pediatric Neurology, Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio
Lymphadenopathy; Pallor and Anemia
Headaches in Childhood
David J. Beste, MD Medical Director, Speech and Audiology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Robert J. Cunningham III, MD Chair, Medical Subspecialty Pediatrics and Head, Section of Pediatric Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio
Neck Masses in Childhood
Proteinuria
vii
viii
Contributors
Leona Cuttler, MD Professor of Pediatrics, Case Western Reserve University School of Medicine; Chief, Division of Endocrinology, Diabetes, and Metabolism, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
Larry A. Greenbaum, MD, PhD Associate Professor, Department of Pediatrics, Medical College of Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Delirium and Coma
Short Stature
Jack S. Elder, MD Professor of Pediatrics and Carter Kissell Professor of Urology, Case Western Reserve University School of Medicine; Director, Pediatric Urology, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
Marjorie Greenfield, MD Associate Professor of Reproductive Biology, Case Western Reserve University School of Medicine; Associate Professor of Obstetrics and Gynecology and Pediatrics, University Hospitals of Cleveland, Cleveland, Ohio
Acute and Chronic Scrotal Swelling; Ambiguous Genitalia
Menstrual Problems and Vaginal Bleeding
Susan Feigelman, MD Associate Professor of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Ajay Gupta, MD Staff, Section of Pediatric Neurology and Epilepsy, Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio
Failure to Thrive and Malnutrition
Thomas Ferkol, MD Associate Professor of Pediatrics, Washington University School of Medicine; Director, Cystic Fibrosis Center, St. Louis Children’s Hospital, St. Louis, Missouri Respiratory Distress
Michele A. Frommelt, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Cyanosis
Peter C. Frommelt, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Director of Pediatric Echocardiography, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Cyanosis
Michael W. L. Gauderer, MD Professor of Surgery, University of South Carolina School of Medicine; Adjunct Professor of Bioengineering, Clemson University; Chief, Pediatric Surgery, Children’s Hospital of the Greenville Hospital System, Greenville, South Carolina
Headaches in Childhood
Peter L. Havens, MD Professor of Pediatrics and Epidemiology, Medical College of Wisconsin; Consultant in Infectious Diseases, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Meningismus and Meningitis
Jeffrey S. Hyams, MD Professor of Pediatrics, University of Connecticut School of Medicine, Farmington, Connecticut; Head, Division of Digestive Diseases, Connecticut Children’s Medical Center, Hartford, Connecticut Gastrointestinal Bleeding
David M. Jaffe, MD Dana Brown Professor of Pediatrics, Washington University School of Medicine; Director, Division of Emergency Services, St. Louis Children’s Hospital, St. Louis, Missouri Fever without Focus
Abdominal Masses
Candice E. Johnson, MD, PhD Professor of Pediatrics, University of Colorado School of Medicine; Attending Physician, Children’s Hospital, Denver, Colorado
Mitchell E. Geffner, MD Professor, University of Southern California Keck School of Medicine; Physician and Director of Fellowship Training, Division of Endocrinology, Diabetes, and Metabolism, Childrens Hospital Los Angeles, Los Angeles, California
Hugh F. Johnston, MD Professor, Departments of Psychiatry and Educational Psychology, University of Wisconsin Medical School; University of Wisconsin Hospital and Clinics, Madison, Wisconsin
Dysuria
Disorders of Puberty
Unusual Behaviors
Manju E. George, MD Resident in Dermatology, University of Kansas Medical Center, Kansas City, Kansas
Virginia Keane, MD Associate Professor of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Rashes and Skin Lesions
Failure to Thrive and Malnutrition
William M. Gershan, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Pediatric Pulmonologist, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Carolyn M. Kercsmar, MD Professor of Pediatrics, Case Western Reserve University School of Medicine; Director, Children’s Asthma Center, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
Cough
Respiratory Distress
Contributors Robert M. Kliegman, MD Professor and Chair, Department of Pediatrics, Medical College of Wisconsin; Pediatrician-in-Chief and Pam and Les Muma Chair in Pediatrics, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Airway Obstruction in Children; Acute and Chronic Abdominal Pain
ix
Amy Jo Nopper, MD Associate Professor of Pediatric Dermatology, University of Missouri–Kansas City School of Medicine; Chief, Section of Pediatric Dermatology, Children’s Mercy Hospital, Kansas City, Missouri Rashes and Skin Lesions
Subra Kugathasan, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Diarrhea
Susan R. Orenstein, MD Professor of Pediatrics, Division of Pediatric Gastroenterology, University of Pittsburgh School of Medicine; Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Vomiting and Regurgitation
Robert M. Lembo, MD Associate Professor of Clinical Pediatrics and Director, Medical Education, Department of Pediatrics, New York University School of Medicine; Attending Physician, Bellevue Hospital Center, New York, New York Fever and Rash
Michael J. Painter, MD Professor of Neurology and Pediatrics, Division of Child Neurology, University of Pittsburgh School of Medicine; Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Hypotonia and Weakness
David A. Lewis, MD Associate Professor of Pediatrics, Division of Pediatric Cardiology; Director, Graduate Medical Education Program, Medical College of Wisconsin, Milwaukee, Wisconsin (Deceased) Syncope and Dizziness
Cynthia G. Pan, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Medical Director, Dialysis Unit and Nephrology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Polyuria and Urinary Incontinence
Gregory S. Liptak, MD, MPH Professor of Pediatrics, University of Rochester Medical Center; Attending Physician, Strong Memorial Hospital, Rochester, New York Mental Retardation and Developmental Disability
Andrew N. Pelech, MD Associate Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Heart Sounds and Murmurs
Patricia S. Lye, MD Associate Professor, Department of Pediatrics, Medical College of Wisconsin; Children’s Hospital of Wisconsin, Milwaukee, Wisconsin Earache
John M. Peters, DO Assistant Professor of Pediatrics, Division of Pediatric Gastroenterology, University of Pittsburgh School of Medicine; Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Saleem I. Malik, MD Associate Director, Comprehensive Epilepsy Center, Cook Children’s Hospital, Fort Worth, Texas
Vomiting and Regurgitation
Hypotonia and Weakness
Emory M. Petrack, MD Associate Clinical Professor, Department of Pediatrics, Case Western Reserve University School of Medicine; President, Petrack Consulting, Inc., Cleveland, Ohio
Kelly W. Maloney, MD Assistant Professor of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
The Irritable Infant
Splenomegaly
Andrea C. S. McCoy, MD Associate Professor of Pediatrics, Temple University School of Medicine and Temple University Children’s Medical Center, Philadelphia, Pennsylvania
Philip A. Pizzo, MD Professor of Pediatrics and of Microbiology and Immunology; Dean, Stanford University School of Medicine, Stanford, California Fever and Neutropenia
Daniel W. McKenney, MD Associate Professor of Pediatrics, Nephrology and Hypertension Division, University of Louisville, Louisville, Kentucky
Robert M. Reece, MD Clinical Professor of Pediatrics, Tufts University School of Medicine; Visiting Professor of Pediatrics, Dartmouth Medical School; Director of Child Protection Program, The Floating Hospital for Children at New England Medical Center, Boston, Massachusetts
Renal Failure
Child Abuse
James J. Nocton, MD Associate Professor of Pediatrics, Medical College of Wisconsin; Director, Pediatric Residency Training Program, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Michael J. Rivkin, MD Associate Professor of Neurology, Harvard Medical School; Attending Physician, Department of Neurology; Director, Developmental Neuroimaging Laboratory, Children’s Hospital, Boston, Massachusetts
Arthritis
Stroke in Childhood
Fever of Unknown Origin
x
Contributors
Mark S. Ruttum, MD Professor of Ophthalmology, Medical College of Wisconsin; Chief of Pediatric Ophthalmology, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Francisco A. Sylvester, MD Associate Professor of Pediatrics, University of Connecticut School of Medicine; Pediatric Gastroenterologist, Connecticut Children’s Medical Center, Hartford, Connecticut
Eye Disorders
Gastrointestinal Bleeding
John R. Schreiber, MD, MPH Professor of Pediatrics and Pathology, Case Western Reserve University School of Medicine; Chief, Division of Infectious Diseases, Allergy, Immunology, and Rheumatology, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
Robert R. Tanz, MD Professor and Director of Medical Education, Department of Pediatrics, Northwestern University Feinberg School of Medicine; Attending Physician, Division of General Academic Pediatrics, Children’s Memorial Hospital, Chicago, Illinois
Lymphadenopathy
Sore Throat
J. Paul Scott, MD Professor, Medical College of Wisconsin; Attending Physician, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
John G. Thometz, MD Professor of Orthopaedic Surgery, Medical College of Wisconsin; Chief, Pediatric Orthopaedic Surgery and Medical Director, Orthopaedic Surgery, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Bleeding and Thrombosis
Stanford T. Shulman, MD Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Chief, Division of Infectious Diseases, Children’s Memorial Hospital, Chicago, Illinois Sore Throat
Garry S. Sigman, MD Professor, Northwestern University Feinberg School of Medicine; Director, Adolescent Medicine, Evanston Northwestern Healthcare, Evanston, Illinois Chest Pain
Mark L. Splaingard, MD Professor of Pediatrics, Medical College of Wisconsin; Director of Pediatric Pulmonary Care, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin
Back Pain in Children and Adolescents
George H. Thompson, MD Professor of Orthopaedic Surgery and Pediatrics, Case Western Reserve University School of Medicine; Director, Pediatric Orthopaedics, Rainbow Babies and Children’s Hospital, Cleveland, Ohio Gait Disturbances
George F. Van Hare, MD Associate Professor of Pediatrics, Stanford University School of Medicine; Director, Pediatric Arrhythmia Center, Lucile Packard Children’s Hospital at Stanford University Medical Center; Director, Pediatric Arrhythmia Center, University of California, San Francisco, Children’s Hospital, San Francisco, California Palpitations and Arrhythmias
Apnea and Sudden Infant Death Syndrome
Charles A. Stanley, MD Professor of Pediatrics, University of Pennsylvania School of Medicine; Chief, Division of Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Hypoglycemia
Rita Steffen, MD Staff, Department of Pediatric Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio Constipation
Frederick J. Suchy, MD Professor and Chair, Department of Pediatrics, Mount Sinai School of Medicine; Pediatrician-in-Chief, Mount Sinai Hospital, New York, New York
Kristine G. Williams, MD, MPH Instructor of Pediatrics, Division of Pediatric Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri Fever without Focus
Martha S. Wright, MD Associate Professor of Pediatrics, Case Western Reserve University School of Medicine; Associate Director, Pediatric Emergency Medicine, Rainbow Babies and Children’s Hospital/University Hospitals of Cleveland, Cleveland, Ohio Bites
Elaine Wyllie, MD Head, Section of Pediatric Neurology and Pediatric Epilepsy, Cleveland Clinic Foundation, Cleveland, Ohio Paroxysmal Disorders
Hepatomegaly
William J. Swift, MD Professor Emeritus of Child and Adolescent Psychiatry, University of Wisconsin Medical School and Wisconsin Psychiatric Institute and Clinic, Madison, Wisconsin; Regional Medical Officer and Psychiatrist, U.S. Department of State, Pretoria, South Africa Unusual Behaviors
Robert Wyllie, MD Chair, Department of Pediatric Gastroenterology, Cleveland Clinic Foundation, Cleveland, Ohio Constipation
Preface
Most children’s hospitals and pediatric residency training programs have multiple educational conferences, such as professor rounds, patient management conference, clinicopathologic conference, and senior resident intake rounds. In these high-quality learning activities, experienced master clinician-educators lead a discussion of a particular patient-based issue, permitting the trainees to see how a master clinician thinks through diagnostic or therapeutic challenges. The advice given is derived from the knowledge accumulated over many years of clinical experience and careful analysis of the medical literature. The synthesis of the facts of the case with the clinician’s practical experience and knowledge of the literature often results in the diagnosis and the appropriate treatment strategy. These master clinician-educators provide wisdom that gives clarity to confusing clinical cases and helps to reconcile discrepancies between practice and theory. In addition, master clinician-educators focus on the importance of a detailed history and a complete physical examination. The chief complaint directs the questioning during the history, whereas the physical examination focuses on clues obtained by the history. Laboratory and other studies are then employed to support the diagnosis, not to make the diagnosis. The goal of this book is to put into a written text the oral teaching rounds–based approaches toward clinical problem solving of the many expert clinician-educators who present at teaching conferences. The combination of clinical experience and evidenced-based strategies will provide guidance in developing a differential diagnosis, then a specific diagnosis, and finally the appropriate therapy of common pediatric problems. This book is arranged in chapters that cover specific chief complaints, mirroring clinical practice. Patients do not usually present with a chief complaint of cystic fibrosis; rather, they may present with a cough, respiratory distress, or chronic diarrhea.
This text is intended to help the reader begin with a specific chief complaint that may encompass many disease entities. In a userfriendly, well-tabulated, and illustrated approach, the text will help the reader differentiate between the many disease states causing a common chief complaint. The inclusion of many original tables and figures should help the reader identify distinguishing features of diseases and work through a diagnostic and/or therapeutic approach to the problem using decision trees. Modified, adapted, and borrowed artwork and tables from other outstanding sources have been added as well. The combination of all of these illustrations and tables will help provide a quick visual guide to the differential diagnosis or treatment of the various diseases under discussion. We greatly appreciate the hard work of our contributing authors. Writing a chapter in this type of format is quite different from writing in the format of a disease-based book. In addition, we greatly appreciate the efforts of Judy Fletcher of Elsevier, whose patience and expertise contributed to the publication of this book. We are all also greatly appreciative of Carolyn Redman of the Department of Pediatrics at the Medical College of Wisconsin, whose editorial assistance and organization has made this edition a reality. The authors also wish to make a special acknowledgment to Dr. Brendan M. Reilly, for his courtesy and assistance. Finally, we acknowledge the support and, at times, sacrifice of our families: Sharon, Jonathan, Rachel, Alison, and Matthew Kliegman; Jordan, Harry, and Irene Greenbaum; and Dale, Erin, John, and Therese Lye, whose understanding helped make the time and effort put into this book meaningful. ROBERT M. KLIEGMAN LARRY A. GREENBAUM PATRICIA S. LYE
1
Sore Throat
Robert R. Tanz Stanford T. Shulman
The enteroviruses (coxsackievirus and echovirus) can cause sore throat, especially in the summer. High fever is common, and the throat is slightly red; tonsillar exudate and cervical adenopathy are unusual. Symptoms resolve within a few days. Enteroviruses can
Sore throat is a common chief complaint. Each year approximately 20 million patients in the United States visit physicians because of throat complaints. The majority of these illnesses are nonbacterial and neither necessitate nor are alleviated by antibiotic therapy (Tables 1-1 to 1-3). Acute streptococcal pharyngitis, however, warrants accurate diagnosis and therapy to prevent serious suppurative and nonsuppurative complications. Furthermore, life-threatening infectious complications of streptococcal and nonstreptococcal oropharyngeal infections may manifest with mouth pain, pharyngitis, parapharyngeal space infectious extension, and airway obstruction (Tables 1-4 and 1-5).
Table 1-1. Etiology of Sore Throat
Infection Bacterial (see Tables 1-2, 1-3) Viral (see Tables 1-2, 1-3) Fungal (see Table 1-3) Neutropenic mucositis (invasive anaerobic mouth flora) Tonsillitis Epiglottitis Uvulitis Peritonsillar abscess (quinsy sore throat) Retropharyngeal abscess (prevertebral space) Ludwig angina (submandibular space) Lateral pharyngeal space cellulitis-abscess Buccal space cellulitis Suppurative thyroiditis Lemierre disease (septic jugular thrombophlebitis) Vincent angina (mixed anaerobic bacteria–gingivitis–pharyngitis)
VIRAL PHARYNGITIS Most episodes of pharyngitis are caused by viruses (see Tables 1-2 and 1-3). It is difficult to clinically distinguish between viral and bacterial pharyngitis with a very high degree of precision, but certain clues may help the physician. Accompanying symptoms of conjunctivitis, rhinitis, croup, or laryngitis are common with viral infection but rare in bacterial pharyngitis. Many viral agents can produce pharyngitis (see Tables 1-2 and 1-3). Some cause distinct clinical syndromes that are readily diagnosed without laboratory testing (see Tables 1-1, 1-4, and 1-6). In pharyngitis caused by parainfluenza and influenza viruses, rhinoviruses, coronaviruses, and respiratory syncytial virus (RSV), the symptoms of coryza and cough often overshadow sore throat, which is generally mild. Influenza virus may cause high fever, cough, headache, malaise, myalgias, and cervical adenopathy in addition to pharyngitis. In young children, croup or bronchiolitis may develop. RSV is associated with bronchiolitis, pneumonia, and croup in young children. RSV infection in older children is usually indistinguishable from a simple upper respiratory tract infection. Pharyngitis is not a prominent finding of RSV infection in either age group. Parainfluenza viruses are associated with croup and bronchiolitis; minor sore throat and signs of pharyngitis are common at the outset but rapidly resolve. Infections caused by parainfluenza, influenza, and RSV are often seen in seasonal (winter) epidemics. Adenoviruses can cause upper and lower respiratory tract disease, ranging from ordinary colds to severe pneumonia. The incubation period of adenovirus infection is 2 to 4 days. Upper respiratory tract infection typically produces fever, erythema of the pharynx, and follicular hyperplasia of the tonsils, together with exudate. Enlargement of the cervical lymph nodes occurs frequently. When conjunctivitis occurs in association with adenoviral pharyngitis, the resulting syndrome is called pharyngoconjunctival fever. Pharyngitis may last as long as 7 days and does not respond to antibiotics. There are many adenovirus serotypes; adenovirus infections may therefore develop in children more than once. Laboratory studies may reveal a leukocytosis and an elevated erythrocyte sedimentation rate. Outbreaks have been associated with swimming pools and contamination in health care workers.
Irritation Cigarette smoking Inhaled irritants Reflux esophagitis Chemical toxins (caustic agents) Paraquat ingestion Smog Dry hot air Hot foods, liquids Other Tumor, including Kaposi sarcoma, leukemia Wegener granulomatosis Sarcoidosis Glossopharyngeal neuralgia Foreign body Stylohyoid syndrome Behçet disease Kawasaki syndrome Posterior pharyngeal trauma—pseudodiverticulum Pneumomediastinum Hematoma Systemic lupus erythematosus Bullous pemphigoid Syndrome of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA)
3
Section One Respiratory Disorders
4
Table 1-2. Infectious Etiology of Pharyngitis
Definite Causes Streptococcus pyogenes (Group A streptococci) Corynebacterium diphtheriae Arcanobacterium haemolyticum Neisseria gonorrhoeae Epstein-Barr virus Parainfluenza viruses (types 1–4) Influenza viruses Rhinoviruses Coronavirus Adenovirus (types 3, 4, 7, 14, 21, others) Respiratory syncytial virus Herpes simplex virus (types 1, 2) Probable Causes Group C streptococci Group G streptococci Chlamydia pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae
cause meningitis, rash, and two specific syndromes that involve the oropharynx: Herpangina is characterized by distinctive discrete, painful, graywhite papulovesicular lesions distributed over the posterior oropharynx (Table 1-6). The vesicles are 1 to 2 mm in diameter and are initially surrounded by a halo of erythema before they ulcerate. Fever may reach 39.5°C. The illness generally
Table 1-3. Additional Potential Pathogens Associated
with Sore Throat Bacteria Fusobacterium necrophorum (Lemierre disease) Neisseria meningitidis Yersinia enterocolitica Tularemia (orpharyngeal) Yersinia pestis Bacillus anthracis Chlamydia psittaci Secondary syphilis Mycobacterium tuberculosis Lyme disease Corynebacterium ulcerans Leptospira species Mycoplasma hominis Virus Coxsackievirus A, B Cytomegalovirus Viral hemorrhagic fevers Human immunodeficiency virus (HIV) (primary infection) Human herpesvirus 6 Measles Varicella Rubella Fungus Candida species Histoplasmosis Cryptococcosis
lasts less than 7 days, but severe pain may impair fluid intake and necessitate medical support. Coxsackievirus A16 causes hand-foot-mouth disease. Vesicles can occur throughout the oropharynx; they are painful, and they ulcerate. Vesicles also develop on the palms, soles, and, less often, on the trunk or extremities. Fever is present in most cases, but many children do not appear seriously ill. This disease lasts less than 7 days. Primary infection caused by herpes simplex virus (HSV) usually produces high fever with acute gingivostomatitis, involving vesicles (which become ulcers) throughout the anterior portion of the mouth, including the lips. There is sparing of the posterior pharynx in herpes gingivostomatitis; the infection usually occurs in young children. High fever is common, pain is intense, and intake of oral fluids is often impaired, which may lead to dehydration. In addition, HSV may manifest in adolescents with pharyngitis. Approximately 35% of new-onset HSV-positive adolescent patients have herpetic lesions; most patients with HSV pharyngitis cannot be distinguished from patients with other causes of pharyngitis. The classic syndrome of herpetic gingivostomatitis in infants and toddlers lasts up to 2 weeks; data on the course of more benign HSV pharyngitis are lacking. The differential diagnosis of vesicular-ulcerating oral lesions is noted in Table 1-6. A common cause of a local and large lesion of unknown etiology is aphthous stomatitis (Fig. 1-1). Some children have a combination of periodic fever (recurrent at predictable fixed times), aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA); this syndrome is idiopathic and may respond to oral prednisone or cimetidine. PFAPA usually begins before the age of 5 years and is characterized by high fever lasting 4 to 6 days, occurring every 2 to 8 weeks, and resolving spontaneously. Infants and toddlers with measles often have prominent oral findings early in the course of the disease. In addition to high fever, cough, coryza, and conjunctivitis, the pharynx may be intensely and diffusely erythematous, without tonsillar enlargement or exudate. The presence of Koplik spots, the pathognomonic white or bluewhite enanthem of measles, on the buccal mucosa near the mandibular molars provides evidence of the correct diagnosis before the rash develops.
INFECTIOUS MONONUCLEOSIS PATHOGENESIS Acute exudative pharyngitis commonly occurs with infectious mononucleosis caused by primary infection with Epstein-Barr virus (EBV) (Table 1-7). Mononucleosis is a febrile, systemic, self-limited lymphoproliferative disorder that is usually associated with hepatosplenomegaly and generalized lymphadenopathy. The pharyngitis may be mild or severe, with significant tonsillar hypertrophy (possibly producing airway obstruction), erythema, and impressive tonsillar exudates. Regional lymph nodes may be particularly enlarged and slightly tender. Infectious mononucleosis usually occurs in adolescents and young adults; EBV infection is generally milder or subclinical in preadolescent children. In United States high school and college students, attack rates are 200 to 800 per 100,000 population per year. EBV is transmitted primarily by saliva. CLINICAL FEATURES After a 2- to 4-week incubation period, patients with infectious mononucleosis usually experience an abrupt onset of malaise, fatigue, fever, and headache, followed closely by pharyngitis. The tonsils are enlarged with exudates and cervical adenopathy. More generalized adenopathy with hepatosplenomegaly often follows. Fever and pharyngitis typically last 1 to 3 weeks, while lymphadenopathy and
Penicillin for abscess and cellulitis Aspiration for abscess (needle or I and D) Needle is preferred
Peptostreptococcus, Fusobacterium, Bacteroides (usually melaninogenicus).
Treatment
Staphylococcus aureus, oral anaerobes,† group A streptococci, “suppurative adenitis” Infancy, preteens, occasionally teens Fever, dyspnea, stridor, dysphagia, drooling, stiff neck, pain, cervical adenopathy, swelling of posterior pharyngeal space Descending mediastinitis (rare) Lateral neck radiograph reveals swollen retropharyngeal prevertebral space: infants, >1 × width of adjacent vertebral body (>2–7 mm); teens, > 1/3 × width of vertebral body (>1–7 mm) CT distinguishes cellulitis from abscess Airway management, nafcillin, ceftriaxone, ampicillinsulbactam Surgical drainage if an abscess
CT, computed tomography.
*Often odontogenic; check for tooth abscess, caries, tender teeth.
†
Teens
Age
Manifestations Initial episode of pharyngitis, followed by sudden worsening of unilateral odynophagia, trismus, hot potato (muffled) voice, drooling, displacement of uvula
Group A streptococci, oral anaerobes†
Etiology
Peritonsillar Abscess
Retropharyngeal Abscess (Cellulitis)
Airway management Penicillin, clindamycin, ampicillinsulbactam Rarely surgical drainage
Fever, dysphagia, odynophagia, stiff neck, dyspnea; airway obstruction, swollen tongue and floor of mouth (tender) Muffled voice
Teens
Oral anaerobes†
Submandibular Space (Ludwig Angina)*
Penicillin, clindamycin, ampicillinsulbactam Surgical drainage usually required
Severe pain, fever, trismus, dysphagia, edematous appearing, painful lateral facial (jaw) or neck swelling (induration) May lead to Lemierre disease
Teens
Oral anaerobes†
Lateral Pharyngeal Space*
Table 1-4. Distinguishing Features of Parapharyngeal–Upper Respiratory Tract Infections
Penicillin, clindamycin, ampicillinsulbactam
Pain, prominent trismus, fever Swelling not always evident
Teens
Oral anaerobes†
Masticator Space* Parainfluenza virus; influenza adeno-virus and respiratory syncytial virus less common 3 mo–3 yr
Airway management (intubation), ceftriaxone
Airway management (rare) Cool mist, racemic epinephrine, dexamethasone
Sudden-onset Low-grade fever, high fever, barking cough, “toxic ” hoarsenessappearance, aphonia, muffled voice, stridor; mild anxiety, pain, retractions; retractions, radiograph dysphagia, shows drooling, “steeple sign” stridor, sitting of subglottic up, leaning narrowing on forward tripod anteroposterior position, neck view cherry-red swollen epiglottis Usually not hoarse or coughing Lateral neck radiograph shows “thumb sign” of swollen epiglottis
2–5 yr
Haemophilus influenzae type b
Epiglottitis
Laryngotracheobronchitis (Croup)
Airway management (frequent intubation) Ceftriaxone with or without nafcillin
Prior history of croup with sudden onset of respiratory distress, high fever, “toxic” appearance, hoarseness, stridor, barking cough, tripod sitting position; radiograph as per croup plus ragged tracheal air column
Moraxella catarrhalis, S. aureus, H. influenzae type b or nontypable 3–10 yr
Bacterial Tracheitis
Clindamycin, penicillin, or cefoxitin
Prior pharyngitis with suddenonset fever, chills, odynophagia, neck pain, septic thrombophlebitis of internal jugular vein with septic emboli (e.g., lungs, joints), bacteremia
Teens
Fusobacterium necrophorum
Postanginal Sepsis* (Lemierre Disease)
Chapter 1 Sore Throat
5
Section One Respiratory Disorders
6
Table 1-5. “Red Flags” Associated with Sore Throat
Fever > 2 weeks Duration of sore throat > 2 weeks Trismus Drooling Cyanosis Hemorrhage Asymmetric tonsillar swelling or asymmetric cervical adenopathy Respiratory distress (airway obstruction or pneumonia) Suspicion of parapharyngeal space infection Suspicion of diphtheria (bull neck, uvula paralysis, thick membrane) Apnea Severe, unremitting pain “Hot potato” voice Chest or neck pain Weight loss
hepatosplenomegaly subside over 3 to 6 weeks. Malaise and lethargy can persist for several months, possibly leading to impaired school or work performance. DIAGNOSIS Laboratory studies of diagnostic value include atypical lymphocytosis; these lymphocytes are primarily EBV-specific, cytotoxic T lymphocytes that represent a reactive response to EBV-infected B lymphocytes. A modest elevation of serum transaminase levels, reflecting EBV hepatitis, is common. Tests useful for diagnosis include detection of heterophile antibodies that react with bovine erythrocytes (most often detected by the monospot test) and specific antibody against EBV viral capsid antigen (VCA), early antigen (EA), and nuclear antigen (EBNA). Acute infectious mononucleosis is usually associated with a positive heterophile test result and antibody to VCA and EA (Fig. 1-2). The findings of acute exudative pharyngitis together with hepatomegaly, splenomegaly, and generalized lymphadenopathy suggest infectious mononucleosis. Early in the disease and in cases without liver or spleen enlargement, differentiation from other causes of pharyngitis, including streptococcal pharyngitis, is difficult. Indeed, a small number of patients with infectious mononucleosis have a throat culture positive for group A streptococci. Serologic evidence of mononucleosis should be sought when splenomegaly or other features are present or if symptoms persist beyond 7 days. TREATMENT Patients with infectious mononucleosis require supportive treatment. Corticosteroids may be indicated for acute life-threatening conditions, such as airway obstruction caused by enlarged tonsils.
GROUP A STREPTOCOCCAL INFECTION In the evaluation of a patient with sore throat, the primary concern is usually accurate diagnosis and treatment of pharyngitis caused by group A streptococci, which accounts for about 15% of all episodes of pharyngitis. The sequelae of group A streptococcal pharyngitis, especially acute rheumatic fever and acute glomerulonephritis, at one time resulted in considerable morbidity and mortality in the United States and continue to do so in other parts of the world. Prevention of acute rheumatic fever in particular depends on timely diagnosis of streptococcal pharyngitis and prompt antibiotic treatment.
Group A streptococci are characterized by the presence of group A carbohydrate in the cell wall, and they are further distinguished by several kinds of cell wall protein antigens (M, R, T). These protein antigens are useful for studies of epidemiology and pathogenesis. EPIDEMIOLOGY Group A streptococcal pharyngitis has been endemic in the United States; epidemics occur sporadically. Episodes peak in the late winter and early spring; rates of group A streptococcal pharyngitis are highest among children aged 5 to 11 years old. Spread of group A streptococci in classrooms and among family members, especially in crowded living conditions, is common. Transmission occurs primarily by inhalation of organisms in large droplets or by direct contact with respiratory secretions. Pets do not appear to be a frequent reservoir. Untreated streptococcal pharyngitis is particularly contagious early in the acute illness and for the first 2 weeks after the organism has been acquired. Antibiotic therapy effectively prevents disease transmission. Within 24 hours of institution of therapy with penicillin, it is difficult to isolate group A streptococci from patients with acute streptococcal pharyngitis, and infected children can return to school. Molecular epidemiology studies of streptococcal pharyngitis have shown that numerous distinct strains of group A streptococci circulate simultaneously in the community during the peak season. “DNA-fingerprinting” techniques further demonstrate that children with streptococcal pharyngitis serve as a community reservoir for strains that cause invasive disease (e.g., sepsis, streptococcal toxic shock syndrome, cellulitis, necrotizing fasciitis) in the same geographic area and season. CLINICAL FEATURES The classic patient with acute streptococcal pharyngitis has a sudden onset of fever and sore throat. Headache, malaise, abdominal pain, nausea, and vomiting occur frequently. Cough, rhinorrhea, conjunctivitis, stridor, diarrhea, and hoarseness are distinctly unusual and suggest a viral etiology. Examination of the patient reveals marked pharyngeal erythema. Petechiae may be noted on the palate, but they can also occur in viral pharyngitis (see Table 1-7). Tonsils are enlarged, symmetric, and red, with patchy exudates on their surfaces. The papillae of the tongue may be red and swollen; hence the designation “strawberry tongue.” Anterior cervical lymph nodes are often tender and enlarged. Combinations of these signs can be used to assist in diagnosis; in particular, tonsillar exudates in association with fever, palatal petechiae, and tender anterior cervical adenitis strongly suggest infection with group A streptococci. However, other diseases can produce this constellation of findings. Some or all of these classic characteristics may be absent in patients with streptococcal pharyngitis. Younger children often have coryza with crusting below the nares, more generalized adenopathy, and a more chronic course, a syndrome called streptococcosis. When rash accompanies the illness, accurate clinical diagnosis is easier. Scarlet fever, so-called because of the characteristic fine, diffuse red rash, is essentially pathognomonic for infection with group A streptococci. Scarlet fever is rarely seen in children younger than 3 years old or in adults. SCARLET FEVER The rash of scarlet fever is caused by infection with a strain of group A streptococci that contains a bacteriophage encoding for production of an erythrogenic (redness-producing) toxin, usually erythrogenic (or pyrogenic) exotoxin A. Scarlet fever is simply group A streptococcal pharyngitis with a rash and should be explained as such to patients and their families. Although patients with the streptococcal
Ulcerative vesicles of pharynx, tongue, and palate plus lesions of mucocutaneous (perioral) margin Less than 5 yr
Fever, mouth pain, toxic, fetid breath, drooling, anorexia, cervical lymphadenopathy; cracked, swollen hemorrhagic gums; secondary inoculation possible (fingers, eye, skin); reactivation with long latency (any age)
Avoid dehydration; acyclovir if immunocompromised
Location
Manifestations
Treatment
Age
Herpes simplex virus (HSV) I
Etiology
Gingivostomatitis
Avoid dehydration; rarely, secondary aseptic meningitis or myocarditis
Fever, sore throat, odynophagia; summer outbreaks; 6–12 lesions (2 to 4 mm papule) → vesicle → ulceration; headache, myalgias
3–10 yr
Coxsackievirus A, B; echovirus or HSV (rarely) Anterior fauces (tonsils), soft palate (uvula), less often pharynx
Herpangina
Avoid dehydration;
Painful bilateral vesicles, fever
1 yr–teens
Coxsackievirus A, coxsackievirus B (rarely) Tongue, buccal mucosa, palate, palms, soles, anterior oral cavity
Hand-FootMouth Disease
Avoid dehydration, secondary infection; acyclovir if immunocompromised
Fever, pruritic cutaneous vesicles, painful oral lesions
Tongue, gingiva, buccal mucosa, marked cutaneous lesions; trunk > face Any age
Varicellazoster virus
Chickenpox
Table 1-6. Vesicular-Ulcerating Eruptions of the Mouth and Pharynx
Specific therapy for SLE
Renal, central nervous system, arthritis, cutaneous, hematologic, other organ involvement; ulcers minimally to moderately painful; may be painless
Any age
Oral, nasal mucosa; palate, pharynx, buccal mucosa
Unknown; autoimmune
Systemic Lupus Erythematosus (SLE)
Specific therapy for IBD
Multiple recurrences; painful ulcerations 1–2 mm, but may be 5–15 mm
Any age
Lips, tongue, buccal mucosa, oropharynx
Unknown; autoimmune
Inflammatory Bowel Disease (IBD)
Topical corticosteroids; must exclude SLE, IBD, human immunodeficiency virus (HIV), Behçet disease
Similar to IBD
Teens and adulthood
As in IBD
Unknown
Aphthous Stomatitis
Painful ulcerations (heal without scarring); uveitis, arthralgia, arthritis, lower gastrointestinal ulceration (similar to IBD); recurrences; spontaneous remissions Topical corticosteroids; oral (viscous) lidocaine
Teens, adulthood, occasionally 95%), with the throat culture used as the standard. Unfortunately, the sensitivity of most of these rapid tests can be considerably lower. In comparison to hospital or reference laboratory throat culture results, the sensitivities of these tests are generally 80% to 85% and can be lower. However, when both throat cultures and rapid tests performed in physicians’ offices are compared with cultures performed in reference laboratories,
Chapter 1 Sore Throat Table 1-8. Characteristics of Severe Invasive and/or
Toxigenic Group A Streptococcal Infection Positive Culture Sites Blood Soft tissue abscess Synovial fluid Throat Peritoneal fluid Surgical wound Cellulitis aspirate Clinical Manifestations Fever Toxic Shock* Confusion Headache Abdominal pain Vomiting Local extremity pain and swelling Hypesthesia Cellulitis Scarlatiniform rash (40%) Erythroderma (25%) Conjunctival injection Red pharynx Pneumonia with or without empyema Osteomyelitis Vaginitis Proctitis Desquamation Necrotizing fasciitis Diarrhea
9
Testing patients for serologic evidence of an antibody response to extracellular products of group A streptococci is not useful for diagnosing acute pharyngitis. Because it generally takes several weeks for antibody levels to rise, streptococcal antibody tests are valid only for determining past infection. Specific antibodies include antistreptolysin O (ASO), anti-DNase B, and antihyaluronidase (AHT). When antibody testing is desired in order to evaluate a possible post-streptococcal illness, more than one of these tests should be performed to improve sensitivity. TREATMENT
Laboratory Manifestations Leukocytosis Lymphopenia Thrombocytopenia Hyponatremia Hypoalbuminemia Hyperbilirubinemia (direct) Elevated AST, ALT, BUN Renal sediment abnormalities Coagulopathy Hypoxia
*Case definition of streptococcal toxic shock syndrome requires (I) isolation of group A streptococci from (a) a normally sterile site (blood, synovial or peritoneal fluid) or (b) a nonsterile site (throat, wound). (II) Severity is defined by (a) hypotension and (b) two or more of renal impairment, coagulopathy, liver involvement, adult respiratory distress syndrome, a generalized erythematous macular rash (with or without later desquamation), and soft tissue necrosis (necrotizing fasciitis, myositis, gangrene). The definitive diagnosis requires criteria IA and IIA plus B. Criteria IB and IIA plus B are considered probable if no other identifiable cause is present. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen.
the sensitivities, specificities, and overall accuracy of the office culture and the office rapid test are quite similar; the latter often performs better than the culture. The low sensitivity of these tests, coupled with their excellent specificity, has led to the recommendation that two swabs be obtained from patients with suspected streptococcal pharyngitis. One swab is used for a rapid test. When the rapid antigen detection test result is positive, it is highly likely that the patient has group A streptococcal infection, and the extra swab can be discarded. When the rapid test result is negative, group A streptococci may nonetheless be present; thus, the extra swab should be processed for culture. Physician offices that have demonstrated that their rapid test and throat culture results are comparable may be able to rely on the rapid test result even when it is negative, without performing a backup culture. In general, patients with a negative result of the rapid test do not require treatment before culture verification unless there is a particularly high suspicion group A streptococcal infection (e.g., scarlet fever, peritonsillar abscess, or tonsillar exudates in addition to tender cervical adenopathy, palatal petechiae, fever, and recent exposure to a person with group A streptococcal pharyngitis).
Treatment begun within 9 days of the onset of group A streptococcal pharyngitis is effective in preventing acute rheumatic fever. Therapy does not appear to affect the risk of the other nonsuppurative sequela, acute post-streptococcal glomerulonephritis. Antibiotic therapy also reduces the incidence of suppurative sequelae of group A streptococcal pharyngitis, such as peritonsillar abscess and cervical adenitis. In addition, treatment produces a more rapid resolution of signs and symptoms and terminates contagiousness within 24 hours. For these reasons, antibiotics should be instituted as soon as the diagnosis is supported by laboratory studies. There are numerous antibiotics available for treating streptococcal pharyngitis (Table 1-10). The drug of choice is penicillin. Despite the widespread use of penicillin to treat streptococcal and other infections, penicillin resistance among group A streptococci has not developed. Penicillin can be given by mouth for 10 days or intramuscularly as a single injection of benzathine penicillin. Intramuscular benzathine penicillin alleviates concern with patient compliance. A less painful alternative is benzathine penicillin in combination with procaine penicillin. Intramuscular procaine penicillin alone is inadequate for prevention of acute rheumatic fever because adequate levels of penicillin are not present in blood and tissues for a sufficient time. Other β-lactams, including semisynthetic derivatives of penicillin and the cephalosporins, are at least as effective as penicillin for treating group A streptococcal pharyngitis. Their broader spectrum, their higher cost, and the lack of formal data concerning prevention of acute rheumatic fever relegate them to second-line status. The decreased frequency of dose administration of some of these agents may improve patient compliance and makes their use attractive in selected circumstances. Patients who are allergic to penicillin should receive erythromycin or another non–β-lactam antibiotic, such as clarithromycin, azithromycin, or clindamycin. Resistance of group A streptococci to erythromycin has increased dramatically in areas such as Japan, France, Spain, Taiwan, and Finland, where erythromycin has been widely used. This has not yet emerged as a major problem in the United States, where the rate of macrolide resistance is about 5%. Sulfa drugs (including sulfamethoxazole combined with trimethoprim), tetracyclines, and chloramphenicol should not be used for treatment of acute streptococcal pharyngitis because they do not eradicate group A streptococci. COMPLICATIONS Suppurative Complications Antibiotic therapy has greatly reduced the likelihood of developing suppurative complications caused by spread of group A streptococci from the pharynx or middle ear to adjacent structures. Peritonsillar abscess (“quinsy”) manifests with fever, severe throat pain, dysphagia, “hot potato voice,” pain referred to the ear, and bulging of the peritonsillar area with asymmetry of the tonsils and sometimes displacement of the uvula (Fig. 1-4; see Table 1-4). On occasion, there is peritonsillar cellulitis without a well-defined abscess cavity. Trismus may be present. When an abscess is found clinically or by an imaging study such as a computed tomographic scan, surgical drainage is indicated. Peritonsillar abscess occurs most commonly in older children and adolescents.
Section One Respiratory Disorders
10
Table 1-9. Differential Diagnosis of Scarlet Fever Scarlet Fever
Kawasaki Disease
Measles
Agent
Group A streptococci
Unknown
Measles virus
Age range
All (peak, 5–15 yr)
Usually 1.5 cm); thrombocytosis; pyuria (sterile); gallbladder hydrops
Fever, coryza cough, conjunctivitis Koplik spots Diffusely red, no cracked lips
Rash
Other
Cervical adenitis, gallbladder hydrops, fever
Retropharyngeal abscess represents extension of infection from the pharynx or peritonsillar region into the retropharyngeal (prevertebral) space, which is rich in lymphoid structures (Figs. 1-5 and 1-6; see Table 1-4). Children younger than 4 years old are most often affected. Fever, dysphagia, drooling, stridor, extension of the neck, and a mass in the posterior pharyngeal wall may be noted. Surgical drainage is often required if frank suppuration has occurred. Spread of group A streptococci via pharyngeal lymphatic vessels to regional nodes can cause cervical lymphadenitis. The markedly swollen and tender anterior cervical nodes that result can suppurate. Otitis media, mastoiditis, and sinusitis also may occur as complications of group A streptococcal pharyngitis. Additional parapharyngeal suppurative infections that may mimic streptococcal disease are noted in Table 1-4. Furthermore, any pharyngeal infectious process may produce torticollis if there is inflammation that extends to the paraspinal muscles and ligaments, producing pain, spasm, and, on occasion, rotary subluxation of the cervical spine. The differential diagnosis of torticollis is presented in Table 1-11. Oropharyngeal torticollis lasts less than 2 weeks and is not associated with abnormal neurologic signs or pain over the spinous process. Nonsuppurative Sequelae Nonsuppurative complications include acute rheumatic fever (see Chapters 11 and 44), acute post-streptococcal glomerulonephritis (see Chapter 25), and possibly reactive arthritis/synovitis. In addition, an association between streptococcal infection and neuropsychiatric disorders such as obsessive-compulsive disorder and Tourette syndrome has been postulated. This possible association has been called PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci). Therapy with an appropriate antibiotic within 9 days of onset of symptoms is highly effective in
Staphylococcal Toxic Shock Syndrome
Staphylococcal Scalded Skin Syndrome
Staphylococcus aureus All (especially > 10 yr) Usually no
S. aureus Usually < 5yr
No Usually normal
Limited Erythema
Maculopapular; progressing from forehead to feet; may desquamate
Diffuse erythroderma; desquamates
Erythema, painful bullous lesions; positive Nikolsky sign; desquamates
“Toxic” appearance; dehydration; encephalitis, pneumonia; fever
Shock (hypotension, including orthostatic); encephalopathy; diarrhea; headache
Fever, cracked lips; conjunctivitis
No
preventing rheumatic fever, but acute glomerulonephritis is not prevented by treatment of the antecedent streptococcal infection. Pharyngitis caused by one of the nephritogenic strains of group A streptococci precedes the glomerulonephritis by about 10 days. Unlike acute rheumatic fever, which occurs only after group A streptococcal pharyngitis, acute glomerulonephritis also can follow group A streptococcal skin infection. TREATMENT FAILURE AND CHRONIC CARRIAGE Treatment with penicillin cures group A streptococcal pharyngitis but is unable to eradicate group A streptococci from the pharynx in approximately 25% of patients (Fig. 1-7). This causes considerable consternation among such patients and their families. Penicillin resistance is not the cause of treatment failure. A small proportion of these patients are symptomatic and are thus characterized as having clinical treatment failure. Reinfection with the same strain or a different strain is possible, as is intercurrent viral pharyngitis. Some of these patients may be chronic pharyngeal carriers of group A streptococci who are suffering from a new superimposed viral infection; others may be noncompliant with regard to therapy. Many patients who do not respond to antimicrobial treatment are asymptomatic and are identified when follow-up culture specimens are obtained, a practice that is usually unnecessary. Patients who are compliant with regard to therapy are at minimal risk for acute rheumatic fever. One explanation for asymptomatic persistence of group A streptococci after treatment is that these patients were chronic carriers of group A streptococci who were initially symptomatic because of a concurrent viral pharyngitis and who did not truly have acute streptococcal pharyngitis. Patients who are chronically colonized with group A streptococci are called chronic carriers. Carriers do not appear to be at risk for acute
Chapter 1 Sore Throat Signs and Symptoms Compatible with GAS Yes
No
Viral pharyngitis Symptomatic therapy (No antibiotics)
Scarlet fever? Yes GAS pharyngitis
No
Rapid test Positive Negative
Confirm with rapid test or throat culture; Treat with antibiotics
Not GAS pharyngitis
Throat culture
Negative
Positive
GAS pharyngitis
Treat with antibiotics
GAS pharyngitis
Sore throat persists ≥7 days?
Positive 1) Repeat throat culture 2) Mono test Negative
Viral pharyngitis
Intramuscular benzathine penicillin plus oral rifampin (10 mg/kg/ dose up to 300 mg, given twice daily for 4 days beginning on the day of the penicillin injection) ● Oral clindamycin, given for 10 days (20 mg/kg/day up to 450 mg, divided into three equal doses) Clindamycin may be preferred because it is easier to use than intramuscular penicillin plus oral rifampin and may be somewhat more effective. In controlled, comparative trials, no other antibiotic regimens have been demonstrated to reliably terminate the chronic streptococcal carrier state. Successful eradication of the carrier state makes evaluation of subsequent episodes of pharyngitis much easier, although chronic carriage can recur upon reexposure to group A streptococci. RECURRENT ACUTE PHARYNGITIS
Yes
Negative
Available treatment options for the physician faced with a chronic streptococcal carrier include the following: 1. Obtaining a rapid test, throat culture, or both each time the patient has pharyngitis with features that suggest streptococcal pharyngitis, and treating with penicillin each time a test is positive. 2. Treating with one of the regimens effective for terminating chronic carriage. The first option is simple, as safe as penicillin, and appropriate for many patients. The second option should be reserved for particularly anxious patients; those with a history of acute rheumatic fever or living with someone who had it; or those living or working in nursing homes, chronic care facilities, hospitals, and perhaps schools. The two antibiotic treatment regimens that have been effective for eradication of the carrier state are: ●
Viral pharyngitis Symptomatic therapy (No antibiotics)
No
11
Positive
Viral pharyngitis Symptomatic therapy (No antibiotics)
Mononucleosis
No antibiotics Figure 1-3. Management of patients with sore throat. GAS, group A streptococci.
rheumatic fever or for development of suppurative complications, and they are rarely sources of spread of group A streptococci in the community. There is no reason to exclude these carriers from school. There is no easy way to identify chronic carriers prospectively among patients with symptoms of acute pharyngitis. The clinician should consider the possibility of chronic group A streptococcal carriage when a patient or a family member has multiple culturepositive episodes of pharyngitis, especially when symptoms are mild or atypical. A culture specimen is usually positive for group A streptococci when the suspected carrier is symptom-free or is receiving treatment with penicillin (intramuscular benzathine penicillin is recommended in order to eliminate concern about compliance). Carriers often receive multiple unsuccessful courses of antibiotic therapy in attempts to eliminate group A streptococci. Physician and patient anxiety is common and can develop into “streptophobia.” Unproven and ineffective therapies include tonsillectomy, prolonged administration of antibiotics, use of β-lactamase–resistant antibiotics, and culture or treatment of pets.
Some patients seem remarkably susceptible to group A streptococci. The reasons for frequent bona fide acute group A streptococcal pharyngitis are obscure, but appropriate antibiotic treatment results in resolution of symptoms and eradication of group A streptococci. The role of tonsillectomy in the management of patients with multiple episodes of streptococcal pharyngitis is controversial. Fewer episodes of sore throat have been reported among patients treated with tonsillectomy (in contrast to patients treated without surgery) during the first 2 years after operation. The patients enrolled in that study had experienced numerous episodes of pharyngitis, but it appears that not all episodes were caused by group A streptococci. Of particular concern is the reported tonsillectomy complication rate of 14% and the improvement over time noted among the nontonsillectomy patients. In addition, the presence of tonsils is not necessary for group A streptococci to infect the throat. Tonsillectomy cannot be recommended except in unusual circumstances. It seems preferable to treat most patients with penicillin whenever symptomatic group A streptococcal pharyngitis occurs. Obtaining follow-up throat specimens for culture helps distinguish recurrent pharyngitis from chronic carriage.
NON–GROUP A STREPTOCOCCAL INFECTION Certain β−hemolytic streptococci of serogroups other than group A cause acute pharyngitis. Well-documented epidemics of food-borne group C and group G streptococcal pharyngitis have been reported in young adults. In these situations, a high percentage of individuals who have ingested the contaminated food promptly developed acute pharyngitis, and throat cultures yielded virtually pure growth of the epidemiologically linked organism. There have been outbreaks of group G streptococcal pharyngitis among children. However, the role of these non–group A streptococcal organisms as etiologic agents of acute pharyngitis in endemic circumstances has been difficult to establish. Group C and group G β streptococci may be responsible for acute pharyngitis, particularly in adolescents.
Section One Respiratory Disorders
12
Table 1-10. Treatment Regimens for Acute Streptococcal Pharyngitis Children
Standard Penicillin V Benzathine penicillin G Amoxicillin
250 mg 600,000 U (weight < 27 kg) 125 mg (weight < 15 kg)
Adolescents/Adults
500 mg 1.2 million U (weight ≥ 27 kg) 250 mg (weight ≥ 15 kg)
Frequency
Route
Duration
bid-tid Once tid
Oral IM Oral
10 days Once 10 days
Penicillin-Allergic Patients Oral Dose
Erythromycin Ethylsuccinate Estolate Clarithromycin Azithromycin* Clindamycin Cephalosporins†
40 mg/kg/day up to 1000 mg/day 20-40 mg/kg/day up to 1000 mg/day 15 mg/kg/day up to 500 mg/day 12 mg/kg/day 10-25 mg/kg/day up to 450 mg/day Varies with agent chosen
Frequency
Duration
bid bid bid Once daily tid
10 days 10 days 10 days 5 days 10 days 10 days
Frequency
Duration
Once daily Once daily Once daily Once daily Once daily Once daily bid bid bid
5 days 10 days 10 days 10 days 10 days 10 days 5 days 5 days 4 or 5 days
Once Daily and Short Duration Treatment Schedules Oral Dose
Azithromycin* Amoxicillin‡ Cefadroxil Cefixime Cefdinir Ceftibuten Cefpodoxime Cefdinir Cefuroxime‡ *
12 mg/kg 50 mg/kg up to 750 mg 30 mg/kg up to 1000 mg 8 mg/kg up to 400 mg 14 mg/kg up to 600 mg 9 mg/kg up to 400 mg 10 mg/kg/day up to 200 mg/day 14 mg/kg/day up to 600 mg/day 20 mg/kg/day up to 500 mg/day
Maximum dose for children is 500 mg/day. Adult dosage: 500 mg the first day, 250 mg the subsequent 4 days.
†
First-generation cephalosporins (e.g., cephalexin, cefadroxil) are preferred; dosage and frequency vary among agents. Avoid use in patients with history of immediate (anaphylactic) hypersensitivity to penicillin or other beta-lactam antibiotics.
‡
Not approved by the U.S. Food and Drug Administration for use in this manner.
From Tanz RR, Shulman ST: Pharyngitis. In Long SS, Pickering LK, Prober CG (eds): Principles and Practice of Pediatric Infectious Diseases. New York, Churchill Livingstone, 1997, p 204.
However, the exact role of these agents, most of which are carried asymptomatically in the pharynx of some children and young adults, remains to be fully characterized. When they are implicated as agents of acute pharyngitis, groups C and G organisms do not appear to necessitate treatment, inasmuch as they cause self-limited infections. Acute rheumatic fever is not a sequela to these infections, although post-streptococcal acute glomerulonephritis has been documented in rare cases after epidemic group C and group G streptococcal pharyngitis.
ARCANOBACTERIUM INFECTION
Figure 1-4. Peritonsillar abscess (quinsy, sore throat). The left tonsil is asymmetrically inflamed and swollen; there is displacement of the uvula to the opposite side. The supratonsillar space (arrow) is also swollen; this is the usual site of the surgical incision for drainage. Prominent unilateral cervical adenopathy typically coexists. (From Reilly BM: Sore throat. In Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia: WB Saunders, 1991.)
Arcanobacterium (formerly Corynebacterium) haemolyticum is a gram-positive rod that has been reported to cause a scarlet fever–like illness with acute pharyngitis and scarlatinal rash, particularly in teenagers and young adults. Detecting this agent requires special methods for culture, and it has not routinely been sought in patients with scarlet fever or pharyngitis. The clinical features of A. haemolyticum pharyngitis are indistinguishable from group A streptococcal pharyngitis; pharyngeal erythema is present in almost all patients, patchy white to gray exudates in about 70%, cervical adenitis in about 50%, and moderate fever in 40%. Palatal petechiae and strawberry tongue may also occur. The scarlatiniform rash usually spares the face, palms, or soles. It is erythematous and blanches; it may be pruritic and demonstrate minimal desquamation. Erythromycin appears to be the treatment of choice.
Chapter 1 Sore Throat
A
13
B
Figure 1-5. Retropharyngeal abscess. A, Lateral neck radiograph shows marked increased soft tissue (arrow) between the upper airway and cervical spine. B, Axial computed tomographic scan shows the lower attenuation center of the abscess (A), the anterior and leftward shift of the trachea (T), and the soft tissue mass (M) of abscess and surrounding edema. (Courtesy of A. Oestreich, M.D., Cincinnati, Ohio.)
DIPHTHERIA Diphtheria is a very serious disease that is caused by pharyngeal infection by toxigenic strains of Corynebacterium diphtheriae. It has become very rare in the United States and other developed countries as a result of immunization. The handful of diphtheria cases recognized annually in the United States usually occur in unimmunized individuals, and the fatality rate is about 5%. A relatively large outbreak
of diphtheria in the former Soviet Union has been recorded (1990 to 1995), and infection has been documented in several travelers from Western Europe. PATHOGENESIS The pathogenesis of diphtheria involves nasopharyngeal mucosal colonization by C. diphtheriae and toxin elaboration after an incubation period of 1 to 5 days. Toxin leads to local tissue inflammation and necrosis (producing an adherent grayish membrane made up of fibrin, blood, inflammatory cells, and epithelial cells) and it is absorbed into the blood stream. Fragment B of the polypeptide toxin binds particularly well to cardiac, neural, and renal cells, and the smaller fragment A enters cells and interferes with protein synthesis. Toxin fixation by tissues may lead to fatal myocarditis (with arrhythmias) within 10 to 14 days and to peripheral neuritis within 3 to 7 weeks. CLINICAL FEATURES
Figure 1-6. In a teenager, the retropharyngeal space normally does not exceed 7 mm when measured from the anterior aspect of the C2 vertebral body to the posterior pharynx. In infants, the retropharyngeal space is usually less than one width of the adjacent vertebral body. However, during crying, this distance may be three widths of the vertebral body. Also, under normal circumstances, the retrotracheal space does not exceed 22 mm in teenagers when measured from the anterior aspect of C- 6 to the trachea. Dotted lines depict the “thumbprint” sign, noted on a lateral neck radiograph, made by a swollen epiglottis. (From Reilly BM: Sore throat. In Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia: WB Saunders, 1991.)
Acute tonsillar and pharyngeal diphtheria is characterized by anorexia, malaise, low-grade fever, and sore throat. The grayish membrane forms within 1 to 2 days over the tonsils and pharyngeal walls and occasionally extends into the larynx and trachea. Cervical adenopathy varies but may be associated with development of a “bull neck.” In mild cases, the membrane sloughs after 7 to 10 days and the patient recovers. In severe cases, an increasingly toxic appearance can lead to prostration, stupor, coma, and death within 6 to 10 days. Distinctive features include palatal paralysis, laryngeal paralysis, ocular palsies, diaphragmatic palsy, and myocarditis. Airway obstruction (from membrane formation) may complicate the toxigenic manifestations. DIAGNOSIS AND TREATMENT Accurate diagnosis requires isolation of C. diphtheriae on culture of material from beneath the membrane, with confirmation of toxin production by the organism isolated. Laboratories must be forewarned that diphtheria is suspected. Other tests are of little value. Treatment includes equine antitoxin to neutralize circulating toxin, as well as systemic penicillin or erythromycin.
Section One Respiratory Disorders
14
Signs and Symptoms of bona fide Acute GAS Pharyngitis
Table 1-11. Differential Diagnosis of Torticollis
(Wryneck) Congenital Muscular torticollis Positional deformation Hemivertebra (cervicosuperior dorsal spine) Unilateral atlanto-occipital fusion Klippel-Feil syndrome Unilateral absence of sternocleidomastoid Pterygium colli Trauma Muscular injury (cervical muscles) Atlanto-occipital subluxation Atlantoaxial subluxation C2–C3 subluxation Rotary subluxation Fractures Inflammation Cervical lymphadenitis Retropharyngeal abscess Cervical vertebral osteomyelitis Rheumatoid arthritis Spontaneous (hyperemia, edema) subluxation with adjacent head and neck infection (rotary subluxation syndrome) Upper lobe pneumonia Neurologic Visual disturbances (nystagmus, superior oblique paresis) Dystonic drug reactions (phenothiazines, haloperidol, metoclopramide) Cervical cord tumor Posterior fossa brain tumor Syringomyelia Wilson disease Dystonia musculorum deformans Spasmus nutans Other Acute cervical disk calcification Sandifer syndrome (gastroesophageal reflux, hiatal hernia) Benign paroxysmal torticollis Bone tumors (eosinophilic granuloma) Soft-tissue tumor Hysteria From Behrman RE (ed): Nelson Textbook of Pediatrics; 14th ed. Philadelphia: WB Saunders, 1992, p 1718.
GONOCOCCAL PHARYNGITIS Acute symptomatic pharyngitis caused by Neisseria gonorrhoeae occurs occasionally in sexually active individuals as a consequence of oral-genital contact. In cases involving young children, sexual abuse must be suspected. The infection usually manifests as an ulcerative, exudative tonsillopharyngitis but may be asymptomatic and resolve spontaneously. Gonococcal pharyngitis occurs in homosexual men and heterosexual women after fellatio and is less readily acquired after cunnilingus. Gonorrhea rarely is transmitted from the pharynx to a sex partner, but pharyngitis can serve as a source for gonococcemia. Diagnosis requires culture on appropriate selective media (e.g., Thayer-Martin medium). Recommended therapeutic regimens include a single intramuscular dose of 125 mg of ceftriaxone or a single oral 500-mg dose of ciprofloxacin. Spectinomycin is ineffective
No
Yes
Probable GAS carrier
Recurrent pharyngitis
Special situation? Family or physician overly concerned?
No
Evaluate and treat each symptomatic episode individually
Yes
Throat culture
Negative
Positive
GAS carrier
Antibiotic treatment (optional) 1. Oral clindamycin or 2. IM benzathine penicillin plus oral rifampin
Figure 1-7. Management of patients with repeated or frequent positive rapid tests or throat cultures. GAS, group A streptococci; IM, intramuscular.
Table 1-12. Spectrum of Mycoplasma Pneumoniae
Infection Common Primary atypical pneumonia* (with or without pleural effusion) Pharyngitis Tracheobronchitis Less Common Wheezing Rhinitis Bullous myringitis Otitis media Myocarditis Pericarditis Meningoencephalitis—aseptic meningitis Polyneuritis—Guillain-Barré syndrome Transverse myelitis Sinusitis Erythema multiforme—Stevens Johnson syndrome Erythema nodosum Urticaria Intravascular hemolysis (high-titer cold agglutinins) Arthralgia *Manifestations during pneumonia include sore throat, hoarseness, malaise, headache, cough, earache, chills, and fever >102°F (38.9°C). Less often there may be coryza, rash, pleuritis, diarrhea, or leukocytosis > 10,000/mm3.
Chapter 1 Sore Throat in gonococcal pharyngitis. Examination and testing for other sexually transmitted diseases and pregnancy are recommended.
CHLAMYDIAL AND MYCOPLASMAL INFECTIONS Chlamydia species and Mycoplasma pneumoniae may cause pharyngitis, although the frequency of these infections is disputed. Chlamydia trachomatis has been implicated serologically as a cause of pharyngitis in as many as 20% of adults with pharyngitis, but isolation of the organism from the pharynx has proved more difficult. Chlamydia pneumoniae has also been identified as a cause of pharyngitis. Because antibodies to this organism show some crossreaction with C. trachomatis, it is possible that infections formerly attributed to C. trachomatis were really caused by C. pneumoniae. Diagnosis of chlamydial pharyngitis is difficult, whether by culture or serologically, and neither method is readily available to the clinician. M. pneumoniae most likely causes pharyngitis. Serologic (positive mycoplasma immunoglobulin M [IgM]) or, less often, culture methods can be used to identify this agent, which was found in 33% of college students with pharyngitis in one study. Polymerase chain reaction (PCR) is diagnostic. There is no need to seek evidence of these organisms routinely in pharyngitis patients in the absence of ongoing research studies of nonstreptococcal pharyngitis. The efficacy of antibiotic treatment for M. pneumoniae and chlamydial pharyngitis is not known, but these illnesses appear to be self-limited. Treatment of more complicated M. pneumoniae infections, such as pneumonia (Table 1-12), is indicated with erythromycin, azithromycin, or clarithromycin; doxycycline may be used if the patient is older than 10 years. REFERENCES Group A Streptococci Attia MW, Zaoutis T, Klein JD, et al: Performance of a predictive model for streptococcal pharyngitis in children. Arch Pediatr Adolesc Med 2001; 155:687-691. Bisno AL: Group A streptococcal infections and acute rheumatic fever. N Engl J Med 1991;325:783-793. Bisno AL: Acute pharyngitis. N Engl J Med 2001;344:205-211. Gerber MA, Tanz RR, Kabat W, et al: Optical immunoassay test for Group A ß-hemolytic streptococcal pharyngitis: An office-based, multicenter investigation. JAMA 1997;277:899-903. Gerber MA, Tanz RR, Kabat W, et al: Potential mechanisms for failure to eradicate group A streptococci from the pharynx. Pediatrics 1999;104:911-917. Hoge CW, Schwartz B, Talkington DF, et al.: The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome: A retrospective populationbased study. JAMA 1993;269:384-389. Podbielski A, Kreikemeyer B: Persistence of group A streptococci in eukaryotic cells—A safe place? Lancet 2001;358:3. Tanz RR, Gerber MA, Shulman ST: What is a throat culture? Adv Exp Med Biol 1997;418:29-33. Tanz RR, Shulman ST: Streptococcal pharyngitis: The carrier state, definition and management. Pediatric Annals 1998;27:281-285. Torres-Martinez C, Mehta D, Butt A, et al: Streptococcus associated toxic shock. Arch Dis Child 1992;67:126-130. Veasy LG, Tani LY, Hill HR: Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr 1994;124:9-16. Wheeler MC, Roe MH, Kaplan EL, et al: Outbreak of group A streptococcus septicemia in children: Clinical, epidemiologic, and microbiological correlates. JAMA 1991;266:533-537. Working Group on Severe Streptococcal Infections: Defining the group A streptococcal toxic shock syndrome: Rationale and consensus definition. JAMA 1993;269:390-391.
15 Other Pathogens
Gerber MA, Randolph MF, Martin NJ, et al: Community-wide outbreak of group G streptococcal pharyngitis. Pediatrics 1991;87:598-603. Feder HM Jr: Periodic fever, aphthous stomatitis, pharyngitis, adenitis: a clinical review of a new syndrome. Curr Opin Pediatr 2000;12:253-256. Karpathios T, Drakonaki S, Zervoudaki A, et al: Arcanobacterium haemolyticum in children with presumed streptococcal pharyngotonsillitis or scarlet fever. J Pediatr 1992;121:735-737. Komaroff AL, Branch WT, Aronson MD, et al: Chlamydial pharyngitis. Ann Intern Med 1989;111:537-538. Lajo A, Borque C, Del Castillo F, et al: Mononucleosis caused by Epstein-Barr virus and cytomegalovirus in children: A comparative study of 124 cases. Pediatr Infect Dis J 1994;13:56-60. McMillan JA, Weiner LB, Higgins AM, et al: Pharyngitis associated with herpes simplex virus in college students. Pediatr Infect Dis J 1993; 12:280-284. Nakayama M, Miyazaki C, Ueda K, et al: Pharyngoconjunctival fever caused by adenovirus type 11. Pediatr Infect Dis J 1992;11:6-9. Straus SE, Cohen JI, Tosato G, et al: Epstein-Barr virus infections: Biology, pathogenesis, and management. Ann Intern Med 1993;118:45-58. Sumaya CV, Ench Y: Epstein-Barr virus infectious mononucleosis in children: I. Clinical and general laboratory findings. Pediatrics 1985;75 1003-1010. Sumaya CV, Ench Y: Epstein-Barr virus infectious mononucleosis in children: II. Heterophil antibody and viral-specific responses. Pediatrics 1985;75:1011-1019. Waagner DC: Arcanobacterium haemolyticum: Biology of the organism and diseases in man. Pediatr Infect Dis J 1991;10:933-939. Complications Chow AW: Life-threatening infections of the head and neck. Clin Infect Dis 1992;14:991-1004. de Marie S, Tham RT, van der Mey AGL, et al: Clinical infections and nonsurgical treatment of parapharyngeal space infections complicating throat infection. Rev Infect Dis 1989;11:975-982. Fiesseler FW, Riggs RL: Pharyngitis followed by hypoxia and sepsis: Lemierre syndrome. Am J Emerg Med 2001;19:320-322. Savolainen S, Jousimies-Somer HR, Makitie AA, et al: Peritonsillar abscess: Clinical and microbiologic aspects and treatment regimens. Arch Otolaryngol Head Neck Surg 1993;119:521-524. Wald ER, Guerra N, Byers C: Upper respiratory tract infections in young children: Duration of and frequency of complications. Pediatrics 1991; 87:129-133. White B: Deep neck infections and respiratory distress in children. Ear Nose Throat J 1985;64:30-38. Treatment Gerber MA, Tanz RR: New approaches to the treatment of group A streptococcal pharyngitis. Curr Opin Pediatr 2001;13:51-55. Markowitz M, Gerber MA, Kaplan EL: Treatment of streptococcal pharyngotonsillitis: Reports of penicillin’s demise are premature. J Pediatr 1993;123:679-685. Massel BF, Chute CG, Walker AM, et al: Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. N Engl J Med 1988;318:280-286. Paradise JL, Bluestone CD, Bachman RZ, et al: Efficacy of tonsillectomy for recurrent throat infection in severely affected children: Results of parallel randomized and nonrandomized clinical trials. N Engl J Med 1984; 310:674-683. Randolph MF, Gerber MA, DeMeo KK, et al: Effect of antibiotic therapy on the clinical course of streptococcal pharyngitis. J Pediatr 1985;106: 870-875. Seppala H, Nissinen A, Jarvinen H, et al: Resistance to erythromycin in group A streptococci. N Engl J Med 1992;326:292-297. Shulman ST, Gerber MA, Tanz RR, et al: Streptococcal pharyngitis: The case for penicillin therapy. Pediatr Infect Dis J 1994;13:1-7. Snellman LW, Stang HJ, Stang JM, et al: Duration of positive throat cultures for group A streptococci after initiation of antibiotic therapy. Pediatrics 1993;91:116-117. Tanz RR, Poncher JR, Corydon KE, et al: Clindamycin treatment of chronic pharyngeal carriers of group A streptococci. J Pediatr 1991;119:123-128.
2
Cough
William M. Gershan*
or inhaled drugs. Socioeconomic factors must be considered; a family that cannot afford central heating may use a smoky woodburning stove; spending time at a day care center may expose an infant to respiratory viruses; and several adult smokers in a small home expose children to a high concentration of respiratory irritants.
Cough is an important defense mechanism of the lungs and is a common symptom, particularly during winter months. In most patients, it is self-limited. However, cough can be ominous, indicating serious underlying disease, because of accompanying problems (hemoptysis) or because of serious consequences of the cough itself (e.g., syncope and hemorrhage).
CHARACTERISTICS OF THE COUGH
PATHOPHYSIOLOGY OF COUGH
The various cough characteristics can help determine the cause of cough. The causes of acute, recurrent, and chronic coughs may be quite different from each other (Fig. 2-2; see Table 2-1). A cough can be paroxysmal, brassy, productive, weak, volitional, and “throatclearing,” and it may occur at different times of the day (Tables 2-2 and 2-3).
The cough reflex serves to prevent the entry of harmful substances into the tracheobronchial tree and to expel excess secretions and retained material from the tracheobronchial tree. Cough begins with stimulation of cough receptors, located in the upper and lower airways, and in many other sites such as the ear canal, tympanic membrane, sinuses, nose, pericardium, pleura, and diaphragm. Receptors send messages via vagal, phrenic, glossopharyngeal, or trigeminal nerves to the “cough center,” which is in the medulla. Because cough is not only an involuntary reflex activity but also one that can be initiated or suppressed voluntarily, “higher centers” must also be involved in the afferent limb of the responsible pathway. The neural impulses go from the medulla to the appropriate efferent pathways to the larynx, tracheobronchial tree, and expiratory muscles. The act of coughing (Fig. 2-1) begins with an inspiration, followed by expiration against a closed glottis (compressive phase), resulting in the buildup of impressive intrathoracic pressures (50 to 300 cm H2O). These pressures may be transmitted to vascular, cerebrospinal, and intraocular spaces. Finally, the glottis opens, allowing for explosive expiratory air flow (300 m/second) and expulsion of mucus, particularly from the larger, central airways. The inability to seal the upper airway (tracheostomy) impairs, but does not abolish, the effectiveness of cough. Weak ventilatory muscles (muscular dystrophy) impair both the inspiratory and the compressive phase.
HISTORY The history often provides the most important body of information about a child’s cough. A diagnosis can often be discerned with relative certainty from the family history, the environmental and exposure history, and the acuteness and characterization of the cough. DEMOGRAPHICS The patient’s age (Table 2-1) helps to focus the diagnostic possibilities. Congenital anatomic abnormalities may be symptomatic from birth, whereas toddlers, who may have incomplete neurologic control over swallowing and often put small objects in their mouths, are at risk for foreign body aspiration; adolescents may experiment with smoking Figure 2-1. Cough mechanics, showing changes in expiratory flow rate, air volume, subglottic pressure, and sound recording during cough. (Adapted from Yanagihara N, et al: The physical parameters of cough: The larynx in a normal single cough. Acta Otolaryngol 1996;61:495-510.)
*This chapter is an updated and edited version of the chapter by David M. Orenstein that appeared in the first edition.
16
Chapter 2 Cough
17
Table 2-1. Causes of Cough Age Group
Acute
Recurrent
Chronic (>3 weeks)
Infants
Infection1* Aspiration2 Foreign body3
Reactive airways1 CF1 GER1 Aspiration2 Anatomic abnormality3† Passive smoking3
Toddlers
Infection1 Foreign body2 Aspiration3
Reactive airways1 CF1 GER1 Aspiration2 Anatomic abnormality3 Passive smoking3
Children
Infection1 Foreign body3
Reactive airways1 CF1 GER1 Passive smoking3
Adolescents
Infection1
Reactive airways1 CF1 GER1 Aspiration2 Anatomic abnormality3
Reactive airways1 CF1 GER1 Aspiration2 Pertussis2 Anatomic abnormality3† Passive smoking3 Miscellaneous3 (see Table 2-26) Reactive airways1 CF1 GER1 Aspiration2 Pertussis2 Anatomic abnormality3 Passive smoking3 Miscellaneous3 Reactive airways1 CF1 GER2 Pertussis2 Mycoplasma3 Psychogenic3 Anatomic abnormality3 Passive smoking3 Miscellaneous3 Reactive airways1 CF1 GER2 Smoking2 Mycoplasma2 Psychogenic2 Pertussis3 Aspiration3 Anatomic abnormality3 Miscellaneous3
*Infections include upper (pharyngitis, sinusitis, tracheitis, rhinitis, otitis) and lower (pneumonia, abscess, empyema) respiratory tract disease. †
Anatomic abnormality includes tracheobronchomalacia, tracheoesophageal fistula, vascular ring, abnormal position, or take-off of large bronchi.
1
common; 2less common; 3much less common.
CF, cystic fibrosis; GER, gastroesophageal reflux.
RESPONSES TO PREVIOUS TREATMENT: DRUG HISTORY The previous response or lack of response to some therapies for recurrent and chronic cough can provide important information (see Table 2-3). Furthermore, some coughs may be caused or worsened by medications (Table 2-4). ASSOCIATED SYMPTOMS A history of accompanying signs or symptoms, whether localized to the respiratory tract (wheeze, stridor) or elsewhere (failure to thrive, frequent malodorous stools) can give important clues (Table 2-5; see Tables 2-2 and 2-3). It is essential to remember that the daily language of the physician is full of jargon that may be adopted by parents but with a different meaning from that understood by physicians. If a parent says that a child “wheezes” or “croups” or is “short of breath,” it is important to find out what the parent means by that term.
FAMILY AND PATIENT’S MEDICAL HISTORY Because many disorders of childhood have genetic or nongenetic familial components, the family history can provide helpful information: Are there older siblings with cystic fibrosis (CF) or asthma? Is there a coughing sibling whose kindergarten class has been closed because of pertussis? Similarly, the key to today’s problems may be found in the past: Was the child premature and, if so, did he or she spend a month on the ventilator, and does he or she now have chronic lung disease (bronchopulmonary dysplasia)? Did the toddler choke on a carrot or other food 3 months ago? Did the child receive a bone marrow transplant a year ago? Is the child immunized? Did the infant have a tracheoesophageal fistula repaired in the neonatal period?
Section One Respiratory Disorders
18
COUGH
Consider Foreign body Pulmonary embolism Inhaled irritant
Yes Sudden onset
No Consider Nasopharyngitis Sinusitis Laryngotracheitis
Yes
Fever, rhinorrhea Normal chest exam
The respiratory rate is often elevated with parenchymal lung disease or extrathoracic obstruction. Respiratory rates vary with the age of the child (Fig. 2-3) and with pulmonary infection, airway obstruction, activity, wakefulness and sleep, fever, metabolic acidosis, and anxiety. Odors may also give helpful clues. Does the examining room or the clothing smell of stale cigarette smoke? Is there a foul odor from a diaper with a fatty stool, which may suggest pancreatic insufficiency and CF? Is the child’s breath malodorous, as can be noticed in sinusitis, nasal foreign body, lung abscess, or bronchiectasis? Fingers It has been said that the examination of the lungs begins at the fingertips. Cyanotic nail beds suggest hypoxemia, poor peripheral circulation, or both. The examiner looks for the presence of digital clubbing (Fig. 2-4), which makes asthma or acute pneumonia extremely unlikely. The absence of digital clubbing but a history of severe chronic cough in an older child makes CF unlikely.
No Consider Viral, bacterial pneumonia Hypersensitivity pneumonia
Chest and Abdomen Yes
Fever, abnormal chest exam, acute onset
No Consider Cystic fibrosis Asthma Tuberculosis Mediastinal disease Habit Other (see below)
Yes Chronic cough
No Consider Yes Recurrent cough Cystic fibrosis and pneumonia Immunodeficiency (HIV, agammaglobulinemia, combined immunodeficiency) Leukocyte disorders (e.g.,chronic granulomatous disease) Ciliary dyskinesia (dysmotile cilia syndrome, Kartagener syndrome) Anatomic disorders (sequestration, reflux, bronchiectasis, lobar emphysema, cystic adenomatoid malformation, aspiration) Sickle cell anemia Figure 2-2. Algorithm for differential diagnosis of cough. HIV, human immunodeficiency virus.
The shape of the chest gives information. Is the anteroposterior (AP) diameter increased, which indicates hyperinflation of the lungs from obstruction of small airways (asthma, bronchiolitis, CF)? Is this diameter small, as can be seen with some restrictive lung diseases with small lung volumes (muscular dystrophy, spinal muscular atrophy)? The normal infant has a “round” chest configuration, with the AP diameter of the chest about 84% of the transverse (lateral) diameter. With growth, the chest becomes more flattened in the AP dimension, and the AP-to-transverse ratio is closer to 70% to 75%. Although obstetric calipers can be used to give an objective assessment of the AP diameter of the chest, most clinicians rely on their subjective assessment of whether the diameter is increased: Does the patient look “barrel-chested”? Intercostal, subcostal, suprasternal, and supraclavicular retractions (inspiratory sinking in of the soft tissues) indicate increased effort of breathing and reflect both the contraction of the accessory muscles of respiration and the resulting difference between intrapleural and extrathoracic pressure. Retractions occur most commonly with obstructed airways (upper or lower), but they may occur with any condition leading to the use of the accessory muscles. Any retractions other than the mild normal depressions seen between an infant’s lower ribs indicate a greater-than-normal work of breathing. Less easy to notice than intercostal retractions is their bulging out with expiration in a child with expiratory obstruction (asthma). Contraction of the abdominal muscles with expiration is easier to notice and is another indication that a child is working harder than normal to push air out through obstructed airways. Spine Inspection of the spine may reveal kyphosis or scoliosis. There is a risk of restrictive lung disease or static pneumonia if the curvature is severe. PALPATION
PHYSICAL EXAMINATION INSPECTION Initial inspection often reveals the seriousness of an illness: Is the child struggling to breathe (dyspnea)? Does the child have an anxious look? Can the child be calmed or engaged in play? Is the child’s skin blue (representing cyanosis) or ashen? Does the child appear wasted, with poor growth that may indicate a chronic illness?
Palpating the trachea, particularly in infants, may reveal a shift to one side, which suggests loss of volume of the lung on that side or extrapulmonary gas (pneumothorax) on the other side. Placing one hand on each side of the chest while the patient breathes may enable the examiner to detect asymmetry of chest wall movement, either in timing or in degree of expansion. The former indicates a partial bronchial obstruction, and the latter suggests a smaller lung volume, voluntary guarding, or diminished muscle function on one side. Palpating the abdomen gently during expiration may allow the examiner to feel the contraction of the abdominal muscles in cases of expiratory obstruction.
Chapter 2 Cough
19
Table 2-2. Clinical Clues about Cough Characteristic
Think of
Staccato, paroxysmal Followed by “whoop” All day, never during sleep Barking, brassy Hoarseness Abrupt onset Follows exercise Accompanies eating, drinking Throat clearing Productive (sputum) Night cough Seasonal Immunosuppressed patient
Pertussis, cystic fibrosis, foreign body, Chlamydia species, Mycoplasma species Pertussis Psychogenic, habit Croup, psychogenic, tracheomalacia, tracheitis, epiglottitis Laryngeal involvement (croup, recurrent laryngeal nerve involvement) Foreign body, pulmonary embolism Reactive airways disease Aspiration, gastroesophageal reflux, tracheoesophageal fistula Postnasal drip Infection Sinusitis, reactive airways disease Allergic rhinitis, reactive airways disease Bacterial pneumonia, Pneumocystis carinii, Mycobacterium tuberculosis, Mycobacterium avium–intracellulare, cytomegalovirus Hypoxia, hypercarbia Chlamydia psittaci (birds), Yersinia pestis (rodents), Francisella tularensis (rabbits), Q fever (sheep, cattle), hantavirus (rodents), histoplasmosis (pigeons) Histoplasmosis (Mississippi, Missouri, Ohio River Valley), coccidioidomycosis (southwest), blastomycosis (north and midwest) Occupational exposure
Dyspnea Animal exposure Geographic Workdays with clearing on days off
Palpation for tactile fremitus, the transmitted vibrations of the spoken word (“ninety-nine” is the word often used to accentuate these vibrations), helps determine areas of increased parenchymal density and hence increased fremitus (as in pneumonic consolidation) or decreased fremitus (as in pneumothorax or pleural effusion). PERCUSSION The percussion note determined by the examiner’s tapping of one middle finger on the middle finger of the other hand, which is firmly placed over the patient’s thorax, may be dull over an area of consolidation or effusion and hyperresonant with air trapping. Percussion can also be used to determine diaphragmatic excursion. The lowest level of resonance at inspiration and expiration determines diaphragmatic motion. AUSCULTATION Because lung sounds tend to be higher-pitched than heart sounds, the diaphragm of the stethoscope is better suited to pulmonary auscultation
than is the bell, whose target is primarily the lower-pitched heart sounds (Table 2-6). The adult-sized stethoscope generally is far superior to the smaller pediatric or neonatal diaphragms, even for listening to small chests, because its acoustics are better. The two-headed stethoscope enables the user to hear homologous segments of both lungs simultaneously (Fig. 2-5) in order to identify instances in which there is a delay in air entry or exit. The traditional single-headed stethoscope is adequate in most children with cough. The ability to recognize normal breath sounds comes with practice (Fig. 2-6). Adventitious Sounds Adventitious sounds come in a few varieties, namely, stridor, crackles, rhonchi, and wheezes. Other sounds should be described in clear, everyday language. Stridor is a continuous musical sound usually heard on inspiration and is caused by narrowing in the extrathoracic airway, as with croup or laryngomalacia. Crackles are discontinuous, representing the popping open of air-fluid menisci as the airways dilate with inspiration. Fluid in
Table 2-3. Cough: Some Aspects of Differential Diagnosis
Cause
Reactive airways disease/asthma Cystic fibrosis Infection Aspiration Gastroesophageal reflux Foreign body Habit
Only Abrupt Onset
Responds to Inhaled Responds to When Yellow Bronchodilator Awake Sputum (by History)
Responds Antibiotics (by History)
to Steroids (by History)
Failure to Thrive
Wheeze
Digital Clubbing
+
++
++
+++
+
+++
+
+++
−
+ + +
++ + +
++ ++ +
+ – +
+++ ++ +
+ – +
++ + ++
++ + ++
+++ − +
+ +++ –
++ + +++
– ++ –
– + –
– ++ –
+ + –
++ + –
++ ++ –
− + −
+++, Very common and suggests the diagnosis; ++, common; +, uncommon; –, almost never and makes examiner question the diagnosis.
Section One Respiratory Disorders
20 Table 2-4. Drugs Causing Cough Drug
Mechanism
Tobacco, marijuana β-Adrenergic blockers ACE inhibitors Bethanechol Nitrofurantoin Antineoplastic agents Sulfasalazine Penicillamine Diphenylhydantoin Gold Aspirin, NSAIDs Nebulized cromolyn Nebulized antibiotics Inhaled/nebulized bronchodilators Theophylline, caffeine Metabisulfite Cholinesterase inhibitors
Direct irritants Potentiate reactive airways disease (?) Possibly potentiate reactive airways disease Potentiates reactive airways disease (?) Via oxygen radicals versus via autoimmunity Various (including pneumonitis/fibrosis, hypersensitivity, noncardiogenic pulmonary edema) (?) Causes bronchiolitis obliterans (?) Causes bronchiolitis obliterans Hypersensitivity pneumonitis (?) Causes interstitial fibrosis Potentiate reactive airways disease Potentiates reactive airways disease via hypotonicity (?) Direct irritant Increases tracheal/bronchial wall instability in airway malacia; or via reaction to vehicle Indirect, via worsened gastroesophageal reflux (relaxation of lower esophageal sphincter) Induces allergic reactive airways disease Induce mucus production (bronchorrhea)
ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs.
LABORATORY FINDINGS RADIOGRAPHY The chest radiograph is often the most useful diagnostic test in the evaluation of the child with cough. Table 2-7 highlights some of the
Table 2-5. Nonpulmonary History Suggesting Cystic
radiographic features of the most common causes of cough in pediatric patients. Radiographic findings are often similar for a number of disorders, and thus these studies may not indicate a definitive diagnosis. Chest films are normal in children with psychogenic (habit) cough and in children with sinusitis or gastroesophageal reflux (GER) as the primary cause of cough. A normal chest radiograph indicates the unlikelihood of pneumonia caused by respiratory syncytial virus (RSV), influenza, parainfluenza, adenovirus, Chlamydia species, or bacteria. Although children with cough resulting from CF, Mycoplasma species, tuberculosis, aspiration, a bronchial foreign body, or an anatomic abnormality usually have abnormal chest radiographs, a normal radiograph does not exclude these diagnoses. Hyperinflation of the lungs is commonly seen on chest films of infants with RSV bronchiolitis or Chlamydia pneumonia, and a lobar or round (coin lesion) infiltrate is the radiographic hallmark of 60 Respiratory rate (breaths/min)
larger airways causes crackles early in inspiration (congestive heart failure); crackles that tend to be a bit lower in pitch (“coarse” crackles) than the early, higher-pitched (“fine”) crackles are associated with fluid in small airways (pneumonia). Although crackles usually signal the presence of excess airway fluid (pneumonia, pulmonary edema), they may also be produced by the popping open of noninfected fibrotic or atelectatic airways. Fine crackles are not audible at the mouth, whereas coarse crackles may be. Crackles is the preferred term, rather than the previously popular “rales.” Rhonchi, or “large airway sounds,” are continuous gurgling or bubbling sounds typically heard during both inhalation and exhalation. These sounds are caused by movement of fluid and secretions in larger airways (asthma, viral URI). Rhonchi, unlike other sounds, may clear with coughing. Wheezes are continuous musical sounds (lasting longer than 200 milliseconds), caused by vibration of narrowed airway walls, as with asthma, and perhaps vibration of material within airway lumens. These sounds are much more commonly heard during expiration than inspiration.
50 40 30 20 10
Fibrosis Maldigestion, malabsorption, steatorrhea (in 80%-90%) Poor weight gain Family history of cystic fibrosis Salty taste to skin Rectal prolapse (up to 20% of patients) Digital clubbing Meconium ileus (in 10%-15%) Intestinal atresia Neonatal cholestatic jaundice
0 0
12
24
Age (months)
36
4
8
12
16
Age (years)
Figure 2-3. Mean values (solid line) ±2 standard deviations (dotted lines) of the normal respiratory rate at rest (during sleep in children younger than 3 years). There is no significant difference between the sexes. (Data from Pasterkamp H: The history and physical examination. In Chernick V [ed]: Kendig’s Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998, p 88.)
Chapter 2 Cough NORMAL
CLUBBING
Phalangeal Depth Ratio
IPD>DPD
DPD>IPD
Hyponychial Angle
c
b
b
c
a a
abc 195°
21
are based on culturing the organism from nasopharyngeal washings. In some cases, the viruses can be rapidly identified with immunofluorescence or amplification of viral genome through polymerase chain reaction (PCR). In bacterial pneumonia, the offending organism can be cultured from the blood in a small proportion (10%) of patients. A positive culture provides definitive diagnosis, but a negative culture specimen is not helpful. Throat cultures are seldom helpful (except in CF) in identifying lower respiratory tract organisms. Sputum cultures and Gram stains may help guide initial empirical therapy in older patients with pneumonia or purulent bronchitis, but their ability to identify specific causative organisms with certainty (again with the exception of CF) has not been shown clearly. Infants and young children usually do not expectorate but, rather, swallow their sputum. Specimens obtained via bronchoscopy may be contaminated by mouth flora, but heavy growth of a single organism in the presence of polymorphonuclear neutrophils certainly supports the organism’s role in disease. If pleural fluid or fluid obtained directly from the lung via needle aspiration is cultured, the same rules apply: Positive cultures are definitive, but negative cultures are not. Bacterial antigen detection in serum or urine by various techniques (latex agglutination) can help identify pneumococcus and Haemophilus influenzae type b.
‘
Schamroth s Sign
Figure 2-4. Measurement of digital clubbing. The ratio of the distal phalangeal depth (DPD) to the interphalangeal depth (IPD), or the phalangeal depth ratio, is normally less than 1 but increases to more than 1 with finger clubbing. The DPD/IPD ratio can be measured with calipers or, more accurately, with finger casts. The hyponychial angle is measured from lateral projections of the finger contour on a magnifying screen and is normally less than 180 degrees but greater than 195 degrees with finger clubbing. Schamroth’s sign is useful for bedside assessment. The dorsal surfaces of the terminal phalanges of similar fingers are placed together. With clubbing, the normal diamond-shaped aperture or “window” at the bases of the nail beds disappears, and a prominent distal angle forms between the end of the nails. In normal subjects, this angle is minimal or nonexistent. (From Pasterkamp H: The history and physical examination. In Chernick V [ed]: Kendig’s Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998.)
bacterial pneumonia. The diagnosis of sinusitis cannot be sustained with normal sinuses on radiograph or computed tomography (CT) scan. HEMATOLOGY/IMMUNOLOGY The white blood cell (WBC) count may help exclude or include certain entities for a differential diagnosis, but, with the possible exception of pertussis, can seldom establish a diagnosis with certainty. A WBC count of 35,000 with 85% lymphocytes strongly suggests pertussis, but not every child with pertussis presents such a clear hematologic picture. The presence of a high number or large proportions of immature forms of WBCs suggests an acute process, such as a bacterial infection. Immunoglobulins provide supportive evidence for a few diagnoses, such as chlamydial infection, which rarely occurs without elevated serum concentrations of immunoglobulins G and M. BACTERIOLOGY/VIROLOGY Specific bacteriologic or virologic diagnoses can be made in a number of disorders causing cough, including RSV, influenza, parainfluenza, adenovirus, and Chlamydia pneumonia. In most cases, these diagnoses
OTHER TESTS A number of specific tests can help to establish diagnoses in a child with cough (see Table 2-7). These include a positive response to bronchodilators in a child with asthma; visualizing the red, swollen epiglottis in epiglottitis (to be done only under very controlled conditions, as described later); the bronchoscopic visualization of the peanut, plastic toy, or other offender in foreign body aspiration; a positive purified protein derivative in tuberculosis; and several studies of the esophagus in GER. Several imaging techniques, such as CT or magnetic resonance imaging (MRI), can help to delineate various intrathoracic anatomic abnormalities. Finally, multiple tests can be employed to confirm the diagnosis of CF (Table 2-8).
DIFFERENTIAL DIAGNOSIS AND TREATMENT INFECTION Infections are the most common cause of acute cough in all age groups and are responsible for some chronic coughs. The age of the patient has a large impact on the type of infection. Infants Viral upper respiratory infections (common cold); croup (laryngotracheobronchitis); viral bronchiolitis, particularly with RSV; and viral pneumonia are the most frequently encountered respiratory tract infections and hence the most common causes of cough in infancy. Viral illness may predispose to bacterial superinfection (croup and Staphylococcus aureus tracheitis or influenza and H. influenzae pneumonia). Common Cold
Cold symptoms and signs usually include stuffy nose, with nasal discharge (rhinorrhea); sore throat and sneezing frequently occur. There may be fever, constitutional signs (irritability, myalgias, headache), or both. Cough is common and may persist for 5 to 7 days. The mechanism by which upper respiratory infections cause cough in children is undetermined. In adults, it is generally thought that “postnasal drip”—that is, nasal or sinus secretions draining into the posterior nasopharynx—causes cough and, in fact, may be one of the most frequent causes of cough. Indeed, sinus CT in older patients
No
Shift toward lesion Tension deviates trachea and PMI to opposite side Deviation to opposite side No
Bronchospasm
Atelectasis Pneumothorax
Reduced
Reduced over area
Hyperexpansion with limited motion Reduced over area Reduced over area
Reduced over area, splinting
Chest Motion
Normal to increased
None
Decreased None
Normal or decreased
Increased
Fremitus
Normal
Dull
Dull Resonant, tympanitic
Hyperresonant
Dull
Percussion
Normal
None
Reduced or absent None
Normal to decreased
Bronchial or reduced
Breath Sounds
Friction rub; splash, if hemopneumothorax Crackles
None or crackles None
Wheezes, crackles
Crackles
Adventitious Sounds
Whispering pectoriloquy produces clearer sounding whispered words (e.g., “ninety-nine”).
PMI, point of maximal impulse.
†
*Egophony is present when e sounds like a.
Adapted from Dantzker D, Tobin M, Whatley R: Respiratory diseases. In Andreoli TE, Carpenter CJ, Plum F, Smith LH (eds): Cecil Essentials of Medicine. Philadelphia, WB Saunders, 1986, p 126-180.
Interstitial process
Pleural effusion
No
Mediastinal Deviation
Consolidation (pneumonia)
Disease Process
Table 2-6. Physical Signs of Pulmonary Disease
None
None
None None
Egophony,* whispering pectoriloquy increased† Normal to decreased
Voice Signs
22 Section One Respiratory Disorders
Chapter 2 Cough
23
with colds often reveals involvement of the sinus mucosa. Whether this is true in children remains undetermined. Other authorities believe that cough in a child with a cold indicates involvement (inflammation or bronchospasm) of the lower respiratory tract. The physician’s bias on this matter will probably influence how to treat the child with cough accompanying a cold. In adults, the cough of the common cold may respond to a combination antihistaminedecongestant preparation, presumably from the decreased postnasal drip. It is uncertain whether such treatment is effective or indicated in children, particularly young infants, in whom toxicity of the drugs may be a greater concern than in adults. Common viral pathogens include rhinovirus, RSV, and parainfluenza virus. The differential diagnosis includes allergic rhinitis, which often demonstrates clear nasal secretions with eosinophils and pale nasal mucosa, in contrast to mucopurulent nasal secretions with neutrophils and erythematous mucosa. Croup (Laryngotracheobronchitis)
Figure 2-5. Projections of the pulmonary lobes on the chest surface. The upper lobes are white, the right-middle lobe is black, and the lower lobes are dotted. (From Pasterkamp H: The history and physical examination. In Chernick V [ed]: Kendig’s Disorders of the Respiratory Tract in Children, 6th ed. Philadelphia, WB Saunders, 1998.)
Infectious croup (see Chapter 5) is most common in the first 2 years of life. Its most dramatic components are the barking (“croupy”) cough and inspiratory stridor, which appear a few days after the onset of a cold. In most cases, the patient has a low-grade fever, and the disease resolves within a day or two. In severe cases, the child can be extremely ill and is at risk for complete laryngeal obstruction. There may be marked intercostal and suprasternal retractions and cyanosis. Stridor at rest signifies significant obstruction. Diminishing stridor in a child who is becoming more comfortable is a good sign, but diminishing stridor in and of itself is not necessarily good: If the child becomes fatigued because of the tremendous work of breathing through an obstructed airway and can no longer breathe effectively, smaller-than-needed tidal volumes make less noise.
Figure 2-6. Characteristics of breath sounds. Tracheal breath sounds are very harsh, loud, and high-pitched; they are heard over the extrathoracic portion of the trachea. Bronchial breath sounds are loud and high-pitched; normally, they are heard over the lower sternum and sound like air rushing through a tube. The expiratory component is louder and longer than the inspiratory component; a definite pause is heard between the two phases. Bronchovesicular breath sounds are a mixture of bronchial and vesicular sounds. The inspiratory (I) and expiratory (E) components are equal in length. They are usually heard only in the first and second interspaces anteriorly and between the scapulae posteriorly, near the carina and mainstem bronchi. Vesicular breath sounds are soft and lowpitched; they are heard over most of the lung fields. The inspiratory component is much longer than the expiratory component; the latter is softer and often inaudible. (From Swartz MH: The chest. In Textbook of Physical Diagnosis: History and Examination. Philadelphia: WB Saunders, 1989.)
+ – + + + + – + +
+
+ – +++
++
+ +++ +
– + ++7 + + + –
++
++ +++ –
– – – ++ – +
+ – – +++ + + +++
Epiglottitis Sinusitis Bronchiolitis Pneumonia Influenza Paraflu Adenovirus Pertussis Chlamydia Mycoplasma
TB Bacterial Foreign body GE reflux Aspiration Anatomic Habit
“Swollen thumb”: sign of thickened epiglottis.
Low yield on culture in paroxysmal stage.
Pleural effusion relatively common.
4
5
+ + + – – – –
+ +++ + +
+ – +
+
+ +
↑ LY
+ + + – + – –
+ + ++ +
+ + +
+
++ +
↑ EOS
Complete Blood Count
+ +++ ++ – + + –
+ + ++ + + +
+++ +++ +
–
– ++
↑ PMN
+ – – – –
– – – –
+ +++ ++
+ +
↑ IgM
++
++ +++ –
++
+ ++
↑ IgG
+ – – – –
+ + – –
RSV +++ +++ +++ +++ +4 +++
Paraflu +++
+ NP Cult
+
– – –
+
++ +
↑ IgE
12
10
+Cold agglutinin, PCR +PPD +Bld cult6 Bronch Esoph pH8
+PCR +PCR
+PCR
Direct look
+PCR
+bdilator1 See Table 2-8
Other
Esophageal biopsy specimen shows esophagitis.
Multilobular or multisegmental, dependent lobes.
8
9
+Bld Cult, blood culture may be positive; Bronch, bronchoscopy can reveal the foreign body; Diff, diffuse or scattered; ↑ EOS, increased eosinophil count; Esoph pH, prolonged esophageal pH probe monitoring; GE, gastroesophageal; Hyper, hyperinflated; Ig, immunoglobulin; Infil, infiltrates; ↑ LY, increased lymphocyte count; +NP Cult, nasopharyngeal culture positive for specific organism; Paraflu, parainfluenza virus; PCR, polymerase chain reaction; ↑ PMN, increased polymorphonuclear neutrophil count; PPD, purified protein derivative (TB); RAD, reactive airways disease; RSV, respiratory syncytial virus; TB, tuberculosis; ↑ WBC, increased white blood cell count.
+++, almost always—if not present, must question diagnosis; ++, common; +, less common; –, seldom—if present, must question diagnosis.
Bronchoscopy; computed tomography; MRI.
12
Right-sided arch, mass effect on airways, mass identified; magnetic resonance imaging (MRI).
11
(?) Lipid-laden macrophages from bronchoscopy or gastric washings; barium swallow or radionuclide study showing aspiration.
10
Localized hyperinflation is common; localized atelectasis in common; inspiratory-expiratory films may show ball-valve obstruction.
7
Blood culture positive in 10%; needle aspiration of pleural fluid or lung fluid may yield organism; bacterial antigen in urine. In older infants and children, common pathogens include pneumococci and group A streptococci; Staphylococcus aureus is rare and may be associated with pneumatoceles or empyema.
6
“Steeple” sign: narrowing of upper tracheal air column.
+ +++ ++ – + + –
++ ++ ++ ++ + +
+++ ++ +
–
+ ++
3
– – – + + – –
– – – – – +
– +++ –
–
+ +++
↑ WBC
Positive response to bronchodilators, either as a home therapeutic trial or in a pulmonary function test in the laboratory.
++ ++5 ++7 – ++9 ++11 –
+ + + + + ++5
++3 – +
++2
– ++
Other
Abnormal Sinus Radiograph
2
+ + – – + – –
++ ++ ++ + +++ +
+ – ++
+
– +
Diff Infil
1
++ +++ ++ – + + –
+
– +
++ ++
+ +
RAD/asthma Cystic fibrosis Other infection Croup
Hyper
Normal
Lobar Infil
Chest Radiograph
Table 2-7. Cough: Laboratory Evaluation
24 Section One Respiratory Disorders
Chapter 2 Cough
25
Table 2-8. Laboratory Tests for Cystic Fibrosis Usefulness
Definitive Suggestive
Supportive
Test
“Sweat test” DNA analysis Throat or sputum culture* positive for mucoid Pseudomonas aeruginosa Sinus radiographs Pansinusitis Positive IRT newborn screen Typical histologic appearance of appendix Absent stool trypsin Abnormal Chymex test result for pancreatic insufficiency Pulmonary function tests: Obstructive pattern, especially small airways and especially if patient is poorly responsive to bronchodilator Chest film: Hyperinflation, ± other findings; especially with right upper lobe infiltrate/atelectasis Throat or sputum culture*: Positive for Staphylococcus aureus Positive for Haemophilus influenzae
Sensitivity
Specificity
.99+ .85-.90
.95+ .99
.70-.80
.85
.95 .98 .95 .40-.75 .70-.90
.90 .25 .98 .75(?) .90+
.70+
?
.70+
?
.20 .05-.20
.20 .15
Cost
$175 $35 $140 $179 $1 — $103 $98 $100-$800 $160 $140
*Throat is usually deep pharyngeal culture. IRT, immunoreactive trypsinogen.
It is important to distinguish croup from epiglottitis in the child with harsh, barking cough and inspiratory stridor because the natural histories of the two diseases are quite different (see Table 2-7). Epiglottitis occurs more commonly in toddlers than in infants (see Chapter 5). Treatment of mild croup is usually not needed. For decades, pediatricians have recommended putting a child with croup in a steamy bathroom or driving to the office or emergency room with the car windows rolled down. (It is likely that these remedies are effective because of the heat exchange properties of the upper airway; air that is cooler or more humid than the airway mucosa will serve to cool the mucosa, thus causing local vasoconstriction and probably decreasing local edema.) In a child who has stridor at rest, hospitalization is indicated. Symptomatic, often dramatic relief through decreased laryngeal edema can usually be achieved with aerosolized racemic epinephrine (2.25% solution, 0.25 to 0.5 mL/dose). It is essential to remember that the effects of the epinephrine are transient, lasting only a few hours, although the course of the illness is often longer. The result is that when the racemic epinephrine’s effect has worn off, the child’s cough and stridor will probably be as bad or even worse than before the aerosol was administered. This is not a “rebound” effect: The symptoms are not worse because of the treatment but, rather, because of the natural progression of the viral illness. Repeating the aerosol will probably again have a beneficial effect and reduce the likelihood of requiring a tracheotomy or endotracheal intubation. A child who responds favorably to such an aerosol needs to be observed for several hours because further treatment may be needed. A single dose of dexamethasone (0.6 mg/kg orally, intramuscularly, or intravenously) reduces the severity and hastens recovery. Aerosolized steroids (budesonide) may also be effective in patients with mild to moderately severe croup. Bronchiolitis
Bronchiolitis is a common and potentially serious lower respiratory tract disorder in infants (see Chapters 3 and 5). It is caused usually by RSV but on occasion by parainfluenza, influenza, or adenovirus. It occurs in the winter months, often in epidemics. RSV bronchiolitis
is seen uncommonly in children older than 4 years. Typically, “coldlike” symptoms of rhinorrhea precede the harsh cough, increased respiratory rate, and retractions. Respiratory distress and cyanosis can be severe. The child’s temperature is seldom elevated above 38°C. The chest is hyperinflated, widespread crackles are audible on inspiration, and wheezing marks expiration. The most striking laboratory abnormalities are in the chest radiograph, which invariably reveals hyperinflation, as depicted by a depressed diaphragm, with an enlarged retrosternal air space in as many as 60% of patients, peribronchial thickening in approximately 50%, and consolidation and/or atelectasis in 10% to 25%. The diagnosis is confirmed with demonstration of RSV by immunofluorescent stain or PCR of nasopharyngeal washings. In most cases, no treatment is needed because the disease does not interfere with the infant’s eating or breathing. Apnea is a common complication of RSV bronchiolitis in young infants and may necessitate close monitoring. In severe cases, often those in which there is underlying chronic heart, lung, or immunodeficiency disease, RSV can be life-threatening. In these cases, hospital care with supplemental oxygen and intravenous fluids is indicated. The effect of aerosolized bronchodilators is not clear but is probably beneficial in some infants. The aerosolized antiviral agent ribavirin may be beneficial for the sickest infants. It is expensive and difficult to administer; it needs to be given 12 to 18 hours per day (some studies advocate 2 hours three times a day) and may block ventilator tubing and valves. Ribavirin may improve oxygenation but should not be used in lieu of mechanical ventilation in patients with hypoxia and hypercarbia (respiratory failure). Viral Pneumonia
Viral pneumonia can be similar to RSV bronchiolitis in its manifestation, with cough and tachypnea, after a few days of apparent upper respiratory infection. There can be variable degrees of fever and of overall illness. Infants and children with viral pneumonia may appear relatively well or, particularly with adenovirus, may have a rapidly progressive course, which ends in death within a few days after the onset of illness. Frequent symptoms include poor feeding, cough, cyanosis, fever (some patients may be afebrile), apnea, and
Section One Respiratory Disorders
26
rhinorrhea. Frequent signs include tachypnea, retractions, crackles, and cough. Cyanosis is less common. The most common agents causing viral pneumonia in infancy and childhood are RSV, influenza, and parainfluenza. Adenovirus is less common, but it is important because it can be severe and leave residua, including bronchiectasis and bronchiolitis obliterans. Adenovirus pneumonia is often accompanied by conjunctivitis and pharyngitis, in addition to leukocytosis and an elevated erythrocyte sedimentation rate (ESR); the ESR and leukocyte count are usually not elevated in other types of viral pneumonia. Additional viral agents include enteroviruses and rhinovirus. Radiographs most often reveal diffuse, bilateral peribronchial infiltrates, with a predilection for the perihilar regions, but occasionally lobar infiltrates are present. Pleural effusions are not common. On occasion, if an infant is extremely ill, bronchoscopy with bronchoalveolar lavage may be indicated to isolate the virus responsible for the pneumonia. Treatment is largely supportive, with oxygen and intravenous fluids. Mechanical ventilation may be necessary in a small minority of infants. In young infants, the afebrile pneumonia syndrome may be caused by Chlamydia, Ureaplasma, or Mycoplasma species; cytomegalovirus; or Pneumocystis carinii. In this syndrome, cough and tachypnea are common. Severe pneumonia may develop in neonates as a result of herpes simplex. Pertussis (Whooping Cough)
Pertussis is an extremely important cause of lower respiratory tract infection in infants and children. The causative organism, Bordetella pertussis, has a tropism for tracheal and bronchial ciliated epithelial cells; thus, the disease is primarily bronchitis, but spread of the organism to alveoli, or secondary invasion by other bacteria, can cause pneumonia. The disease can occur at any age, from early infancy onward, although its manifestations in young infants and in those who have been partially immunized may be atypical. Most commonly, pertussis has three stages: ●
●
●
catarrhal, in which symptoms are indistinguishable from the common cold paroxysmal, dominated by repeated forceful, paroxysmal coughing spells; many spells may be punctuated by an inspiratory “whoop,” post-tussive emesis, or both convalescent, in which the intensity and frequency of coughing spells gradually diminish
Each stage typically lasts 1 to 2 weeks, except the paroxysmal stage, which lasts many weeks. The Chinese term for pertussis translates to “100 days of cough.” Most children are entirely well between coughing spells, when physical findings are remarkably benign. Infants younger than 3 months of age may have the most severe illness, and in this age group, the rate of mortality from pertussis is as high as 40%. Diagnosis can be difficult because the definitive result—namely, culturing the organism from nasopharyngeal secretions—requires special culture medium (Bordet-Gengou, which must be prepared fresh for each collection). Culture specimens are much less likely to be positive during the paroxysmal stage than during the catarrhal stage, when the diagnosis is not being considered. Fluorescent antibody stains (for the antigen) of secretions are also helpful if they are positive, but, similarly, they are more likely to be positive before the paroxysmal stage. Serum antibodies against B. pertussis may occasionally be helpful, although they are often difficult to interpret in immunized individuals. Perhaps the laboratory test that is most helpful is the WBC count, which is typically elevated; values are as high as 20,000 to 50,000, with lymphocytes predominating. PCR is also useful. Chest radiographic findings are nonspecific. Infants with severe disease may require hospitalization. Treatment is largely supportive, with oxygen, fluids, and small frequent feedings for patients who do not tolerate their normal feedings. Treatment with erythromycin estolate (50 mg/kg/day for
14 days, every 6 hours, orally) decreases infectivity and may ameliorate the course of the disease if given during the catarrhal stage. Studies suggest that azithromycin or clarithromycin may also be effective. In some patients, aerosolized bronchodilators (albuterol) or systemic steroids may help, although such treatment is controversial. Cough suppressants are not helpful, but good hydration, oxygenation, and nutrition, in addition to not disturbing the infant, are important. Complications include those related to severe coughing (Table 2-9) and those specific to pertussis, such as seizures and encephalopathy. Pertussis is prevented by three primary immunizations (at 2, 4, and 6 months of age) and regular booster immunizations at 15 to 18 months and 4 to 6 years of age. Pertussis infection produces lifelong immunity. Chlamydial Infection
Chlamydia trachomatis can cause pneumonia in young infants, particularly those aged 3 to 12 weeks. Cough, nasal congestion, lowgrade or no fever, and tachypnea are common. Conjunctivitis is an important clue to chlamydial disease but is present in only 50% of infants with chlamydial pneumonia at the time of presentation. Affected infants may have a paroxysmal cough similar to that of pertussis, but post-tussive emesis is less common. Crackles are commonly heard on auscultation, but wheezing is much less common than the overinflated appearance of the lungs on radiographs would suggest. The organism may be recovered from the nasopharynx by culture or antigen testing. The complete blood cell count may reveal eosinophilia. Chlamydial infection responds to oral erythromycin therapy (40 to 50 mg/kg/day, every 6 hours for 10 to 14 days).
Table 2-9. Potential Complications of Cough
Musculoskeletal
Pulmonary
Cardiovascular
Central nervous system
Gastrointestinal
Miscellaneous
*Common.
Rib fractures Vertebral fractures Rupture of rectus abdominis muscle Asymptomatic elevation of serum creatine phosphokinase Chest wall pain* Bronchoconstriction Pneumomediastinum Pneumothorax Mild hemoptysis Subcutaneous emphysema Irritation of larynx and trachea Rupture of subconjunctival,* nasal,* and anal veins Bradycardia, heart block Transient hypertension Cough syncope Headache Subarachnoid hemorrhage Hernias (ventral, inguinal) Emesis Rectal prolapse Pneumoperitoneum Anorexia* Malnutrition Sleep loss* Urinary incontinence Disruption of surgical wounds Vaginal prolapse Displacement of intravenous catheters
Chapter 2 Cough Ureaplasmal Infection
Ureaplasma urealyticum pneumonia is difficult to diagnose but causes cough in some infants. There are no particularly outstanding features to distinguish this relatively uncommon infection from viral pneumonias. Bacterial Pneumonia
Bacterial pneumonia is relatively less common in infants than is viral pneumonia but can cause severe illness, with cough, respiratory distress, and fever. Chest films are strikingly abnormal; the WBC count is elevated. Treatment is with broad-spectrum intravenous antibiotics effective against pneumococci, group A (possibly B) streptococci, and, if illness is severe, S. aureus. Cefotaxime with or without nafcillin may be effective. Toddlers and Children Colds
In early childhood, as children attend day care and nursery schools, they are constantly exposed to respiratory viruses to which they have little or no immunity (e.g., rhinoviruses, adenoviruses, parainfluenza, and coxsackievirus). Such children may have as many as 6 to 8 or even more colds in a year. The remarks concerning colds and cough in infants (see previous discussion) apply to this older age group. The differential diagnosis of rhinorrhea is noted in Table 2-10. Sinusitis
The sinuses may become the site for viral and subsequent secondary bacterial infection spreading from the nasopharynx (Fig. 2-7). The
27
signs and symptoms are usually localized, including nasal congestion, a feeling of “fullness” or pain in the face (Fig. 2-8), headache, sinus tenderness, day or night cough, and fever. Maxillary toothache, purulent nasal discharge for more than 10 days, a positive transillumination (opacification), and a poor response to oral antihistamines or nasal decongestants are important clues. Sinus radiographs or (more accurate) CT scan may facilitate the diagnosis of sinusitis by demonstrating opacification of the sinus with mucosal thickening. Sinusitis is thought to be a cause of cough in adults and can probably be listed, with lower certainty, as a cause of cough in children. Sinusitis is frequently seen in other conditions known to cause cough, especially CF, asthma, and ciliary dyskinesia. It may be difficult to ascertain whether the cough is a direct result of the sinus infection or the underlying problem (purulent bronchitis in the child with CF or ciliary dyskinesia, exacerbation of asthma). In the first two situations, it may not matter because treatment is the same. In the case of the child with asthma, it is important to treat the asthma with bronchodilating and antiinflammatory agents, as well as to treat the infected sinuses with antibiotics. The treatment of sinusitis involves the use of oral antibiotics active against the common pathogens (Streptococcus pneumoniae, nontypable H. influenzae, Moraxella catarrhalis, and, in rare cases, anaerobic bacteria or Streptococcus pyogenes). Treatment regimens include the use of amoxicillin, amoxicillin-clavulanate, cefuroxime, cefpodoxime, or cefdinir. Amoxicillin is considered the initial agent of choice. Oral (pseudoephedrine, phenylephrine) or topical (phenylephrine, oxymetazoline) decongestants may be of benefit by increasing the patency of the sinus ostia, which permits drainage of the infected and obstructed sinuses. Oral antihistamines may benefit patients with an allergic history. Treatment with antimicrobial agents should continue for at least 7 days after the patient has responded. This may require 14 to 21 days of therapy. Many patients with presumed sinusitis recover without antibiotic therapy.
Table 2-10. Differential Diagnosis of Rhinorrhea Etiology
Frequency
Duration*
Discharge
Viral
Common
Acute
Purulent
Allergic Vasomotor Sinusitis Rhinitis medicamentosus Response to stimuli Nasal polyps Granulomatous disease
Common Common Common Common Common Uncommon Uncommon
Acute/chronic Chronic Chronic Chronic Acute Chronic Chronic
Clear Variable Purulent Variable Clear Variable Bloody
Cerebrospinal fluid fistula Foreign body Tumor
Uncommon Uncommon Uncommon
Chronic Chronic Chronic
Watery Purulent Clear to bloody
Choanal atresia, stenosis Nonallergic eosinophilic rhinitis syndrome Septal deviation Drugs
Uncommon Uncommon
Chronic Chronic
Clear to purulent Clear
Unknown Uncommon
Chronic Chronic
Clear Variable
Hypothyroidism Cluster headache Horner syndrome
Uncommon Uncommon Uncommon
Chronic Intermittent Chronic
Clear Clear Clear
*Less than 1 week is considered acute.
Comment
Polymorphonuclear neutrophils in smear Eosinophils in smear, seasonal ? Environmental triggers Sinus tenderness Medication use Odors, exercise, cold air, pollution Consider cystic fibrosis Sarcoid, Wegener granulomatosis, midline granuloma Trauma, encephalocele Often malodorous Angiofibroma, hemangioma, rhabdomyosarcoma, lymphoma, nasopharyngeal carcinoma, neuroblastoma Congenital Eosinophils in smear Congenital, trauma Cocaine, glue and organic solvents, angiotensin-converting enzyme inhibitors, β blockers Associated tearing, headache Ptosis, miosis, anhidrosis
Section One Respiratory Disorders
28
Figure 2-7. The paranasal sinuses. 1, Frontal. 2, Ethmoid. 3, Maxillary. 4, Sphenoid. (From Smith RP: Common upper respiratory tract infections. In Reilly B [ed]: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991.)
Complications of acute sinusitis include orbital cellulitis, abscesses (orbital, cerebral), cranial (frontal) osteomyelitis (Pott puffy tumor), empyema (subdural, epidural), and thrombosis (sagittal or cavernous sinus). Croup and Epiglottitis
See previous text and Chapter 5. Pneumonia Viral Pneumonia. The features discussed for viral pneumonia in
infants are relevant for viral pneumonia in older children. The differentiation of viral or atypical pneumonia from classical bacterial pneumonia is noted in Table 2-11. Bacterial Pneumonia. Bacterial pneumonia is more common in
toddlers and older children than in infants. The most common pathogen is S. pneumoniae; other bacterial causes vary with age (Table 2-12). Cough may not be as prominent a presenting symptom or sign as tachypnea and grunting, sometimes (especially in infants) with vomiting (see Table 2-11). Raised respiratory rates (≥50 in infants 2 to 12 months old, ≥40 in children 1 to 5 years old) plus retractions and grunting with or without hypoxia (oxygen saturation 3 g Pleural/serum protein ratio Glucose* pH* Gram stain
Transudate
Exudate
Complicated Empyema
Clear 0.5 Low 7.20-7.40 Usually positive
Purulent >5000 PMNs >1000 U/L >0.6 Common >0.5 Very low* (50% of patients) Head, eyes, ears, nose, and throat Nasal polyps (20%) Chest Cough Barrel chest (↑ anteroposterior diameter) Intercostal, suprasternal retractions Crackles, especially upper lobes Wheeze Abdomen Hepatomegaly (10%) Right lower quadrant fecal mass (5%-10%) Extremities Digital clubbing (80%) Reproductive tract Bilateral atresia or absence of vas deferens (>95% of males)
The diagnosis is confirmed by a positive sweat test or confirming the presence of two CF mutations on chromosome 7. The sweat test, if not performed correctly in a laboratory with extensive experience with the technique (as, for example, in an accredited CF center), yields many false-positive and false-negative results. The proper technique is to use the Gibson-Cooke method, with quantitative analysis of the concentration of sodium, chloride, or both, in the sweat produced after pilocarpine iontophoretic stimulation. Chloride (and sodium) concentrations higher than 60 mEq/L are considered positive indications, and those lower than 40 mEq/L are negative (normal). Healthy adults have slightly higher sweat chloride concentrations than do children, but the same guidelines hold for positive tests in adults. The non-CF conditions yielding elevated sweat chloride concentrations are listed in Table 2-18. False-negative results of sweat tests can be seen in CF children presenting with edema or hypoproteinemia and in samples from children with an inadequate sweat rate. Sweat testing can be performed at any age; newborns within the first few weeks of life may not produce a large enough volume of sweat to analyze (75 mg minimum), but in those who do (the majority), the results are accurate. Indications for sweat testing are noted in Table 2-19. In patients for whom sweat testing is difficult (e.g., because of distance from an experienced laboratory, small infants who have not produced enough sweat, patients with extreme dermatitis, or patients with intermediate-range sweat chloride concentrations), DNA testing can be useful. Demonstration of two known CF mutations confirms the diagnosis. Finding one or no known mutation makes the diagnosis less likely but is not exclusive, inasmuch as there are patients with not-yet-characterized mutations. Furthermore, commercial laboratories do not identify all of the 1000-plus mutations. Recovery of mucoid P. aeruginosa from respiratory tract secretions is strongly suggestive of CF. Similarly, pansinusitis is nearly universal among CF patients but is quite uncommon in other children. Some states are using a neonatal screen for CF. The CF screen is for immunoreactive trypsinogen (IRT) levels, which are elevated in most infants with CF for the first several weeks of life. (Some states do genetic testing on DNA.) Because of the very high sensitivity of this test (almost no one with CF has normal IRT levels) and because early institution of treatment is beneficial, this test may come into wider use. Its main drawback is that it has relatively poor specificity; as many as 90% of the positive results on the initial screen are false-positive results. If an infant’s IRT screen is positive, the test should be repeated; at 2 to 3 weeks of age, which is when the test is repeated, the false-positive rate has fallen dramatically but is
Table 2-17. Causes of Digital Clubbing in Children
Pulmonary Cystic fibrosis ++ Non–cystic fibrosis bronchiectasis + Ciliary dyskinesia Bronchiolitis obliterans Empyema Lung abscess Malignancy Tuberculosis Mesothelioma Pulmonary arteriovenous fistula Cardiac Cyanotic congenital heart disease ++ Subacute bacterial endocarditis + Chronic congestive heart disease Gastrointestinal Crohn disease Ulcerative colitis Celiac disease + Severe gastrointestinal hemorrhage Small bowel lymphoma Multiple polyposis Hepatic Biliary cirrhosis Chronic active hepatitis Hematologic Thalassemia Congenital methemoglobinemia Miscellaneous Familial Thyroid deficiency Thyrotoxicosis Chronic pyelonephritis Heavy metal poisoning Scleroderma Lymphoid granulomatosis Hodgkin disease Human immunodeficiency virus ++, very common cause of digital clubbing; +, common cause of digital clubbing.
Table 2-18. Conditions Other than Cystic Fibrosis with
Elevated Sweat Electrolytes Adrenal insufficiency (untreated) Ectodermal dysplasia Autonomic dysfunction Hypothyroidism Malnutrition, including psychosocial dwarfism Mucopolysaccharidosis Glycogen storage disease (type I) Fucosidosis Hereditary nephrogenic diabetes insipidus Mauriac syndrome Pseudohypoaldosteronism Familial cholestasis Nephrosis with edema
33
34
Section One Respiratory Disorders
Table 2-19. Indications for Sweat Testing
Table 2-20. Complications of Cystic Fibrosis
Pulmonary Indications Chronic or recurrent cough Chronic or recurrent pneumonia (especially RUL) Recurrent bronchiolitis Atelectasis Hemoptysis Staphylococcal pneumonia Pseudomonas aeruginosa in the respiratory tract (in the absence of such circumstances as tracheostomy or prolonged intubation) Mucoid P. aeruginosa in the respiratory tract
Pulmonary Complications Bronchiectasis, bronchitis, bronchiolitis, pneumonia Atelectasis Hemoptysis Pneumothorax Nasal polyps Sinusitis Reactive airways disease Cor pulmonale Respiratory failure Mucoid impaction of the bronchi Allergic bronchopulmonary aspergillosis
Gastrointestinal Indications Meconium ileus Neonatal intestinal obstruction (meconium plug, atresia) Steatorrhea, malabsorption Hepatic cirrhosis in childhood (including any manifestations such as esophageal varices or portal hypertension) Pancreatitis Rectal prolapse Vitamin K deficiency states (hypoprothrombinemia) Miscellaneous Indications Digital clubbing Failure to thrive Family history of cystic fibrosis (sibling or cousin) Salty taste when kissed; salt crystals on skin after evaporation of sweat Heat prostration, especially under seemingly inappropriate circumstances Hyponatremic hypochloremic alkalosis in infants Nasal polyps Pansinusitis Aspermia From Kercsmar CM: The respiratory system. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 451. RUL, right upper lobe.
still quite high (25%). Definitive testing needs to be carried out on infants with two elevated IRT levels. In the unusual older child whose appendix is removed and examined carefully by a knowledgeable pathologist, the diagnosis may be suggested by the typical histologic appearance of the appendix (the mucus-secreting glands are overdistended with eosinophilic material). Laboratory data that may support the diagnosis of CF include absence of stool trypsin or chymotrypsin. This suggests pancreatic insufficiency, which occurs most commonly in CF but can be seen in other diseases. The test is not perfect even for confirming pancreatic insufficiency, because intestinal flora may produce or destroy trypsin. Pulmonary function test findings with an obstructive pattern, incompletely responsive to bronchodilators, are consistent with CF but, of course, can be seen in other conditions. Conversely, some patients with CF also have asthma and may show a marked response to a bronchodilator. Complications of CF that should suggest the diagnosis are noted in Table 2-20. The treatment of patients with CF requires a comprehensive approach, best performed in, or in conjunction with, an approved CF center. Several studies have shown survival to be significantly better in center-based care than in non–center-based care. The treatment of the pulmonary aspects of CF involves approaching the obstruction, infection, and inflammation that cause the cough. Cough should be monitored closely, and any increase in frequency or in the intensity should be taken as an indication that there is worsening endobronchial infection, inflammation, or both. Because active
Gastrointestinal Complications Meconium ileus Meconium peritonitis Distal intestinal obstruction syndrome (meconium ileus equivalent) (nonneonatal obstruction) Rectal prolapse Intussusception Volvulus Appendicitis Intestinal atresia Pancreatitis Biliary cirrhosis (portal hypertension: esophageal varices, hypersplenism) Neonatal obstructive jaundice Hepatic steatosis Gastroesophageal reflux Cholelithiasis Inguinal hernia Growth failure Vitamin deficiency states (vitamins A, D, E, K) Insulin deficiency, symptomatic hyperglycemia, diabetes Other Complications Infertility Edema/hypoproteinemia Dehydration/heat exhaustion Hypertrophic osteoarthropathy/arthritis Delayed puberty Amyloidosis From Kercsmar CM: The respiratory system. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia: WB Saunders, 1994, p 451.
infection and inflammation lead to irreversible lung damage, such changes need to be taken seriously and treated aggressively. This is just as true for the appearance of a mild morning cough in the child who was previously cough free as it is for severe coughing spells that keep a child awake through the night. Obstruction is treated with physical means (chest physical therapy, with percussion, vibration, and postural drainage) to dislodge the mucus into the large central airways, where cough can then effectively clear it. Studies have shown this rather crude and timeconsuming procedure to be effective in helping to maintain lung function acutely and over a period of years. Variations on the physical maneuvers to help with mucus clearance include forced expiratory technique, positive airway pressure face masks, and masks with expiratory flutter valves. The frequency with which any of these physical means of expelling mucus should be used varies but should be increased with signs of active infection and obstruction. Other approaches to relieving obstruction in the bronchial tree include the use of inhaled bronchodilators (despite a paucity of studies showing their long-term efficacy) and mucolytic agents.
Chapter 2 Cough N-acetylcysteine (Mucomyst) has been available for years, but it may cause tracheobronchial irritation, with bronchorrhea, bronchospasm, or both, in an unacceptably high proportion of patients. An inhaled drug, dornase alfa, or recombinant human DNase (Pulmozyme), is clearly effective in the test tube for liquefying the thick mucus associated with CF. This occurs because 40% of the mucus viscosity in CF is attributed to DNA released from dying polymorphonuclear cells. Another drug that appears promising is amiloride. Long available as a diuretic, amiloride can bring about a partial correction of the membrane transport defects in CF. Amiloride aerosols seem to decrease sputum viscosity and increase cough clearance. In a small 6-month study, aerosolized amiloride appeared to slow the decline in lung function. The approach to endobronchial infection in children with CF includes prevention and treatment. Prevention involves immunizing patients with CF against preventable respiratory pathogens, particularly influenza, measles, and pertussis. Prevention also means avoiding unnecessary exposure to respiratory viruses (e.g., at day care centers). It should not mean avoiding school or other social functions and settings, because this approach is invariably futile and can cause severe emotional damage. However, spread of bacteria, especially resistant organisms such as B. cepacia, between patients is a concern. Treatment of infection usually proceeds in a stepwise manner. If colonies of H. influenzae or S. aureus are present, appropriate antibiotics should be initiated. If no recent throat or sputum specimens for culture are available, and if the patient is young with very mild lung disease, empirical therapy can also be directed at those organisms. In the older or sicker patient who has any sign of chronic pulmonary involvement, such as pulmonary overinflation, infiltrates on a chest film, digital clubbing, or severe coughing spells, it makes sense to include antibiotics effective against P. aeruginosa (Fig. 2-10; Table 2-21). Treatment of the inflammation associated with CF is evolving. Some patients benefit from short-term oral prednisone. A 4-year study of alternate-day prednisone showed improved pulmonary function but unacceptable side effects (e.g., glucose intolerance, growth failure) in those taking 2 mg/kg/day and similar side effects (although less severe) in those taking 1 mg/kg/day. The beneficial role of oral nonsteroidal antiinflammatory agents has been demonstrated; the role of inhaled topical steroids and α1-antitrypsin is being investigated.
35
ANTIBIOTIC STRATEGIES FOR WORSENED COUGH IN CYSTIC FIBROSIS (for patients culture-positive for Pseudomonas aeruginosa) Oral antibiotic 2 weeks
*At any point, if worsening, go to next step NO
Resolved?
YES
Resolved?
YES
New oral antibiotic (add or substitute) 2 weeks*
Add aerosol antibiotic 2 weeks*
NO
YES
Resolved? Add IV antibiotics 2 weeks*
NO
Resolved?
Resolving?
NO
YES
NO
Add steroids
YES
Place PPD Culture for AFB
Continue 1 more week
Change antibiotics
ANATOMIC ABNORMALITIES
STOP ANTIBIOTICS
Table 2-22 lists the main anatomic abnormalities (most of them congenital) that cause cough.
Figure 2-10. Stepwise therapeutic approach to increased cough in patients with cystic fibrosis and airway colonization with Pseudomonas aeruginosa. AFB, acid-fast bacillus; IV, intravenous; PPD, purified protein derivative.
Vascular Rings and Slings Vascular rings and slings are often associated with inspiratory stridor because the abnormal vessels compress central airways, most commonly the trachea (see Chapter 5). The patient may also have difficulty swallowing if the esophagus is compressed. The diagnosis may be suspected from plain films of the chest, especially those showing tracheal deviation and a right-sided aortic arch. Further support for the diagnosis can be found at bronchoscopy (which shows extrinsic compression of the trachea or a mainstem bronchus), barium swallow study (which shows esophageal compression), or both. The definitive diagnosis is made with magnetic resonance imaging, angiography, or magnetic resonance angiography. Treatment is surgical. Pulmonary Sequestration Pulmonary sequestration is relatively unusual, occurring in 1 in 60,000 children. It occurs most commonly in the left lower lobe and
can manifest in several ways (Fig. 2-11; see Table 2-22). The chest radiograph usually shows a density in the left lower lobe; this density often appears to contain cysts. The feature distinguishing a sequestered lobe from a complicated pneumonia is that the blood supply arises from the aorta and not the pulmonary circulation. Doppler ultrasonography and angiography provide the definitive diagnosis. The treatment is surgical removal. Cystic Adenomatoid Malformation Cystic adenomatoid malformation is a rare condition. It manifests in infancy with respiratory distress in nearly 50% of cases; the other half may manifest as cough with recurrent infection later in childhood or even adulthood. The chest film reveals multiple cysts, separated by dense areas. Chest CT scans can help make the diagnosis with near certainty. Surgical removal is the treatment.
Section One Respiratory Disorders
36
Table 2-21. Antibiotic Treatment of Cough in Cystic Fibrosis Route
Organism
Oral
Staphylococcus aureus
Doses Per 24 Hours
Cost* ($) for 2 Weeks
Comments
50–100
3–4
22
Clindamycin Clarithromycin
20 15
3–4 2
93 77
Erythromycin
50–100
2–4
12
Amoxicillin/ clavulanate Amoxicillin Trimethoprimsulfamethoxazole Chloramphenicol Ciprofloxacin Ofloxacin
40
3
105
50–100 10–20
3 2–3
19 29
50–100 15–30 20
3–4 2 2
64 141 98
Empirical
Tetracycline Doxycycline Chloramphenicol
50–100 2.5–5.0 50–100
3–4 1–2 3–4
5 88 64
S. aureus P. aeruginosa
Oxacillin Gentamicin or tobramycin Amikacin
150–200 8–20
4 1–3
665 78
15–30
2–3
1380
Netilmicin
6–12
2–3
392
Carbenicillin Ticarcillin Piperacillin
250–450 250–450 250–450
4–6 4–6 4–6
495 653 1171
Mezlocillin Azlocillin Ticarcillin/ clavulanate Imipenem/ cilistatin Ceftazidime Aztreonam Gentamicin or tobramycin (TOBI) Colistin Carbenicillin Ceftazidime
250–450 250–450 250–450
4–6 4–6 4–6
883 — 730
45–90
3–4
1881
Also active against Staphylococcus species Nausea with infusion
150 200 —
3 4 2–4
1195 1544 43–186
80–600 mg/dose
— — —
2–4 2–4 2–4
960 77 597
75–150 mg/dose in saline 500 mg–1 g; strong odor May foam
Pseudomonas aeruginosa
Aerosol
Dosage (mg/kg/24 hr)
Cloxacillin
Haemophilus influenzae
Intravenous
Agent
P. aeruginosa
Less gastrointestinal upset than erythromycin Gastrointestinal upset common
Dose based on trimethoprim Bone marrow suppression Not for young children Also active against Staphylococcus species Not for children 5 years
Repiratory distress
14 8
C
large subglottic hemangioma, a tracheostomy is frequently performed and maintained until the mass regresses.
4%), a family history of asthma or allergy, and a personal history of eczema or food allergy
47
are strongly suggestive of the diagnosis of asthma. Other studies include measurement of total serum immunoglobulin E (IgE) levels; this immunoglobulin is often elevated in individuals with asthma and/or allergy, as well as in those predisposed to asthma. Radiographic findings are nonspecific, but the films usually show symmetric hyperinflation and increased peribronchial thickening. A chest radiograph may also help to rule out other causes of wheezing, such as foreign body, pneumonia, or atelectasis (Table 3-4). The peripheral white blood cell count may reveal eosinophilia; if sputum is available, it may also demonstrate eosinophils. Patients with acute asthma typically present with shortness of breath, wheezing, cough, and increased work of breathing. Persistent cough may be the most prominent or even sole feature of acute asthma. Many asthma episodes are misdiagnosed as bronchitis (see Chapter 2). Chest wall and suprasternal notch retractions and nasal flaring may be present. Chest wall retractions and the use of neck strap (accessory) muscles indicate significant airway obstruction. Acute asthma exacerbations that are unresponsive to aggressive bronchodilator administration are termed status asthmaticus. The severity of asthma may be assessed with the parameters presented in Tables 3-5 and 3-6. Common triggers of acute episodes include upper respiratory tract infections, exposure to cold air, exercise, allergens, pollutants, strong odors, and tobacco smoke. A brief but pertinent history should be obtained for every child with acute asthma to determine the duration of symptoms, the character of previous episodes (severity, need for hospitalization, and need for intensive care, including mechanical ventilation), antecedent illness, symptoms, exposures, and both chronic and acute use of medications, including dose and time of last administration. It is critical to rule out other causes of wheezing that are not asthma and that necessitate different therapy (see Table 3-4). Anatomic abnormalities of the airway, such as vascular ring, tracheobronchomalacia, ciliary dyskinesia, and foreign body aspiration, may cause airway obstruction and wheezing, especially in infants and young children. Viral infections, notably those of respiratory syncytial virus (RSV), metapneumovirus, adenovirus, parainfluenza, and influenza, are also common causes of wheezing in infants and young children. Infection with Mycoplasma species may produce airway hyperactivity in older children. Other entities to consider are cystic fibrosis, interstitial lung disease, or a behavioral disorder, such as vocal cord dysfunction. In comparison with asthma, the key distinguishing feature of these diagnoses is that the wheezing does not respond to treatment with bronchodilators. The physical examination should focus on respiratory rate, air exchange, degree and localization of wheezing, other adventitious lung sounds, mental status, presence of cyanosis, and degree of fatigue (see Tables 3-5 and 3-6). An arterial blood gas analysis should be obtained if the clinical evaluation reveals moderate to severe airway obstruction. The presence and degree of hypoxemia and hypoventilation can be determined. Pulse oximetry is a noninvasive means of rapidly assessing oxygenation; when used in conjunction with measurement of the venous CO2 pressure or pH, it is an acceptable alternative to an arterial blood gas determination in mildly to moderately ill patients. Chest roentgenograms should be obtained for all patients with a first episode of wheezing. Patients with recurrent asthma should have a chest radiograph if there is fever, localized crackles or wheezing, decreased breath sounds, a poor response to therapy, or significant tachypnea. Spirometry has limited efficacy in the emergency management of status asthmaticus. Although peak expiratory flow meters are often available in the emergency department, the test with this device is a measure of large airway function only, is effort dependent, and may be most unreliable in an anxious, untrained patient. The major value of peak flow measurements in acute asthma is to provide an objective trend indicative of improvement (or lack thereof) in airway caliber.
Section One Respiratory Disorders
48 DIAGNOSIS
Cough and/or wheeze
Clinical history Physical examination
Suggestive of asthma Episodic Nocturnal Seasonal Exertional Family history asthma/allergy Food allergy Eczema Eosinophilia
Indeterminate features or suggestive of alternative diagnosis Neonatal onset Failure to thrive Chronic infection Vomiting/choking Focal lung or CVS signs
Consider Chest and sinus x rays Lung function Bronchial challenge and/or bronchodilator response
Where possible frequent peak flow measurements Bronchodilator response
Figure 3-2. Diagnostic algorithm for asthma. CVS, cardiovascular system; −, negative; +, positive. (From Special Report of the Steering Committee: Asthma: A follow-up statement from an international paediatric asthma consensus group. Arch Dis Child 1992;67:240-248.)
Mantoux test Sweat test Immune function Ciliary studies Reflux studies
Asthma probable
Assess severity and etiology
Chest x ray if more than mild episodic disease
–
Trial of antiasthma treatment
+
Alternative diagnosis and treatment
Review diagnosis and compliance if poor response to treatment
Consider asthma as an associated problem
A complete blood cell count is not of use unless other complicating conditions (e.g., infection, anemia, hemoglobinopathy) are suspected. Serum electrolyte measurements are of little value unless dehydration is suspected. Hypokalemia is associated with the frequent administration of β-adrenergic agonists. Most children cannot produce sputum, but if sputum is available, it should be examined for the presence of bacteria and inflammatory cells. Treatment Acute Asthma
Treatment of acute asthma should be instituted in any child with wheezing, dyspnea, cough, and no other immediately discernible cause of the symptoms. Patients with moderate to severe airway obstruction have significant hypoxemia as a result of ventilation-perfusion mismatch. Consequently, supplemental humidified oxygen, usually 30% by face mask, is of benefit. Oxygen should be administered to any child who has significant wheezing, accessory muscle use, or an oxygen saturation of less than 93%.
The mainstay of treatment for status asthmaticus is the administration of an inhaled (or, less often, subcutaneous) β-adrenergic agonist. Inhalation of nebulized medication is the route of choice because the onset of action is rapid, sustained, and relatively free of significant side effects even in the most severely affected patients (Table 3-7). Patients who do not respond to initial therapy with aerosolized medication or cannot comply with the regimen should be given a subcutaneous injection. Although subcutaneous injection of epinephrine or a β agonist are equally effective, the procedure causes some discomfort and anxiety and may yield a higher incidence of side effects. Administration of β agonists from metered-dose inhalers with a valved holding chamber is also effective treatment of acute asthma in most children. Anticholinergic agents (ipratropium bromide), when combined with β agonists as inhaled treatment, can provide additional bronchodilation. The effect is most marked in children who present to the emergency department with significant airway obstruction. Corticosteroids are potent antiinflammatory agents that are extremely useful in treating acute asthma exacerbations. With few exceptions, any patient who presents with other than mild wheezing responsive to minimal bronchodilator therapy or any patient requiring hospital
Chapter 3 Respiratory Distress
49
Table 3-4. Causes of Wheezing in Childhood
Acute Reactive Airways Disease Asthma* Exercise-induced asthma* Hypersensitivity reactions
Chronic or Recurrent Continued Aspiration Foreign body Gastroesophageal reflux* Tracheoesophageal fistula (repaired of unrepaired)
Bronchial Edema Infection* (bronchiolitis, ILD, pneumonia) Inhalation of irritant gases or particulates Increased pulmonary venous pressure
Bronchial Hypersecretion or Failure to Clear Secretions Bronchitis, bronchiectasis Cystic fibrosis* Dyskinetic (immotile) cilia syndrome Immunodeficiency disorder Vasculitis Lymphangiectasia α1-antitrypsin deficiency
Bronchial Hypersecretion Infection Inhalation of irritant gases or particulates Cholinergic drugs Aspiration Foreign body* Aspiration of gastric contents (reflux, H-type TEF) Chronic or Recurrent Reactive Airways Disease (same as in Acute) Hypersensitivity Reactions, Allergic Bronchopulmonary Aspergillosis Dynamic Airways Collapse Bronchomalacia Tracheomalacia* Vocal cord adduction*
Intrinsic Airway Lesions Endobronchial tumors Endobronchial granulation tissue Plastic bronchitis syndrome Bronchial or tracheal stenosis Bronchiolitis obliterans Sequelae of bronchopulmonary dysplasia Sarcoidosis Congestive Heart Failure
Airway Compression by Mass or Blood Vessel Vascular ring/sling Anomalous innominate artery Pulmonary artery dilation (absent pulmonary valve) Bronchial or pulmonary cysts Lymph nodes or tumors Modified from Kercsmar CM: The respiratory system. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 445. *Common. ILD, interstitial lung disease; TEF, tracheoesophageal fistula.
admission should receive corticosteroids (Table 3-8; see Table 3-7). Although theophylline (or the intravenous formulation aminophylline) is an effective bronchodilator in chronic use, when optimal amounts of inhaled or parenteral β-adrenergic agonists are administered, the addition of theophylline does not consistently provide further significant improvement. Some severely affected patients respond to intravenous magnesium therapy. Intravenous fluids should be administered to any patient who has clinical or laboratory signs of dehydration. Fluids other than those required for normal homeostasis should not be routinely given. Chest physiotherapy may be useful for the patient who has significant atelectasis or sputum production. A small percentage of children with acute asthma progress to severe status asthmaticus and respiratory failure. A number of clinical signs and symptoms define respiratory failure in such severely affected patients: a PaO2 less than 60 mm in room air or cyanosis in 40% FiO2, a PaCO2 of 40 mm or higher or rising and accompanied by respiratory distress, deterioration in clinical status in spite of aggressive treatment, a change in mental status, and fatigue (see Tables 3-5 and 3-6). Patients meeting any of these criteria should be observed in an intensive care unit, and they should receive maximal medical therapy. Algorithmic approaches to the treatment of asthma are presented in Figure 3-3 and Tables 3-8, 3-9, and 3-10.
Chronic Asthma
Treatment of chronic asthma requires careful assessment of the severity of the disease, according to frequency and intensity of symptoms, and subsequent grading into mild, moderate, and severe categories (see Table 3-9 and 3-10). In general, all patients except those with mild intermittent disease are best managed with chronic administration of an inhaled antiinflammatory agent (corticosteroids) and the intermittent use of an inhaled β-adrenergic agonist for treatment of acute wheezing episodes. Leukotriene receptor antagonists may be considered as an alternative preventive therapy for mild asthma. Oral corticosteroids are administered for short intervals to control more severe exacerbations. Avoidance of environmental triggers (allergens, tobacco smoke) is also paramount to successful management.
RESPIRATORY DISTRESS IN INFANTS AND TODDLERS VIRAL BRONCHIOLITIS Bronchiolitis is a frequent manifestation of acute viral infections of the distal lower respiratory tract and a cause of wheezing and
Section One Respiratory Disorders
50
Table 3-5. Classifying Severity of Asthma Exacerbations* Mild
Symptoms Breathlessness
While walking
Posture Talks in Alertness Signs Respiratory rate
Moderate
Severe
Respiratory Arrest Imminent
While at rest (infant—stops feeding)
—
Can lie down Sentences May be agitated
While talking (infant— softer, shorter cry; difficulty feeding) Prefers sitting Phrases Usually agitated
Sits upright Words Usually agitated
— — Drowsy or confused
Increased
Increased
Often >30/min
—
Guide to rates of breathing in awake children: Age Normal Rate 18 to 24 hours), uterine tenderness, or preterm labor is at increased risk for delivering a
Most children with a UTI present with dysuria, frequency, or fever. It is worthwhile to ask about any urine color change, which suggests the presence of hematuria. A history of anal pruritus is suggestive of pinworms, which may also irritate the urethral area. The child should 397
Section Four Genitourinary Disorders
398
be questioned about the frequency, character, and size of his or her bowel movements. Bulky stools associated with constipation may predispose the child to a UTI; stool softeners, such as mineral oil or fiber, may be indicated (see Chapter 21). ADOLESCENTS In the adolescent, a detailed sexual history is mandatory, focusing on cystitis from sexual intercourse or vaginitis. Herpes simplex, infections with Trichomonas and Chlamydia species, and gonorrhea all cause urethritis. The most likely time for this to appear is within 1 month of beginning a relationship with a new sexual partner. Because the use of a diaphragm for contraception is associated with an increased risk of UTI, adolescents experiencing recurrent UTIs should be offered an alternative form of birth control. Similarly, adolescent girls should be questioned about voiding before or after intercourse, because studies have shown a reduction of UTI with postintercourse urination. Pelvic examination to exclude vaginitis is essential in all sexually active adolescent girls when pyuria is absent or when vaginal discharge is reported. Conversely, adolescents with dysuria and pyuria may be assumed to have a UTI if the urinalysis is free of contaminating squamous epithelial cells. The presence of more than rare epithelial cells suggests contamination of the urine with vaginal white cells and bacteria. The pelvic examination should include cervical cultures for Neisseria gonorrhoeae and Chlamydia species because both organisms can cause urethritis. Trichomonas species and clue cells should be checked with a saline preparation, and any lesions suggestive of herpes simplex should be cultured (see Chapter 29). A cause for dysuria may be found in 90% of young women. About 10% may have vaginitis, whereas about 50% have more than 105 bacteria/mL in a midstream urine sample. The remaining 40% of women with fewer than 105 bacteria/mL were once considered to have “urethral syndrome” and were believed not to have true bacteriuria. However, according to direct bladder sampling, half had positive bacterial cultures of the usual pathogens, one third had positive Chlamydia cultures from the bladder, and 10% had no cause for dysuria. This last group probably had mechanical or chemical irritation of the urethra, from either sexual intercourse or bath soaps. Boys and men with dysuria may also have penile pain or dysuria as a result of phimosis, paraphimosis, balanitis, urethral trauma, epididymitis, or meatal stenosis. Phimosis is a scarring or narrowing of the preputial opening and manifests as failure to retract the foreskin (the foreskin is normally difficult to retract in neonates, but by 3 years of age it is easily retracted). Paraphimosis, an emergent disease, is an incarceration of the prepuce behind the glans. Edema, pain, and swelling are present. Balanitis is an infection of the prepuce (by Streptococcus species, Candida species, mixed flora, Trichomonas species); it may be recurrent and warrants circumcision.
METHODS OF OBTAINING URINE CULTURES A properly obtained urine specimen for urinalysis and culture is critical for accurate treatment. Numerous studies have shown that more than 50% of all positive cultures obtained from a “bagged” specimen are skin contaminants. In the non–toilet-trained toddler, urine should be obtained by a bag only if treatment is not planned that day, and a confirmatory culture may be done the next day. The confirmatory culture may be either a suprapubic aspiration or a catheterized urine specimen. Because aspiration requires a full bladder and infants void every 1 to 2 hours, it is often impractical to wait. Catheterization is more efficient, but it does carry approximately a 1% risk of introducing infection into the bladder. Uncircumcised infants with a nonretractile foreskin should have a suprapubic aspiration.
In the toilet-trained child, a clean-void urine specimen is adequate. There are several exceptions to this rule. Uncircumcised boys have a contamination rate of 5% to 9%, depending on whether soap cleansing was used. Therefore, if treatment is needed urgently in such boys, two urine samples should be cultured, or a suprapubic aspiration should be performed. Adolescent girls may also fail to cleanse adequately, as may obese younger girls. The urine sample should be examined for squamous epithelial cells and should be discarded if such cells are present. The gold standard for a UTI is a positive culture, by the criterion of 105 bacteria/mL; nonetheless, lower colony counts are present in a significant number of patients. Lower colony counts occur in boys, in diluted urine, in specimens from suprapubic or catheterized samples, and in infections with certain pathogens (for Staphylococcus saprophyticus, colony counts may be as low as 102/mL). About 33% of women have true cystitis with colony counts of less than 105 bacteria/mL; therefore some investigators have suggested a criterion of 102 bacteria/mL for dysuric women. In children, the use of colony counts as low as 102 bacteria/mL results in overdiagnosis, which is a problem because it may lead to unnecessary radiologic evaluation of the urinary tract. Of children with positive suprapubic tap results, 90% have at least 104 bacteria/mL; therefore, this seems a reasonable criterion for defining infection on clean-void urine samples. For symptomatic children with less than 104 bacteria/mL, a second specimen must be analyzed before treatment. Table 23-1 summarizes the recommended colony counts to define UTI in children. Escherichia coli is the dominant pathogen causing UTI in all ages; less common pathogens include Klebsiella species, Proteus species, S. saprophyticus, and Enterococcus species. Mixed urine cultures do not always signify a contaminated specimen. Mixed coliform infections were noted in women (19% of all positive cultures) who were catheterized to avoid contamination. Mixed infections are also seen in children, but a catheterized specimen is necessary to confirm the infections. Urinalysis should be performed both microscopically and by the dipstick method to detect the presence of nitrites, hematuria, and leukocyte esterase (Fig. 23-1). Decisions on treatment are usually based on the urinalysis results, not urine culture results, which require 18 to 24 hours of incubation. Fortunately, the sensitivity and specificity of the combination of the presence of leukocyte esterase and nitrite are very high in older children (Table 23-2). The accuracy of these tests in young infants and neonates is much lower. In these patients, presumptive therapy is often begun for presumed sepsis before confirmation of infection from urine, blood, or other cultures. Microscopic evaluation of the urine for white blood cells and bacteria improves the diagnostic accuracy of the urinalysis (see Table 23-2). Therefore, in the evaluation of older children, a dipstick test for the presence of nitrites and leukocyte and a microscopic evaluation should be performed. The presence of leukocytes and bacteria, even with a negative nitrite test result, suggests a diagnosis of a UTI. The presence of only leukocytes indicates a diagnosis of vaginitis or Chlamydia, Mycoplasma hominis, or Ureaplasma
Table 23-1. Criteria for Urinary Infection in Children
Suprapublic aspiration Catheterization* Clean-void urine (CVU) in symptomatic patient CVU in asymptomatic patient
Any growth significant ≥103 bacteria/mL ≥104 bacteria/mL >105 bacteria/mL in 2 samples
*The exception is the uncircumcised neonate with a nonretractile foreskin. If colony count is 5/hpf) Bacteria (any) Leukocytes and/or bacteria Unspun urine in counting chamber† >5 motile bacteria/mm3 >5 WBC/mm3
Specificity (%)
Positive Predictive Value (%)
Negative Predictive Value (%)
79 37 83
73 100 72
34 100 34
95 90 96
80 99 99
84 71 65
47 37 33
96 100 100
96 64
89 92
75 70
99 88
*Adapted from Lohr JA, Portilla MG, Geuder TG, et al: Making a presumptive diagnosis of urinary tract infection by using a urinalysis performed in an on-site laboratory. J Pediatr 1993;122:22-25. †
Adapted from Corman LI, Horbison RW: Simplified urinary microscopy to detect significant bacteriuria. Pediatrics 1982;70:133-135.
hpf, high-power field; WBC, white blood cell.
DIFFERENTIAL DIAGNOSIS OF DYSURIA After the history and physical examination, a list of probable diagnoses should be developed. This list determines which laboratory tests or radiologic studies are needed and cost effective. Table 23-4 outlines the differential diagnosis of dysuria, regardless of patient age. NEONATES UTI in the first month of life has different epidemiologic characteristics than does UTI in later infancy and childhood. It affects more boys than girls at a 5:1 ratio; about 5% of these infant boys have
Table 23-3. Clues on Urinalysis that Point to the
Correct Diagnosis for Dysuria 1. Gross hematuria suggests a. Glomerulonephritis, especially Berger disease (IgA nephropathy) b. Cystitis c. Renal calculi d. Trauma e. Tumor (rare) 2. White blood cell casts suggest pyelonephritis but are rarely seen in children; red blood cell casts suggest acute glomerulonephritis. 3. Proteinuria and yellow urine suggest glomerular damage; reflux nephropathy and polycystic kidney disease may produce a UTI and proteinuria. 4. Proteinuria in pink or red urine may indicate hemolysis or rhabdomyolysis. 5. Urate crystals resemble bacteria but may be dissolved by heating the slide or test tube. 6. Alkaline pH in the presence of pyuria suggests a urease-producing bacterium, such as Proteus species. 7. Salmon-colored urine in neonates is urate crystals, not blood. It is not a sign of UTI but rather of concentrated urine. UTI, urinary tract infection.
obstructive uropathy (Fig. 23-2). It was once thought that all these infections were hematogenous, but the high incidence of VUR and obstructive uropathy suggests that many of these infections are ascending from the bladder to the kidney. In addition, the rate of UTI in the first year of life is 11 times higher among uncircumcised boys than among circumcised boys, which suggests that infection originates in the prepuce. Furthermore, the rate of UTI is lower in the first 72 hours after birth than afterward. In the first 72 hours, 90% of the urinary infections were accompanied by bacteremia, which suggests the presence of disseminated sepsis. Thereafter, the rate of accompanying bacteremia is 10% to 20%. In a prospective screening study of 1762 infants admitted to a neonatal intensive care nursery, 2.4% of patients were bacteriuric, of whom 1.9% had symptomatic bacteriuria and 0.5% had asymptomatic bacteriuria. Of 43 UTIs, only 6 were associated with bacteremia. Radiologic anomalies were found in 44% of the symptomatic neonates, including three children with hydronephrosis. In another study, hydronephrosis caused by obstructive lesions was seen in about 5% of neonates, and severe (grade IV or V) VUR in about 19% of neonates with symptomatic UTI. Many neonates with a UTI require urologic follow-up. When uncircumcised infant boys are evaluated for sepsis, a suprapubic aspiration yields a much lower contamination rate than does a catheter specimen. The bladder is a more superficial abdominal organ until the end of infancy and is readily accessible with a 11/2-inch-long, 22-gauge needle, inserted perpendicular to the abdominal wall, 1 to 2 cm above the symphysis pubis in the midline. Negative pressure is applied while the needle is advanced slowly until urine is obtained. No anesthetic or sterile gloves are necessary, but the infant’s perineum and genitals should be cleansed with an antiseptic solution and should not have voided for 1 hour before the procedure is performed, to ensure that the bladder is full. Obstructive uropathy can also cause neonatal UTI and sepsis. In many affected neonates, it is diagnosed by prenatal ultrasonography; therefore, antibiotic prophylaxis or immediate surgical correction can prevent sepsis and renal injury (see Chapter 22). Any neonate with bilateral hydronephrosis should undergo VCUG before discharge to rule out posterior urethral valves or bladder neck obstruction. If VUR is found, antibiotic prophylaxis should be started. Neonates with the more common diagnoses of ureteropelvic junction obstruction and unilateral multicystic dysplastic kidney do not usually need prophylaxis; subspecialty consultation should be obtained.
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Table 23-4. Differential Diagnosis of Dysuria
Urinary Tract Infections* Urethritis Cystitis Pyelonephritis Adenoviral hemorrhagic cystitis Schistosomiasis Vaginitis* Candida albicans Trichomonas vaginalis Nonspecific vaginitis with clue cells Group A streptococci Proteus species, Escherichia coli, and other enteric pathogens Sexual abuse: gonorrhea, chlamydia, and herpes simplex Foreign body in vagina Herpes simplex Tumor-Related Dysuria Passage of blood clots from kidney tumors (Wilms) Chemotherapy-related hemorrhagic cystitis (cyclophosphamide) Rhabdomyosarcoma of bladder Urethral polyps or diverticula Fibromas of the bladder Hemangiomas Mechanical Irritation of the Urethra Boys Water injection or foreign body insertion Hypercalciuria or frank calculi Balanitis or penile ulcers Urethral stricture Posterior urethral valves Masturbation Girls Hypercalciuria Bubble bath or detergent Pinworms Labial adhesions Urethral prolapse Sexual abuse Other Dysfunctional voiding syndrome Appendicitis Inflammatory bowel disease
Figure 23-2. Distribution by age and sex of 100 infants with urinary tract infections. (From Ginsburg CM, McCracken GH Jr: Urinary tract infections in young infants. Pediatrics 1982;69:409-412.)
bacteriuria should not be treated because of the excellent prognosis for spontaneous clearing of the infection. Several prospective studies have shown that about 5% of febrile infants have a UTI. Among infants younger than 3 months, UTI is more common in boys. After 3 months of age, UTIs were uncommon in infant boys in one study of predominantly uncircumcised infant boys (see Fig. 23-2). Nonetheless, in other studies, some infant boys with UTIs present as late as 1 year of age. Bacteremia is less common in patients with UTIs after the neonatal period (rates range from 6% to 31% in various studies), but fever is seen in most patients. Because pyuria is seen in only about 50% of all infants with UTIs, it is important for a catheterized or suprapubic urine specimen to be obtained from all infants in whom the source of fever cannot be identified. It is impossible to confirm a suspicious urine culture obtained with a urine bag after antibiotic therapy has begun. Therefore, all febrile infants younger than 12 months (and possibly those 4 mg/kg/day defines hypercalciuria). Hypercalciuria may cause dysuria (see Chapter 25). If no diagnosis is reached after these steps, the severity and duration of dysuria should guide the clinician. Referral to a urologist for cystoscopy may be necessary to diagnose the extremely rare occurrence of a bladder tumor in a child. ADOLESCENTS In adolescent boys, lack of circumcision increases the risk of UTI about threefold, in comparison with that in those who are circumcised. Because the risk of UTI is so low in boys of this age group, this is a poor argument in favor of late circumcision. It is useful to obtain a urine culture as well as cultures for Chlamydia species (EIA on urine sediment or EIA or DFA on a urethral swab) and N. gonorrhoeae in all dysuric adolescent boys. Careful examination of the scrotum for signs of epididymitis is indicated (see Chapter 28). Among adolescent girls, cystitis and urethritis are more common in those who are sexually active, especially those using barrier contraception. Diaphragm, spermicide and foam, and condom users have a much higher rate of bacteriuria than do those taking birth control pills. Pyelonephritis occurs in nonsexually active adolescents only rarely and should suggest the possibility of (1) neglected UTI symptoms for days to weeks or (2) VUR. Table 23-6 provides guidelines for evaluating the adolescent with dysuria. Pitfalls in the diagnosis of dysuria are noted in Table 23-7.
Table 23-6. Adolescent History and Physical
Examination for Dysuria Differential Diagnosis Urinary tract infection (UTI) Vaginitis caused by Candida species, herpes simplex, or nonspecific anaerobic overgrowth Cervicitis caused by gonorrhea or chlamydia Chemical irritation (e.g., from douches, bubble bath) History Blood pressure and temperature New sexual partner in past month (suggests sexually transmitted diseases) Hematuria (suggests UTI) Use of a diaphragm with spermicide (predisposes to UTI) Personal history of UTIs Family history of vesicoureteral reflux (suggests UTI) Physical Examination Pelvic examination with wet preparation and cultures Perianal examination for pinworms or group A streptococcal proctitis Laboratory Studies Urinalysis, both dipstick and microscopic Vaginal wet preparation for trichomonas and clue cells Cultures of urine and cervix (gonorrhea, chlamydia, herpes)
Chapter 23 Dysuria Table 23-7. Common Pitfalls in the Correct Diagnosis
of Dysuria Neonates Assume that significant bacteriuria in a bagged urine specimen is a true UTI, and treat before a confirmatory culture is obtained Fail to obtain a urine culture in a neonate older than 3 days and miss obstructive uropathy with a secondary infection Toddlers and School-Aged Children Trust a urine culture from a bagged urine specimen Accept a laboratory report of “no significant growth” on urine, without knowing that the laboratory reports only >5 × 104 CFU/mL as “significant” Fail to label a urine as “catheterized specimen,” so that the laboratory can plate 0.1 mL as well as 0.01 mL Fail to obtain a cystogram after the first infection, trusting to see reflux on sonogram or intravenous pyelogram Adolescents Fail to ask about sexual history suggestive of vaginitis, such as a new sexual partner and condom or other birth control device use Treat pyuria as a UTI in a sample contaminated with vaginal leukocytes CFU, colony-forming unit; UTI, urinary tract infection.
ASYMPTOMATIC BACTERIURIA It was once believed that asymptomatic bacteriuria could lead to silent renal damage and ultimate renal failure. The completion of several long-term prospective studies of school-aged girls with asymptomatic bacteriuria has put such fears to rest. The incidence of asymptomatic bacteriuria in females is about 1.5%. About 33% of girls with asymptomatic bacteriuria have VUR, and as many as 10% to 25% may have renal scarring. However, the long-term prognosis is excellent, even in patients with ongoing bacteriuria. Treatment with short courses of antibiotics may lead to more episodes of pyelonephritis in comparison with no treatment. It is strongly recommended that no prophylaxis be administered; treatment is indicated for symptomatic episodes. For these reasons, it is best not to screen for asymptomatic bacteriuria. When the condition is found incidentally, the family should be counseled with regard to its favorable outcome. Radiologic studies are not indicated unless a symptomatic UTI subsequently develops. The physician may wish to repeat a urine culture in 3 to 6 months because most cases of asymptomatic bacteriuria clear spontaneously, and the family can be reassured. Knowledge of asymptomatic bacteriuria may be beneficial when an affected woman becomes pregnant. During pregnancy, asymptomatic bacteriuria increases the risk of pyelonephritis, preterm labor, and the possibility of sepsis in the infant.
TREATMENT CYSTITIS Treatment of afebrile UTIs in children differs significantly from treatment in adults. This is because until radiologic evaluation has ruled out VUR and other abnormalities, it may be assumed that the child may have occult pyelonephritis and is at risk of renal scarring. Therefore, the first afebrile UTI should be treated with 10 days of antibiotics, followed by prophylaxis until radiologic studies are
403
completed. Subsequent UTIs without fever can then be treated similarly to those in adults, with brief courses of 3 to 7 days of antibiotics. Single-dose therapy has a high failure rate. Culture and sensitivity testing are desirable but not mandatory in adolescents with cystitis, inasmuch as antibiotics are highly concentrated in the bladder urine. For adolescents and adults with recurrent UTIs, providing a 3-day supply of an antibiotic for episodes of dysuria that occur on weekends or while traveling is a good plan. The choice of antibiotic depends on the rate of resistance of E. coli in any geographic area. Amoxicillin resistance rates exceed 40% worldwide, but trimethoprim-sulfamethoxazole resistance rates vary, being highest in the western United States (30%) and lowest in the eastern states (10%). For adults in the western states, a fluoroquinolone for 3 days is preferred. Alternative drugs are cefdinir and cefuroxime. Nitrofurantoin may be used for cystitis but not for pyelonephritis. Adolescents may be treated with fosfomycin for cystitis but it is not approved for those younger than 12 years of age. There is a guideline for treatment of adults by the Infectious Disease Society of America, which is updated every 2 years (http:// www.idsociety.org). PYELONEPHRITIS Infants Younger than 3 Months Because of the higher risk of bacteremia and renal scarring in infants younger than 3 months, management of pyelonephritis is best started on an inpatient basis. About 66% of bacteremic children with a UTI are younger than 3 months; these infants have higher rates of anatomic obstruction of the urinary tract. If the blood culture remains negative after 48 to 72 hours and the child is doing well, the child may complete therapy as an outpatient with an oral antibiotic. Children Older than 3 Months Oral therapy with a second- or third-generation cephalosporin to which E. coli is rarely resistant may be effective and safe in children older than 3 months. Resistance rates to amoxicillin and trimethoprim-sulfamethoxazole exceed 10%; neither drug should be used empirically to treat pyelonephritis. There may be a trend toward more renal scarring in infants receiving only oral antibiotics. About 83% of U.S. pediatricians treat pyelonephritis patients as outpatients, despite the fact that only 30% of U.S. nephrologists recommend doing so. Outpatient therapy is contraindicated if the child is unable to take oral antibiotics or appears septic or there is concern about the family’s reliability. If there is any concern, the initial 24 hours of therapy should be administered intravenously. Adolescent Girls and Women Outpatient management is common in this group, again assuming that there is no contraindication such as toxic appearance or inability to take oral medication because of emesis. Ciprofloxacin is a good choice because of the low rate of antibiotic resistance. FOLLOW-UP MONITORING AND PROPHYLAXIS AFTER A URINARY TRACT INFECTION A follow-up urine culture (proof of cure) is not necessary if the patient is receiving an appropriate antibiotic, unless there is an underlying urologic condition or the response to therapy is poor. Periodic telephone or office follow-up is appropriate for any child who is receiving outpatient management for pyelonephritis. If a child has had three or more afebrile UTIs in a year, or more than one febrile UTI, oral antimicrobial prophylaxis at bedtime for 6 months is a cost-effective method of preventing a new UTI. For sexually active adolescents, an alternative method is to recommend
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Table 23-8. Prophylactic Antibiotics for Childhood Urinary Infections
Trimethoprim-sulfamethoxazole (TMP-SMX) Nitrofurantoin Trimethoprim
Dose
Timing
Side-Effects
2 mg/kg of TMP component (up to 40 mg) (1/2 tablet) 1-2 mg/kg/day up to 100 mg 2 mg/kg up to 40 mg
Bedtime
Rash in 6%, Stevens-Johnson (rare)
Bedtime Bedtime
GI intolerance, pulmonary fibrosis (rare) Rash in 1%
GI, gastrointestinal.
one tablet of trimethoprim-sulfamethoxazole after each episode of sexual intercourse. Drugs appropriate for prophylaxis are shown in Table 23-8. It is not appropriate to use amoxicillin or cephalosporins for prophylaxis, because they alter bowel flora and may select resistant organisms. An exception is made for neonates ( 38.5 (101.3) 2. Back or loin pain 3. C-reactive protein >20 mg/l
performed many studies on localization of UTIs to the kidney or bladder, and they have found the presence of fever with temperature higher than 38.5° C, back or loin pain, or a C-reactive protein level exceeding 20 mg/L to be very reliable in identifying upper tract infection. Many U.S. experts are skeptical and would prefer to use age as the major decision factor in whom to evaluate. Finally, the issue of evaluation of adolescents must be addressed. There is general agreement that recurrent cystitis needs no evaluation unless stones are present or a Proteus species is isolated. Adolescents with pyelonephritis should undergo sonography and cystography after the second episode, if they fail to respond promptly, or if a history of multiple earlier UTIs before puberty is elicited.
MANAGEMENT OF VESICOURETERAL REFLUX 1. After identifying VUR, parents need education about risks and the importance of rapid treatment of UTIs. 2. All children with dilating reflux (grades III to V) or scarring need referral to a pediatric urologist or pediatric nephrologist. Those with grades I and II reflux may be referred as well, depending on the experience of the primary care practitioner. 3. The American Urological Association published guidelines on surgery for VUR in 1997. Immediate surgery is limited to those with bilateral grade V disease after 1 year of age, grade V unilateral disease after 6 years of age, and bilateral grades III and IV after 6 years of age.
4. If surgery is needed, the transabdominal route is standard for care, but endoscopic correction is available at some centers. 5. Children with breakthrough pyelonephritis, especially if taking prophylaxis, need referral for possible surgery. 6. Prophylaxis with low-dose bedtime antibiotics is recommended for grade III and higher VUR by the 1999 Swedish guidelines. They recommend discontinuing prophylaxis at 2 years in boys and 10 years in girls, regardless of the grade of VUR. Alternatively many U.S. nephrologists recommend prophylaxis to all with VUR until age 5 to 6 years and longer if UTIs continue to occur. 7. Blood pressure and urinary protein should be measured yearly. Children with significant scarring should have creatinine measurements. 8. Dysfunctional voiding needs to be corrected if present because it perpetuates VUR. Girls in particular seem to develop detrusorsphincter dyscoordination (i.e., attempting to void with a closed sphincter). This may explain the peak in UTIs among girls at ages 3 to 4 years, which is often during toilet training. Most of these children have enuresis in the daytime, and some have encopresis or constipation. Referral to a pediatric urologist is indicated for all children with UTIs who have these symptoms. A noninvasive urine flow study and measurement of residual urine are performed. Treatment may involve oxybutynin (Ditropan), to reduce bladder spasms; antibiotic prophylaxis; and timed voiding. 9. Finally, pregnancy in adolescent girls or women with VUR needs monitoring by a high-risk obstetric team. This applies even if the woman has undergone reimplantation of her ureters. Pregnant women with VUR and scarring are candidates for antibiotic prophylaxis.
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Table 23-14. Red Flags for Referral to a Pediatric
Urologist or Nephrologist after a Urinary Tract Infection Dilating VUR (grade III, IV, or V) Renal scarring detected on sonography and IVP or a DMSA scan obtained >6 months after the UTI Urinary obstruction seen on a sonogram or IVP Voiding dysfunction (enuresis, frequency, “curtsy” to stop voiding) Breakthrough UTI in the child with VUR receiving prophylaxis Elevated serum creatinine level Hypertension Antenatal hydronephrosis that is confirmed after day 3 after birth DMSA, dimercaptosuccinic acid; IVP, intravenous pyelography; UTI, urinary tract infection; VUR, vesicoureteral reflux.
SUMMARY Dysuria in children who are prepubertal is usually a symptom of UTI. The differential diagnosis expands greatly in adolescents, in whom a sexually transmitted disease may be the cause. Because children younger than 2 years cannot verbalize complaints, the presence of a UTI is often overlooked. It is precisely these infants and toddlers who may suffer the most renal damage from a febrile UTI. Awareness by medical providers that both boys and girls have relatively high rates of UTI in the first year will help prevent renal damage. The second step in preventing renal scarring is to evaluate children radiologically after the first febrile UTI. There remains considerable disagreement among experts on the most cost-effective and painless way to accomplish this. The key point is to obtain a VCUG and/or a DMSA renal scan on each child; a sonogram alone is an inadequate evaluation that does not rule out renal scarring or VUR. Finally, close medical supervision of children with VUR and/ or renal scarring is needed throughout childhood and pregnancy. The medical community finally agrees that surgical intervention is rarely necessary for VUR, but that puts more responsibility on the medical provider to monitor for infection, hypertension, and renal insufficiency. Table 23-14 shows red flags for referral to a pediatric urologist or nephrologist.
REFERENCES
Bladder Dysfunction Austin PF, Ritchey ML: Dysfunctional voiding. Pediatr Rev 2000;21: 336-341. Farhat W, McLorie G: Urethral syndromes in children. Pediatr Rev 2001; 22:17-20. Sillen U: Bladder dysfunction in children with vesico-ureteric reflux. Acta Paediatr Suppl 1999;431:40-47. Diagnosis of Urinary Tract Infection Bachur R, Harper MB: Reliability of the urinalysis for predicting urinary tract infections in young febrile children. Arch Pediatr Adolesc Med 2001;155:60-65. Lin D-S, Huang F-Y, Chiu N-C, et al: Comparison of hemocytometer leukocyte counts and standard urinalysis for predicting urinary tract infections in febrile infants. Pediatr Infect Dis J 2000;19:223-227. Poole C: The use of urinary dipstix in children with high-risk renal tracts. Br J Nurs 1999;8:512-516. Treatment of Urinary Tract Infection Hoberman A, Wald ER, Hickey RW, et al: Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics 1999;104:79-86. Honkinen O, Jahnukainen T, Mertsola J, et al: Bacteremic urinary tract infection in children. Pediatr Infect Dis J 2000;19:630-634. Talan DA, Stamm WE, Hooton TM, et al: Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women—A randomized trial. JAMA 2000;283:1583-1590. Warren JW, Abrutyn E, Hebel JR, et al: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis 1999;29:745-758. Prophylaxis of Urinary Tract Infections Bollgren I: Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr Suppl 1999;431:48-52. Circumcision Christakis DA, Harvey E, Zerr DM, et al: A trade-off analysis of routine newborn circumcision. Pediatrics 2000;105:246-249. Schoen EJ, Colby CJ, Ray GT: Newborn circumcision decreases incidence and costs of urinary tract infections during the first year of life. Pediatrics 2000;105:789-793. Radiologic Evaluation and Sonograms Barry BP, Hall N, Cornford E, et al: Improved ultrasound detection of renal scarring in children following urinary tract infection. Clin Radiol 1998; 53:747-751. Craig JC, Knight JF, Sureshkumar P, et al: Vesicoureteric reflux and timing of micturating cystourethrography after urinary tract infection. Arch Dis Child 1997;76:275-277. Sixt R, Stokland E: Assessment of infective urinary tract disorders. Q J Nucl Med 1998;42:119-125.
General Review Articles
Dimercaptosuccinic Acid Scans
American Academy of Pediatrics Subcommittee on Urinary Tract Infection: Practice Parameter: The diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103:843-852. Hansson S, Bollgren I, Esbjorner E, et al: Urinary tract infections in children below two years of age: A quality assurance project in Sweden. Acta Paediatr 1999;88:270-274. Hellerstein S: Urinary tract infections—Old and new concepts. Pediatr Clin North Am 1995;42:1433-1451. Johnson CE: New advances in childhood urinary tract infections. Pediatr Rev 1999;20:335-342. Kunin CM: Perspectives of a long-time observer. J Infect Dis 2001;183 (Suppl 1):S9-S11. Rushton HG: Urinary tract infections in children—Epidemiology, evaluation, and management. Pediatr Clin North Am 1997;44:1133-1169.
Smellie JM: Technetium-99m–dimercaptosuccinic acid studies and urinary tract infection in childhood. Acta Paediatr 1998;87:132-133. Stokland E, Hellstrom M, Jacobsson B, et al: Evaluation of DMSA scintigraphy and urography in assessing both acute and permanent renal damage in children. Acta Radiol 1998;39:447-452. Stokland E, Hellstrom M, Jakobsson B, Sixt R: Imaging of renal scarring. Acta Paediatr Suppl 1999;431:13-21. Renal Scarring and Long-Term Outcomes Bukowski TP, Betrus GG, Aquilina JW, Perlmutter AD: Urinary tract infections and pregnancy in women who underwent antireflux surgery in childhood. J Urol 1998;159:1286-1289. Jacobson SH, Hansson S, Jakobsson B: Vesico-ureteric reflux: Occurrence and long-term risks. Acta Paediatr Suppl 1999;431:22-30.
Chapter 23 Dysuria Martinell J, Lidin-Janson G, Jagenburg R, et al: Girls prone to urinary infections followed into adulthood. Indices of renal disease. Pediatr Nephrol 1996;10:139-142. Smellie JM, Prescod NP, Shaw PJ, et al: Childhood reflux and urinary infection: A follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998;12:727-736. Wennerstrom M, Hansson S, Jodal U, et al: Renal function 16 to 26 years after the first urinary tract infection in childhood. Arch Pediatr Adolesc Med 2000;154:339-345. Vesicoureteral Reflux Management Decter RM: Vesicoureteral Reflux. Pediatr Rev 2001;22:205-209. Elder JS, Peters CA, Arant BS, et al: Pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157:1846-1851.
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Jodal U, Lindberg U: Guidelines for management of children with urinary tract infection and vesico-ureteric reflux. Recommendations from a Swedish state-of-the-art conference. Acta Paediatr Suppl 1999;431:87-89. Smellie JM, Barratt TM, Chantler C, et al: Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: A randomised trial. Lancet 2001;357:1329-1333.
24
Proteinuria
Robert J. Cunningham III
An evaluation of the pediatric patient with proteinuria requires a consideration of age, gender, the presence of edema, the presence of hypertension, and a measure of renal function. In many cases, the diagnostic workup is brief; it is unusual for a pediatric patient to require a renal biopsy as part of the initial evaluation. Proteinuria may be an inconsequential finding or a manifestation of a more serious disease (Table 24-1). The workup and differential diagnosis in a child with proteinuria depends on the presence or absence of nephrotic syndrome. The four defining features of nephrotic syndrome are proteinuria, hypoalbuminemia, edema (with or without ascites), and hyperlipidemia. Nephrotic syndrome may be a result of many primary etiologic factors, with varying renal pathologic processes and long-term consequences. Most cases of nephrotic syndrome in children are caused by minimal change nephrotic syndrome, defined as normal histologic features of the kidney according to light microscopy and immune stains. Proteinuria that causes edema is always clinically significant, although not all edema is secondary to proteinuria (Table 24-2). All children with nephrotic syndrome must be evaluated, and most require treatment. In contrast, the workup of asymptomatic proteinuria, often a benign condition, is done in a staged manner, and treatment is usually not necessary. There are well-accepted definitions of proteinuria (Table 24-3). Children with nephrotic syndrome invariably have “nephrotic-range” proteinuria. In rare cases, a child with asymptomatic proteinuria has nephrotic-range proteinuria. If there is concomitant hypoalbuminemia and hyperlipidemia, the workup proceeds as if the child presented with nephrotic syndrome, despite the absence of edema. Even without hypoalbuminemia and hyperlipidemia, nephrotic-range proteinuria is less likely to be benign than is less marked asymptomatic proteinuria.
Differential Diagnosis The evaluation requires that the examiner consider the causes of nephrotic syndrome in early childhood. The data in Table 24-7 are from the International Study of Kidney Disease in Children (ISKDC); three diseases constitute 92% of all cases of nephrotic syndrome in children older than 1 year of age but younger than 17: minimal change disease (the most common); focal segmental sclerosis (also called focal glomerular sclerosis), seen in 8.5%; and membranoproliferative glomerulonephritis (MPGN) (7.5%). The features of these three common disorders producing nephrotic syndrome are noted in Table 24-8, and they are compared with membranous nephropathy, a common cause of nephrosis in young adults. Nephrotic syndrome in membranous disease may be primary or secondary to other diseases (e.g., hepatitis or systemic lupus erythematosus [SLE]) or toxins and drugs such as gold, mercury, bismuth, silver, D-penicillamine, trimethadione, probenecid, and captopril. Systemic diseases also cause childhood nephrotic syndrome but account for 10% of cases. The three foremost considerations include SLE, anaphylactoid purpura (Henoch-Schönlein purpura), and hemolytic-uremic syndrome. These diseases have extrarenal manifestations in addition to the proteinuria and must be considered in any child who presents with systemic illness and significant proteinuria. Minimal change nephrotic syndrome is slightly more common in boys than in girls. The hallmark of this disease is total clearing of the proteinuria with a 1-month course of daily oral prednisone therapy. A common misconception is that neither hematuria nor hypertension is present in children with minimal change disease. As demonstrated in Table 24-8, hematuria and hypertension are present in up to 20% of children who have minimal change disease. The blood urea nitrogen (BUN) or serum creatinine level may also be elevated in up to 30% of the cases, although an elevation of creatinine above 1 to 1.5 mg/dL is rarely seen. Serum complement studies, specifically C3, are invariably normal. Older age, hematuria, hypertension, and azotemia may occur with minimal change nephrotic syndrome, but the combination suggests another disease.
NEPHROTIC SYNDROME IN YOUNG CHILDREN MINIMAL CHANGE DISEASE Preschool-aged children constitute the age group in which minimal change nephrotic syndrome is most common. Patients often present with asymptomatic edema, which may manifest as swollen or puffy eyes on awakening in the morning; increasing abdominal girth (increased waist or belt size) from ascites; pedal or leg edema, which causes difficulty in putting on their regular-sized shoes, especially after being upright during the daytime; or swelling in other sites, such as the scrotum, penis, vulva, and scalp. Tense edema or ascites is occasionally painful. The initial evaluation of a patient with proteinuria is presented in Table 24-4. Indications for a referral to a pediatric nephrologist are described in Table 24-5. If there is obvious edema with proteinuria, the diagnostic evaluation noted in Table 24-4 advances directly to the second phase and, if necessary, to the third phase. A biopsy may or may not be indicated, and it is usually avoided until the response to therapy is noted to be poor (Table 24-6).
Diagnosis Studies that would help confirm that a patient with nephrotic syndrome has minimal change disease include urinalysis, serum C3 level, serum cholesterol determination, serum albumin level, BUN level, and serum creatinine level. The urinalysis would be expected to show 3+ to 4+ protein, which is correlated with a urine concentration of 300 to 2000 mg/dL. The urine may also yield positive results for hemoglobin. Microscopic examination of the urine sediment often shows oval fat bodies and/or refractile granular casts, which are seen when there is significant lipiduria. Red blood cells might also be present, but it is unusual to see red blood cell casts. Their presence would suggest a diagnosis of poststreptococcal glomerulonephritis or other causes of nephritis (see Chapter 25). 413
Section Four Genitourinary Disorders
414 Table 24-1. Classification of Proteinuria
Table 24-2. Causes of Edema
Nonpathologic Proteinuria Postural (orthostatic) Febrile Exercise
Kidney Diseases Acute glomerulonephritis Nephrotic syndrome Acute renal failure Chronic renal failure
Pathologic Proteinuria Tubular Hereditary Cystinosis Wilson disease Lowe syndrome Proximal renal tubular acidosis Galactosemia Acquired Analgesic abuse Vitamin D intoxication Hypokalemia Antibiotics Interstitial nephritis Acute tubular necrosis Sarcoidosis Cystic diseases Homograft rejection Penicillamine Heavy metal poisoning (mercury, gold, lead, bismuth, cadmium, chromium, copper) Glomerular Persistent asymptomatic Nephrotic syndrome Idiopathic Minimal change Mesangial proliferation Focal segmental glomerulosclerosis Membranous Membranoproliferative Immunoglobulin A (IgA) Secondary Glomerulonephritis Alport syndrome Collagen-vascular disease Henoch-Schönlein purpura Cancer Congenital
Heart Failure Liver Failure Nutritional and Gastrointestinal Disorders Protein-calorie malnutrition Protein-losing enteropathy Nutritional edema (especially on refeeding) Endocrine Disorders Hypothyroidism Mineralocorticoid excess Miscellaneous Hydrops fetalis Venocaval obstruction Capillary leak syndrome (systemic inflammatory response syndrome) Turner syndrome (lymphedema) Allergic reaction (periorbital edema)
course of prednisone, 2 mg/kg/day for 4 weeks, followed by a dose of 1.5 mg/kg given every other morning for another 4 weeks. In most patients, there is total resolution of proteinuria within 10 to 21 days of initiating therapy. Patients who do not respond to prednisone therapy should be considered candidates for a renal biopsy (see Table 24-6). There are no data to suggest that more prednisone therapy increases the response rate. A longer duration of prednisone treatment increases the side effects without concomitant benefit. Therefore, if there is no response, prednisone should be discontinued after the 2-month course and a renal biopsy performed to guide further therapy. Total clearing of proteinuria in response to prednisone is an excellent prognostic sign. Very few patients progress to renal failure, although many patients who initially respond to prednisone therapy
Table 24-3. Definition of Significant Proteinuria Adapted from Behrman RE (ed): Nelson Textbook of Pediatrics, 16th ed. Philadelphia, WB Saunders, 2000, p 1591.
The C3 complement level is normal in minimal change disease and is depressed in poststreptococcal glomerulonephritis and some other causes of nephritis (see Chapter 25). If hematuria is not present by microscopic examination or dipstick, postinfectious glomerulonephritis is unlikely, and C3 determinations are unnecessary. The serum cholesterol values are elevated in minimal change nephrotic syndrome and are usually higher than 250 mg/dL; levels in the range of 500 to 600 mg/dL may occur. The serum albumin concentration is invariably less than 2.5 and often less than 2.0 g/dL. Studies that are not of help include complete blood cell counts and a 24-hour urinary protein determination. A renal biopsy is not immediately indicated because most patients (>90%) with minimal change disease respond to prednisone, a response that is considered diagnostic.
Qualitative 1+ (30 mg/dL) on dipstick examination of two of three random urine specimens collected 1 week apart if urine specific gravity < 1.015 or 2+ (100 mg/dL) on similarly collected urine specimens if urine specific gravity > 1.015 Semiquantitative Urine protein-to-creatinine ratio (mg/dL:mg/dL) of > 0.2 on an early morning urine specimen
Treatment
Quantitative Normal: 1000 mg/m2/day in a timed 12- to 24-hour urine collection
With a presumptive diagnosis of minimal change nephrotic syndrome, it is recommended that patients be placed on a therapeutic
Modified from Norman ME: An office approach to hematuria and proteinuria. Pediatr Clin North Am 1987;34:545-561.
Chapter 24 Proteinuria Table 24-4. Workup of a Child with Proteinuria
Pediatrician’s Workup: Phase I Early morning urinalysis to include examination of the sediment Ambulatory and recumbent urinalyses for dipstick protein testing Pediatrician’s Workup: Phase II Blood electrolytes, BUN, creatinine, serum proteins, cholesterol ASLO titer, C3 complement, ANA Timed 12-hour urine collections, recumbent and ambulatory Renal ultrasonography, IVP, voiding cystourethrography Pediatric Nephrologist’s Workup: Phase III Renal biopsy Management of established renal disease
415
Table 24-6. When to Consider Renal Biopsy in a Child
with Proteinuria Strong family history of chronic nephritis or unexplained renal failure Unexplained failure to thrive Coexistent hypertension and nephrotic syndrome, or evidence of a systemic inflammatory process Coexistent significant hematuria (≥10 erythrocytes/hpf) with or without erythrocyte casts in the spun sediment Nephrotic-range proteinuria with poor response to prednisone Renal glomerular insufficiency Biochemical evidence of renal tubular dysfunction (e.g., renal tubular acidosis, Fanconi syndrome) Modified from Norman ME: An office approach to hematuria and proteinuria. Pediatr Clin North Am 1987;34:545-561. hpf, high-power field.
Modified from Norman ME: An office approach to hematuria and proteinuria. Pediatr Clin North Am 1987;34:545-562. ANA, antinuclear antibody; ASLO, antistreptolysin O; BUN, blood urea nitrogen; IVP, intravenous pyelography.
with total clearing of proteinuria may have relapses and require intermittent prednisone therapy for many years. Approximately 18% of patients treated with prednisone for minimal change nephrotic syndrome respond to therapy and never experience a relapse. Patients with recurrent nephrotic syndrome are subgrouped into those who experience frequent and infrequent relapses. A patient with infrequent relapse has fewer than two relapses in any 6-month period; a person with frequent relapse has two or more relapses within 6 months. Prednisone should be reinitiated at a dose of 2 mg/kg/day and continued until the urine test results are negative for protein for 4 consecutive days. After that, alternate-day prednisone is given at a dose of 1.5 mg/kg in the morning for another 2 weeks and then discontinued altogether. Relapses are frequent during the influenza virus seasons; any minor upper respiratory infection may trigger a relapse of nephrotic syndrome. Patients who suffer infrequent relapses may be treated with prednisone alone. If there are three relapses a year and clearing of proteinuria in 10 to 12 days after beginning prednisone therapy, a patient would receive approximately 45 days of daily prednisone in a 1-year interval. The patient would also receive 8 weeks of prednisone administered on an alternatemorning schedule. Most patients have few long-term side effects when given this amount of prednisone. Patients with frequently relapsing nephrotic syndrome respond with total clearing of proteinuria after daily prednisone therapy but experience relapse more frequently than four times a year and may
Table 24-5. When to Refer the Child with Proteinuria
to a Nephrologist Persistent nonorthostatic proteinuria A family history of glomerulonephritis, chronic renal failure, or kidney transplantation Systemic complaints such as fever, arthritis or arthralgias, and rash Hypertension, edema, cutaneous vasculitis, or purpura Coexistent hematuria with or without cellular casts in the spun sediment Elevated blood urea nitrogen (BUN) and creatinine levels or unexplained electrolyte abnormalities Increased parental anxiety Modified from Norman ME: An office approach to hematuria and proteinuria. Pediatr Clin North Am 1987;34:545-561.
require constant daily prednisone therapy to maintain a remission. Because constant daily prednisone has significant untoward side effects (growth failure, cushingoid facies, osteoporosis, cataracts, opportunistic infections, hypertension, and glucose intolerance), other therapies need to be considered. Four strategies are employed in the treatment of patients with frequent-relapse but steroid-responsive minimal change nephrotic syndrome: alternate-day prednisone, cyclophosphamide (Cytoxan), chlorambucil, and cyclosporine. Prednisone
On occasion, it is possible to maintain the patient in remission on a low dose of alternate-day prednisone therapy. This is well tolerated with minimal toxicity and is the first method employed in an attempt to maintain the patient in remission and avoid the long-term side effects of daily steroids. In many cases, however, patients relapse while receiving alternate-day prednisone therapy, and other therapies need to be considered. Cyclophosphamide and Chlorambucil
Cyclophosphamide and chlorambucil are given on a daily basis for approximately 8 weeks. After the use of either agent, patients have a 70% chance of long-term remission (2 1/2 to 3 years in duration). Patients require no prednisone therapy. Unfortunately, after this
Table 24-7. Distribution of Unselected Patients with
Nephrotic Syndrome Histology
No. of Patients (%)
Minimal change disease Focal segmental sclerosis Membranoproliferative glomerulonephritis (MPGN) Mesangial proliferation Proliferative glomerulonephritis Membranous nephropathy Chronic glomerulonephritis Unclassified
398 44 39
(76.5) (8.5) (7.5)
12 12 8 3 4
(2.3) (2.3) (1.5) (0.6) (0.8)
Total
520
100
Adapted from a report of the International Study of Kidney Disease in Children.
Section Four Genitourinary Disorders
416
Table 24-8. Summary of Primary Renal Diseases that Manifest as Idiopathic Nephrotic Syndrome Minimal Change Nephrotic Syndrome (MCNS)
Membranoproliferative Glomerulonephritis (MPGN) Focal Segmental Sclerosis
Type I
Type II
Membranous Nephropathy
Frequency* Children Adults
75% 15%
10% 15%
10% 10%
10% 10%
8 mg/kg/day
Follow and repeat in 3 months
Renal biopsy
Prednisone Rx
Protein persists
Protein clears
Pneumococcal vaccine
Follow q 3 months
Prednisone Rx for symptoms
420
Section Four Genitourinary Disorders
Table 24-10. Test for Orthostatic Proteinuria
1. Have patient void before bedtime 9:00-10:00 P.M and save specimen in a labeled container. Dipstick urine for protein, and record result. 2. Patient should then go to bed and lie flat. At midnight, patient should void into a container (while in bed and remaining flat). Again, put the urine specimen in a container and label it. Dipstick for protein, and record result. 3. Patient should void again 5:00-6:00 A.M. (remaining in bed and flat). Again, place specimen in labeled container. Dipstick for protein and record result. 4. Repeat procedure at 7:00-7:30 A.M. (patient still in bed, still lying flat). Record protein result, and place urine in a labeled container. 5. Patient may then rise. Obtain another urine specimen at 9:00-9:30 A.M. The specimen may be obtained with the patient in the standing or sitting position. Place the specimen in a labeled container. Urine should be tested for protein and the result recorded. Patients should bring urine sample to the next clinic visit (all five specimens in separate containers). Note: It is difficult and seemingly silly to have to urinate while lying flat in bed. This is, however, a very important part of the test.
orthostatic proteinuria is a pattern of positive samples at 9 P.M. and 12 A.M. The urine excreted at midnight was probably filtered at the glomerular level before urination at 9 P.M. If the specimen is again positive for protein only when the patient is standing, no further evaluation is necessary. For a patient with persistent proteinuria that is nonorthostatic, further evaluation depends on the child’s age. An overview of the approach to such a patient is outlined in Figure 24-1. For the child younger than 7 or 8 years of age who has persistent proteinuria, with normal total protein and serum albumin levels, normal complement, and no other signs of renal disease, there are two options. One option is to observe the patient carefully with repeated urinalyses every 3 to 6 months and to counsel the parents with regard to swelling and/or ascites, which may develop in association with influenza or an upper respiratory infection. If there is evidence of overt nephrotic syndrome with edema, a decrease in serum albumen, and an increase in serum cholesterol, a trial of daily prednisone therapy is indicated. It is good practice to give the pneumococcal vaccine to patients who have persistent proteinuria but no evidence of edema or nephrotic syndrome, because of the risk of pneumococcal peritonitis if nephrotic syndrome develops. The other option involves instituting prednisone therapy to document that proteinuria has disappeared; this confirms the suspicion that the patient has steroid-responsive nephrotic syndrome. The rationale for withholding prednisone unless symptoms develop is that the natural history of minimal change disease is to remit; this may occur with or without prednisone administration. If the patient has a more serious lesion, symptoms will develop, at which time evaluation and therapy may be undertaken. In a patient older than 8 or 9 years, once the presence of persistent and nonorthostatic proteinuria is established, the next step is to quantify the amount of protein in a 24-hour specimen. If urinary protein excretion is greater than 8 mg/kg/day, a renal biopsy is indicated. The choice of 8 mg/kg/day of proteinuria is arbitrary; the ISKDC definition of proteinuria is 8 mg/m2/hour, and nephrotic syndrome is defined as 40 mg/m2/hour. Hence, for an average 8-year-old patient who weighs 30 kg and is 1 m2 tall, proteinuria by these definitions is a level of 96 mg/day, and nephrotic syndrome is a level of
960 mg/day. Renal biopsy is recommended at a level of 240 mg/day of proteinuria. This guideline helps avoid a biopsy for the patient with minimal proteinuria but does not require full-blown nephrotic syndrome to develop before a definitive workup is initiated. Because the patient has isolated proteinuria, MPGN or SLE is an unlikely possibility. However, the incidence of focal segmental sclerosis is much higher in adolescents than in younger children. With the possibility of treatment with cyclosporine and/or ACE inhibitors preventing future renal failure, aggressive evaluation is warranted to identify patients who might benefit from these therapies. It has become evident that the presence of protein in the urine increases the risk of renal insufficiency regardless of its cause. This has led to therapies that reduce proteinuria, thereby decreasing the risk of progressive loss of renal function. The traffic of protein across the glomerular capillary membrane appears to stimulate a cascade of inflammatory events that cause interstitial fibrosis. ACE inhibitors result in efferent arteriolar vasodilatation, leading to a decrease in intraglomerular pressure, which in turn leads to a decreased transport of protein across the glomerular filter. Patients who are treated with ACE inhibitors are less likely to increase their level of proteinuria and are less likely to lose their renal function than are patients who are not treated with these agents. This was first apparent in the treatment of diabetic nephropathy, but there is evidence that ACE inhibitors offer advantages to patients with other nephropathies as well. Angiotensin II blockers offer another avenue for accomplishing a decrease in intraglomerular pressures, and these also decrease proteinuria when used alone or in conjunction with an ACE inhibitor. ACE inhibitors and angiotensin II blockers may be useful for patients with proteinuria either as a first step or as adjunctive therapy for those who fail to respond to other medications.
SUMMARY AND RED FLAGS Asymptomatic proteinuria may be associated with nonspecific febrile benign illnesses, postural mechanisms, and glomerular or tubular dysfunction. Significant proteinuria with edema suggests the nephrotic syndrome, which in most children suggests minimal change nephrotic syndrome. An age younger than 1 year or older than 10 years plus significant hematuria, azotemia, and hypertension is a red flag that suggests a cause of nephrosis other than the more benign minimal change disease. Additional red flags include a poor response to prednisone therapy and signs of multiple organ system involvement by a primary systemic disease, such as SLE. Fever and abdominal pain in a patient with nephrotic syndrome should suggest spontaneous primary bacterial peritonitis. REFERENCES Bergstein JM: A practical approach to proteinuria. Pediatr Nephrol 1999;13:697-700. Bonilla-Felix M, Parra C, Dajani T, et al: Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int 1999;55:1885-1890. Chesney RW: The idiopathic nephrotic syndrome. Curr Opin Pediatr 1999;11:158-161. Durkan A, Hodson E, Willis N, et al: Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev 2001; (4):CD002290. Gorensek MJ, Lebel MH, Nelson JD: Peritonitis in children with nephrotic syndrome. Pediatrics 1988;81:849. Greenstein SM, Delrio M, Ong E, et al: Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts. Pediatr Nephrol 2000;14:1061-1065. Hodson EM, Knight JF, Willis NS, et al: Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2001;(1):CD001533. Hogg RJ, Portman RJ, Milliner D, et al: Evaluation and management of proteinuria and nephrotic syndrome in children: Recommendations from a pediatric nephrology panel established at the National Kidney
Chapter 24 Proteinuria Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE). Pediatrics 2000:105:1242-1249. Homberg C, Jalanko H. Tryggvason K, Rapola J: Congenital nephrotic syndrome. In Barratt TM, Avner ED, Harmon WE (eds): Pediatric Nephrology. Baltimore, Lippincott Williams & Wilkins, 1999, p 765-777. Korbet SM: Clinical picture and outcome of primary focal segmental glomerulosclerosis. Nephrol Dial Transplant 1999;14:68-73. Leung AK, Robson WL: Evaluating the child with proteinuria. J R Soc Health 2000;120:16-22. Lin CY, Sheng CC, Chen CH, et al: The prevalence of heavy proteinuria and progression risk factors in children undergoing urinary screening. Pediatr Nephrol 2000;14:953-959. McBryde KD, Kershaw DB, Smoyer WE: Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr Adolesc Health Care 2001; 31:280-307. Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int 1978;13:159-165.
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The primary nephrotic syndrome in children: Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981;98:561-564. Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Perspective in Clinical Nephrology. Kidney Int 1997;51:2-15. Roth KS, Amaker BH, Chan JC: Nephrotic syndrome: Pathogenesis and management. Pediatr Rev 2002;23:237-248. Ruggenenti P, Perna A, Gherardi G, et al: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;53:359-364. Rytand DA, Spreiter S: Prognosis in postural (orthostatic) proteinuria. N Engl J Med 1981;305:618. Trompeter RS, Lloyd BW, Hicko J, et al: Long-term outcome for children with minimal change nephrotic syndrome. Lancet 1985;1:368. Vehaskari VM, Rapola J: Isolated proteinuria: Analysis of a school-age population. J Pediatr 1982;101:661. Yashikawa N, Kitagawa K, Ohta K, et al: Asymptomatic constant isolated proteinuria in children. J Pediatr 1991;119:375.
25
Hematuria
Ben H. Brouhard
for blood; these stains represent urate crystals, which disappear from the urine when acid is added. Even the reagent strip may not accurately reflect the presence of red blood cells in the urine. The reagent strip, which is impregnated with orthotolidine peroxide and enhanced with 6-methoxyquinolone, turns blue in the presence of hemoglobin or myoglobin (Table 25-2; see also Fig. 23-1). False-negative results for hemoglobin are unusual but have been reported in the presence of high concentrations of ascorbic acid. False-positive results occasionally occur in urine infected with bacteria that produce peroxidase. With a positive reagent strip result, it is important to determine whether there are red blood cells in the urine or whether this result is caused by free hemoglobin or myoglobin, indicating another disease process and not necessarily disease of the urinary tract. Hemoglobinuria occurs in the setting of brisk hemolysis (often caused by glucose-6-phosphate dehydrogenase deficiency or autoimmune hemolysis) and may be accompanied by pallor, tachycardia, dyspnea, and reduced exercise tolerance (see Chapter 48). Myoglobinuria frequently follows rhabdomyolysis secondary to viral myositis (influenza, enterovirus) in the setting of tender muscles and weakness. Rhabdomyolysis may also occur in patients with inborn errors of energy metabolism affecting the muscle and is often noted in these patients after exercise. Both hemoglobin and myoglobin may produce renal tubular injury and thus produce elevated serum blood urea nitrogen and creatinine levels, giving the false impression of primary renal disease. Forced diuresis is indicated in hemoglobinuria and myoglobinuria. When red blood cells are present, a positive reagent strip result is correlated with more than two to five red blood cells per high-power field (hpf) on fresh centrifuged urine. A result of more than five red blood cells/hpf in centrifuged urine is abnormal.
Hematuria is a common urinary complaint in childhood. The presence of blood in the urine by itself rarely indicates a serious or an immediately life-threatening illness. Because of this, screening for asymptomatic hematuria, or the aggressive evaluation of hematuria in general, may be overly deemphasized. Conversely, the anxiety provoked by blood in the child’s urine may cause physicians to perform extensive and costly evaluations.
INITIAL APPROACH TO HEMATURIA Some general guidelines can be listed for all cases of hematuria, regardless of whether it is gross or microscopic, symptomatic, or asymptomatic. Historically, it is important to inquire about the results of previous urinalyses and about any abnormalities of the urine that might have been present (proteinuria, leukocyturia). Differentiating between acute and chronic hematuria is useful diagnostically. For children with gross hematuria, the number of episodes, how long they last, and the circumstances surrounding the episodes may provide clues to the diagnosis. A history of hypertension suggests a chronic kidney disease. Because a number of familial disorders may manifest with hematuria, documentation of the family history should focus on kidney abnormalities, hypertension, nephrolithiasis, hematuria, deafness, and renal failure (specifically with regard to dialysis and kidney transplantation). The physical examination may be unrevealing in patients with renal disease but must include determining the blood pressure and careful palpation of the abdomen, the flank regions, the back, and the suprapubic region. The initial evaluation must include the urinalysis: the “physical examination of the kidneys.” The color of the urine should be noted. A reagent strip may reveal the presence of proteinuria and may also suggest the presence of blood and leukocytes. Heme-positive findings on a reagent strip must be confirmed by microscopic examination for the presence of red blood cells. Other elements to be particularly noted on microscopic examination are white blood cells, casts, and crystals (see Fig. 23-1). Hematuria is categorized as (1) gross hematuria (blood in the urine visible to the naked eye) or (2) microscopic hematuria (red blood cells found only on microscopic examination of the urine). It is also useful to categorize gross hematuria as symptomatic or asymptomatic. Another useful point to consider is whether the blood is originating from the kidney or the lower urinary tract. These categories provide a framework for the evaluation and the differential diagnosis. However, a specific entity may have variable manifestations. For example, acute postinfectious nephritis may manifest with asymptomatic microscopic hematuria with or without proteinuria; the more classical manifestation is gross hematuria, usually with proteinuria. Regardless of whether the blood is gross or microscopic, it must be determined that red blood cells are present in the urine. Red or brown urine does not always indicate gross hematuria. Table 25-1 indicates causes of urine discoloration that may be mistaken for gross hematuria. Pink stains in the diapers of infants can be mistaken
UPPER VERSUS LOWER TRACT BLEEDING Once the presence of red blood cells is documented, the differential diagnosis is simplified if the abnormality can be categorized into upper or lower tract bleeding. The color of the urine should be noted: Brown, smoky, or tea-colored urine indicates an upper urinary tract source of the bleeding; acidic urine changes hemoglobin to hematin, producing brown coloration. It is also important to determine whether protein is in the urine samples. The presence of protein may localize the origin of the blood to the glomerulus. Grossly bloody urine coming from the lower urinary tract rarely contains significant amounts of protein. Bright red blood is more likely to be originating from the lower urinary tract. Blood noted at the beginning or end of the stream also indicates lower tract bleeding. The presence of clots points to the lower urinary tract as the source of the blood. Microscopic hematuria provides no clue as to the source of the bleeding, unless proteinuria is present; microscopic hematuria and proteinuria are highly suggestive of glomerular disease. Another method used to localize the bleeding is determination of the red blood cell structure. Dysmorphic cells indicate disruption of 423
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424
Table 25-1. Conditions Other than Gross Hematuria
that Cause Urine Discoloration Pink, Red, Cola-Colored, Burgundy Disease-Associated; Multiple Causes Gross hematuria Myoglobinuria Hemoglobinuria Porphyrinuria Associated with Drug/Food Ingestion Aminopyrine Nitrofurantoin Anthrocyanin Phenazopyridine Azo dyes Phenolphthalein Beets Pyridium Blackberries Red food coloring Chloroquine Rifampin Deferoxamine mesylate Rhodamine B Ibuprofen Sulfasalazine Methyldopa Urates Dark Brown, Black Disease-Associated Alkaptonuria Homogentisic aciduria Melanin
Methemoglobinemia Tyrosinosis
Associated with Food/Drug Ingestion Alanine Resorcinol Cascara Thymol From Travis LB, Brouhard BH, Kalia A: An approach to the child with hematuria. In Cornfeld D, Silverman B (eds): Dialogues in Pediatrics Management. East Norwalk, Conn, Appleton-Century-Crofts, 1985.
cell membrane integrity after passing through the glomerular basement membrane, whereas isomorphic cells indicate an origin below the glomerulus. These studies are performed with a phasecontrast microscope. The distinction between dysmorphic and isomorphic red blood cells has a great deal of overlap; it has been proposed that for a diagnosis of upper tract bleeding, at least 75% of the cells should be dysmorphic, whereas for a diagnosis of lower tract hematuria, no more than 17% should be dysmorphic. Other methods that have been proposed include measurement of mean corpuscular volume of the urinary red blood cells or use of the red blood cell distribution width, which would be abnormally high in upper tract bleeding.
GROSS HEMATURIA SYMPTOMATIC HEMATURIA Symptoms can be divided into two groups: those that originate from the kidney itself and those that are associated with systemic illnesses that affect the kidney secondarily (Table 25-3). Nephrolithiasis can occur at any age and may cause the symptoms of renal colic, manifested as intense, episodic flank pain that often radiates to the groin. In young infants, renal colic may manifest as generalized irritability or abdominal pain. The episode of hematuria, which has been reported in 28% of patients with nephrolithiasis, may begin abruptly without a history of hematuria. The physical examination may be unrevealing; the urinalysis may contain crystals, in addition to red blood cells. The family history may suggest the diagnosis because up to 70% of children with hypercalciuria have a family history of stone disease. The medical history of furosemide administration to premature neonates, especially those with bronchopulmonary dysplasia, may suggest nephrolithiasis or nephrocalcinosis with gross hematuria. A high-resolution CT scan is the best radiologic test for confirming the presence of a stone.
Table 25-2. Hemoglobinuria without Hematuria
Disease States Hemolytic anemias: all types Hemolytic-uremic syndrome Septicemia Paroxysmal nocturnal hemoglobinuria Drugs/Chemicals Aspidium Betanaphthol Carbolic acid Carbon monoxide Chloroform Fava beans Mushrooms Naphthalene Pamaquine Phenylhydrazine Potassium chlorate Quinine Snake venom (and occasionally spider venom) Sulfonamide Miscellaneous Cardiopulmonary bypass Drowning (freshwater) Mismatched blood transfusions From Travis B, Brouhard BH, Kalia A: An approach to the child with hematuria. In Cornfeld D, Silverman B (eds): Dialogues in Pediatric Management. East Norwalk, Conn, Appleton-Century-Crofts, 1985.
Table 25-3. Differential Diagnosis of Symptomatic and
Asymptomatic Hematuria Confirm the Presence of Red Blood Cells Symptomatic Renal symptoms Urinary tract infections Nephrolithiasis Urethrorrhagia Systemic symptoms Henoch-Schönlein purpura Tuberous sclerosis Asymptomatic Cystic disease Obstruction Vascular Arteriovenous malformation Thrombosis Trauma Tumor Hemoglobinopathies Coagulopathies Exercise-induced hematuria Benign familial hematuria (thin basement membrane) Glomerulonephritis Acute postinfectious nephritis Immunoglobulin A nephropathy Henoch-Schönlein purpura
Chapter 25 Hematuria Children with nephrolithiasis should undergo a workup to search for a metabolic explanation for their predisposition to form kidney stones. This begins with a 24-hour urine collection for calcium, urate, citrate, oxalate, cystine, and creatinine. Cystinuria, a hereditary cause of stone formation in childhood, results from a defect in the reabsorption of cystine and other dibasic amino acids in the proximal tubule. Primary hyperoxaluria type I and primary hyperoxaluria type II are autosomal recessive disorders that cause a metabolic overproduction of oxalate. The clinical manifestation ranges from severe nephrocalcinosis and renal failure in infancy to recurrent nephrolithiasis in late childhood or even later. Hyperoxaluria may be secondary to excessive intake or excessive absorption in intestinal disorders such as inflammatory bowel disease. Patients with nephrolithiasis may have decreased excretion of citrate, which promotes the crystallization of calcium salts. This commonly occurs in patients with chronic diarrhea or renal tubular acidosis. Uric acid stones, which are radiolucent, may result from high uric acid production in patients with lymphoma or leukemia. On occasion, uric acid stones from overproduction are the initial complaint in Lesch-Nyhan syndrome. Uric acid stones occur in children on a ketogenic diet, presumably because of the decreased solubility of uric acid in highly acidic urine. The determination of creatinine excretion is important to ensure that an adequate collection has been obtained (10 to 15 mg/kg/24 hours). Hypercalciuria is the most common metabolic abnormality found in children with nephrolithiasis. Furthermore, hypercalciuria (defined as urinary calcium levels of 4 mg/kg/day) without an overt stone can manifest as gross hematuria with abdominal or flank pain. Indeed, 2.0% to 9.1% of normal children may have hypercalciuria, and 1.8% have hyperuricosuria. Hypercalciuria can be idiopathic or secondary to another disease, such as renal tubular acidosis (Table 25-4). Hypercalciuria is a frequent cause of hematuria,
Table 25-4. Causes of Hypercalciuria
Physiologic Stimuli to Calcium Excretion Sodium excretion Acidosis Hypophosphatemia Increased Filtered Load Hypercalcemia (hyperparathyroidism, dietary, vitamin D excess) Excess calcium administration Impaired Renal Tubular Reabsorption of Calcium Loop diuretics Selective tubular defects Bartter syndrome Hereditary hypophosphatemic rickets with hypercalciuria Syndrome of hypercalciuria, normocalcemia, growth retardation, polyuria, and proteinuria (Dent disease) Renal tubular acidosis Fanconi syndrome Idiopathic Hypercalciuria Absorptive Renal leak Hypercalciuria of Unknown Cause Medullary sponge kidney Diabetes mellitus Syndrome associated with total parenteral nutrition From Milliner DS, Stickler GB: Hypercalcemia, hypercalciuria and renal disease. In Edelmann CM (ed): Pediatric Kidney Disease, 2nd ed. Boston, Little, Brown, 1992, pp 1661-1687.
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and it increases the risk for future nephrolithiasis. Therapy depends on the cause of the hypercalciuria or the type of stone present. Urinary tract infection is a common cause of symptomatic gross hematuria (see Chapter 23). In this circumstance, the infection is usually confined to the bladder; the blood is bright red rather than brown and may contain clots. As many as 25% of children presenting with gross hematuria have a documented symptomatic urinary tract infection; an additional 35% have a suspected but unproven infection. The urine culture is the sine qua non for a diagnosis of urinary tract infection. Symptoms of urethritis with gross hematuria and a negative urine culture in boys suggest urethrorrhagia. The most common complaint is bloodstained underwear. The symptoms tend to occur at intervals several months apart and may persist for up to 10 years. Cystoscopy does not show a treatable lesion and may be contraindicated because of the possibility of producing a stricture. Low-dose, long-term antibiotic treatment may help in some cases. The condition appears to be benign and self-limited; reassurance is the treatment of choice. Gross hematuria with systemic symptoms may be indicative of a generalized process in which the kidney is involved. The triad of abdominal pain, joint pain, and lower extremity purpuric rash with gross hematuria (with or without proteinuria) suggests anaphylactoid purpura, also known as Henoch-Schönlein purpura (HSP). HSP affects children between the ages of 3 and 10 years, and more boys than girls are affected. In 60% of cases, an upper respiratory tract infection precedes the onset of the disease by 1 to 3 weeks. There is a seasonal variation, with a peak around November to January in the northern hemisphere. The rash is an acute symmetric erythematous maculopapular purpuric vasculitic rash that characteristically starts around the malleoli but extends to the dorsal surface of the legs, the buttocks, and, less commonly, the ulnar side of the arms. These lesions may coalesce into large patches or ecchymoses (palpable purpura) and may persist for up to 2 weeks. Joint pain is present in about 60% to 75% of children with HSP. The arthralgia or periarticular swelling of HSP affects the knees and ankles most commonly. Abdominal pain, occurring in about 50% of cases, consists of severe colicky abdominal pain with melena or bloody diarrhea; in rare cases, intussusception develops. Between 50% and 70% of children have hematuria with mild to moderate proteinuria. It is not known how many children with HSP have gross hematuria. Usually, the other symptoms cause the child to visit the physician. No pathognomonic laboratory test exists for HSP; 50% of children have elevated serum immunoglobulin A (IgA) concentrations. No specific therapy exists, and 5% to 10% of children eventually develop renal failure. These children tend to be more severely affected, with gross hematuria and nephrotic range proteinuria, and show severe lesions on renal biopsy, in addition to IgA deposits in the glomerulus. Classic findings in tuberous sclerosis, an autosomal dominant disorder, include epilepsy, developmental delay, and skin manifestations (see Chapter 56). Hematuria in such patients suggests a diagnosis of renal cysts and/or angiomyolipomas that have bled. The former are uncommon, but the latter occur in 50% to 80% of patients, increasing in size and number with time. These tumors are histologically benign and consist of smooth muscle, adipose tissue, and vascular elements. Symptomatic renal tumors are more common in affected adults. Hematuria, retroperitoneal hemorrhage, and abdominal or flank pain may be present. Ultrasonography suggests the diagnosis, and histologic features are diagnostic.
ASYMPTOMATIC HEMATURIA Gross hematuria is often asymptomatic. The presence of brown or smoky urine or significant proteinuria indicates upper tract bleeding, whereas bright red urine or blood denotes lower tract bleeding.
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Postinfectious Nephritis Gross hematuria appearing 4 days to 3 weeks after a febrile illness suggests a diagnosis of acute postinfectious nephritis, the most common form of acute nephritis in childhood. The classical findings are hematuria, oliguria, edema, and hypertension. Microscopic hematuria is present in virtually all cases; gross hematuria is present in about 30%. The urine is characteristically described as smoky or tea-colored to cola-colored. The gross hematuria usually disappears in 3 to 5 days, proteinuria disappears in several weeks, and microscopic hematuria resolves in months to 1 year. Group A streptococcal infection is the most well-defined cause, having occurred in 80% of patients with postinfectious nephritis; however, other causes have also been documented, ranging from other bacteria to viruses. The usual age at involvement is school age, and the streptococci usually come from cutaneous infection (impetigo) in the southern United States and the pharynx in the northern United States. It is important to document the time of appearance of the hematuria after the infection. It should be between 4 days and 3 weeks; a shorter time may suggest IgA nephropathy or exacerbation of a preexisting nephritis. Laboratory confirmation consists of identifying the streptococcal cause and noting the decrease in serum C3 concentration and variable decreases in C4 levels. Determinations of serum creatinine concentration should also be performed because a rapidly progressive decline in renal function can occur. This situation should also suggest additional diseases (the differential diagnosis is noted in Tables 25-5 and 25-6).
Differential Diagnosis
Important diseases manifesting as an acute proliferative glomerulonephritis include postinfectious nephritis, systemic infections, IgA nephropathy, and HSP. Infectious agents producing postinfectious nephritis other than group A streptococci have included viridans group streptococcus, Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Corynebacterium species, Mycoplasma species, meningococci, Leptospira species, varicella virus, rubella virus, cytomegalovirus, Epstein-Barr virus, Toxoplasma species, Trichinella species, and Rickettsia species. Less common causes of childhood-onset acute proliferative glomerulonephritis include membranoproliferative glomerulonephritis, systemic lupus erythematosus (SLE), familial nephritis, endocarditis, and shunt nephritis; uncommon causes include Wegener granulomatosus and polyarteritis nodosa. Glomerulonephritis may also be classified by its histologic appearance. In crescentic glomerulonephritis, there is a proliferation in the Bowman space. This disorder is usually a problem of adolescents who have hypertension, anemia, hypocomplementemia, hematuria (gross in 50% to 80%), proteinuria, and edema. Primary renal diseases include anti–glomerular basement membrane disease, immune complex disease, IgA nephropathy, and membranous and membranoproliferative glomerulonephritides. Systemic illnesses producing crescentic glomerulonephritis include postinfectious disease, shunt nephritis (infected ventriculoatrial shunts for hydrocephalus), endocarditis, SLE, HSP, polyarteritis, cryoglobulinemia, and Wegener granulomatosus. Membranoproliferative glomerulonephritis is categorized into three types: Type I manifests as nephritis-nephrosis, hypocomplementemia, subendothelial glomerular deposits, mesangial proliferation, and deposition of immunoglobulins and complement; it is rarely asymptomatic. Type II is similar to type I except that the deposits are in the lamina densa, the basement membrane demonstrates dense deposits, the mesangial cell proliferation is milder, and only C3 is deposited.
Table 25-5. Classification of Rapidly Progressive
(Crescentic) Glomerulonephritis (RPGN) Type of RPGN
Frequency
Anti-GBM Antibody–Mediated RPGN Goodpasture syndrome Idiopathic anti-GBM nephritis Membranous nephropathy with crescents
20%
RPGN-Associated with Granular Immune Deposits Postinfectious Poststreptococcal glomerulonephritis Bacterial endocarditis “Shunt” nephritis Visceral abscesses, other nonstreptococcal infections
40%
Noninfectious Systemic lupus erythematosus Henoch-Schönlein purpura Mixed cryoglobulinemia Solid tumors Primary Renal Disease Membranoproliferative glomerulonephritis IgA nephropathy Idiopathic “immune complex” nephritis RPGN Without Glomerular Immune Deposits Vasculitis Polyarteritis Hypersensitivity vasculitis Wegener granulomatosis
40%
Idiopathic RPGN Modified from Couser WG. Glomerular disorders. In Wyngaarden JB, Smith LH, Bennett JC (eds). Cecil Textbook of Medicine, 19th ed. Vol 1. Philadelphia, WB Saunders, 1992, p 552. GBM, glomerular basement membrane; IgA, immunoglobulin A.
Type III differs in that asymptomatic hematuria or proteinuria may be present at first, nephritis-nephrosis is unusual at presentation, and deposition of C3 and C5 with few immunoglobulins occurs within the glomerular basement membrane. Membranoproliferative glomerulonephritis is usually idiopathic, but it may be secondary to immune complex disease (SLE, HSP, hereditary complement deficiencies, other collagen vascular diseases), infections (bacteremia, human immunodeficiency virus), malignancy (lymphoma), chronic liver disease (hepatitis, cirrhosis, α1-antitrypsin deficiency), or other lesions (hemolytic-uremic syndrome, sickle cell anemia, partial lipodystrophy, renal graft rejection). Membranous glomerulopathy involves the glomerular basement membrane in stages with increasing severity of deposits: scant discrete subepithelial deposits (stage I); larger, confluent, diffuse, electron-dense subepithelial deposits (stage II); large deposits in an irregularly thickened glomerular basement membrane surrounded by projection spikes of the glomerular basement membrane (stage III); and a thickened glomerular basement membrane with intramembranous deposits and an electron-lucent pattern (stage IV). Membranous glomerulopathy may be idiopathic (primary) or associated with infectious diseases (hepatitis B, congenital syphilis, malaria, filariasis), immune-mediated diseases (SLE, Crohn disease, pemphigus, enteropathy), drug intake (penicillamine), malignancy (neuroblastoma,
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Table 25-6. Summary of Primary Renal Diseases that Manifest as Acute Glomerulonephritis Poststreptococcal Glomerulonephritis (PSGN)
Diseases
Clinical manifestations Age and sex Acute nephritic syndrome Asymptomatic hematuria Nephrotic syndrome Hypertension Acute renal failure Other Laboratory findings
Immunogenetics Renal pathology Light microscopy Immunofluorescence Electron microscopy Prognosis
Treatment
IgA Nephropathy
Goodpasture Syndrome
Idiopathic Rapidly Progressive Glomerulonephritis (RPGN)
All ages, mean 7 yr, 2:1 male 90% Occasionally 10%-20% 70% 50% (transient) Latent period of 1-3 weeks ↑ ASO titers (70%) Positive streptozyme (95%) ↓ C3-C9; normal C1, C4 HLA-B12, D “EN” (9)*
15-35 yr, 2:1 male 50% 50% Rare 30%-50% Very rare Follows viral syndromes ↑ Serum IgA (50%) IgA in dermal capillaries
15-30 yr, 6:1 male
HLA-Bw 35, DR4 (4)*
HLA-DR2 (16)*
Diffuse proliferation Granular IgG, C3
Focal proliferation Diffuse mesangial IgA Mesangial deposits Slow progression in 25%-50%
Focal → diffuse Crescentic GN proliferation with crescents Linear IgG, C3 No immune deposits No deposits No deposits 75% stabilize or improve 75% stabilize or improve if treated early if treated early
Uncertain (options include steroids, fish oil, and ACE inhibitors)
Plasma exchange, steroids, cyclophosphamide
Subepithelial humps 95% resolve spontaneously 5% RPGN or slowly progressive Supportive
90% Rare Rare Rare 50% Pulmonary hemorrhage; iron deficiency anemia Positive anti-GBM antibody
Mean 58 yr, 2:1 male 90% Rare 10%-20% 25% 60% None Positive ANCA in some
None established
Steroid pulse therapy
Modified from Couser WG: Glomerular disorders. In Wyngaarden JB, Smith LH, Bennett JC (eds). Cecil Textbook of Medicine, 19th ed. Vol 1. Philadelphia, WB Saunders, 1992, p 552. *Relative risk. ACE, angiotensin-converting enzyme; ANCA, antineutrophil cytoplasm antibody; ASO, anti–streptolysin O; GBM, glomerular basement membrane; GN, glomerulonephritis; HLA, human leukocyte antigen; Ig, immunoglobulin.
Wilms tumor, gonadoblastoma), or other diseases (renal transplant graft, Fanconi syndrome, sickle cell anemia, anti–glomerular basement membrane/anti–alveolar basement membrane antibodies, thrombocytopenia with microangiopathic anemia, α1-antitrypsin deficiency). This disorder rarely manifests with macroscopic hematuria; microscopic hematuria is present in 70% of patients. Renal failure and hypocomplementemia are rare, whereas nephrotic syndrome occurs in 70% of patients (see Chapter 24). Treatment
Therapy for postinfectious nephritis is symptomatic, with particular attention to the hypertension that may be present; the acute morbid conditions result principally from hypertension and may include seizures, hypertensive encephalopathy, and congestive heart failure. Renal failure is uncommon. The prognosis of postinfectious nephritis is excellent. The rate of early mortality is 0.5% to 0.8%. The long-term outlook is for complete recovery in 95% of patients. Recurrence caused by streptococcal disease has been documented in fewer than 5% of cases. Early treatment of streptococcal disease does not, however, prevent postinfectious nephritis or recurrences (see Chapter 1). Recurrent hematuria and proteinuria can occur in
patients who have a nonspecific upper respiratory tract febrile illness within 6 weeks of the original episode. Immunoglobulin A Nephropathy IgA nephropathy is a common cause of nephropathy, and its manifestations vary from gross hematuria (30%), nephrotic syndrome (6%), acute nephritis (10%), and malignant hypertension (8%) to chronic (6%) and acute renal failure (6%). Although IgA nephropathy is usually asymptomatic, loin pain has been reported in some patients. There is a male predominance, with a peak incidence in late childhood and early adult life. Gross hematuria appears within 48 hours of an upper respiratory tract infection. Between episodes, the urine may be free of blood or may show microscopic hematuria. No pathognomonic laboratory tests exist for IgA nephropathy; however, the serum IgA concentration may be increased during episodes of gross hematuria. The diagnosis can be made with certainty only with renal biopsy when mesangial deposits of IgA are noted, usually in association with the presence of C3 and immunoglobulin G. No specific therapy exists for IgA nephropathy; alternate-day steroid therapy may be useful for patients with nephrotic-range proteinuria. The prognosis is not necessarily benign.
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Thirty percent of adults and 10% of children progress to end-stage renal disease. Other Causes of Asymptomatic Hematuria Asymptomatic gross hematuria occurring after exercise is known as stress hematuria. It is characterized by gross hematuria immediately or a few hours after exercise. The episodes are usually of short duration and painless. The blood may be bright red or a darker color. Proteinuria does not occur. No laboratory or radiographic abnormalities exist. An extensive investigation is not warranted. With a decrease in exercise, the hematuria disappears. Two less common, familial syndromes can produce asymptomatic gross hematuria: progressive familial nephritis (Alport syndrome) and polycystic kidney disease. A family history of renal disease, deafness, hematuria, or renal failure suggests a diagnosis of Alport syndrome. The first symptoms of hematuria may occur early in life, especially in boys. Approximately 72% of affected children are symptomatic before 6 years of age, and hematuria is the most common sign. Like the renal disease, the hearing loss is progressive. The only definitive method of diagnosis is renal biopsy, which shows the characteristic electron microscopic appearance of attenuation, disruption, and lamellation of the glomerular basement membrane. Although no specific therapy exists, genetic counseling is needed. In most cases, the inheritance is X-linked, although an autosomal recessive variant also exists. Some patients with a more common form of familial hematuria demonstrate persistent microscopic and recurrent gross hematuria without deterioration of renal function. This is called benign familial hematuria, an autosomal dominant disorder. Evidence of disease can also be obtained when urinalyses are performed on family members. An autosomal dominant pattern of inheritance has been proposed. Renal biopsy demonstrates normal light and immunofluorescent microscopic findings; electron micrographs show attenuation and disruption of the glomerular basement membrane (thin basement membrane disease). Autosomal dominant polycystic kidney disease has been documented in children—in rare cases, as early as birth. Gross hematuria may be the first manifestation of this disorder and occurs in 50% of patients; minimal trauma produces hematuria as a result of stretching of the vessels surrounding the cyst. The usual presenting manifestations of the disease (hematuria, hypertension, abdominal mass, and uremia in adults) are seldom seen in children. Adults tend to demonstrate symptoms not seen in children, which include acute and chronic pain (60%), urinary tract infection, and nephrolithiasis (20%). With the use of ultrasonography, it is more common to detect the disease when the children are asymptomatic. The cysts are bilateral and may involve other organs, the liver most commonly. There are no specific laboratory findings and no specific therapy except genetic counseling and control of hypertension if present. The mechanism of hematuria in cystic disease may occur in other conditions that produce dilatation of the upper urinary tract. Hydronephrosis caused by ureteropelvic junction obstruction or vesicoureteral reflux may also result in hematuria when the dilated areas are subjected to even minimal trauma. Coagulation abnormalities and hemoglobinopathies are rarely found in patients with gross hematuria. Sickle cell disease and sickle cell trait are hemoglobinopathies that cause asymptomatic gross hematuria (see Chapter 48). A combination of low oxygen tension, reduced blood flow, low pH, and high osmolality in the medulla induces sickling and sludging of erythrocytes, resulting in areas of infarction and hemorrhage. The bleeding commonly comes from the left kidney, for unknown reasons. Conventional therapy consists of hydration and rest; intravenous desmopressin therapy may also be useful. Renal tumors are a rare cause of gross hematuria in children. Wilms tumor, the most common pediatric renal malignancy, usually
manifests as a flank mass (see Chapter 22). Adenocarcinoma is rarely found in children but has been reported in older children and may manifest as gross hematuria. The diagnosis is suspected radiographically through ultrasonography or computed tomography and is confirmed at the time of surgery. Bladder tumors are a rare cause of asymptomatic gross hematuria. These can be detected with ultrasonography of the bladder. Gross hematuria in the neonate (Table 25-7) can originate from thrombotic events associated with an umbilical artery catheter, trauma, hypercoagulable states, or disseminated intravascular coagulation and may result from thrombosis of the renal vein or renal artery. Thrombosis can be caused by catastrophic events at the time of delivery that cause trauma or hypotension and decreased perfusion to the kidney. The incidence of renal vein thrombosis ranges from 0.26% to 0.70% of autopsies; infants younger than 1 year of age account for up to 90%. A male predominance (2:1) has been reported. Infants of diabetic mothers are more prone to renal vein thrombosis, possibly as a result of polycythemia, dehydration, trauma, or a hypercoagulable state. Along with hematuria, the physical examination may demonstrate a palpable enlarged kidney on the affected side. Another group of children who are susceptible to thrombotic events with gross hematuria are children with nephrotic syndrome (associated with a hypercoagulable state). The diagnosis of renal vein thrombosis can be suspected from the patient’s history and can be confirmed with a Doppler flow study or an isotope scan. A spectrum of therapies has been advocated, ranging from watchful waiting with careful attention to hemodynamic status, hydration, and electrolyte abnormalities to reduction of blood pressure, anticoagulation, and treatment of the underlying abnormality with thrombolytic agents. Nephrectomy, which had been advocated in the past, has been abandoned with the expectation of recovery of renal function without surgery. Follow-up studies have reported that 60% to 80% of patients demonstrate renal atrophy, with 8% to 12% of the patients developing hypertension. Bleeding from arteriovenous malformations of the kidney can manifest as asymptomatic gross hematuria. The blood may be bright
Table 25-7. Causes of Hematuria in Neonates and
Children Common
Neonates Thrombosis (renal vein or artery) Nephrolithiasis (including hypercalciuria) Obstruction Reflux Cystic disease Syphilis (congenital)
Rare
Mesoblastic nephroma Factitious causes
Children Glomerulonephritis Wilms tumor Postinfectious nephritis Arteriovenous malformations Immunoglobulin A Factitious causes nephropathy Henoch-Schönlein purpura Systemic lupus erythematosus Familial nephritis (Alport syndrome) Nephrolithiasis (including hypercalciuria) Cystic disease, reflux Interstitial nephritis
Chapter 25 Hematuria red as a result of the rapid transit of the blood and urine down the ureter. The blood can be localized to one kidney with cystoscopy; angiography is indicated when the bleeding is so severe that surgery for the malformation would be considered. Hemangiomas of the bladder can also be detected with the use of cystoscopy. Gross hematuria can occur from direct injury to the bladder epithelium from cyclophosphamide. This problem results from prolonged contact with the toxic metabolites of this drug. Prevention includes increased hydration to ensure adequate urine flow and the use of mesna, a drug that coats the bladder to prevent contact of the metabolites with the bladder mucosa. Many affected children present with gross hematuria without history or physical findings that suggest a cause. Laboratory data should then be obtained, including determinations of serum creatinine concentration, complement levels (low in postinfectious glomerulonephritis, SLE, serum sickness, endocarditis, membranoproliferative glomerulonephritis, and hypocomplementemic vasculitis), and a 24-hour urine collection for calcium. The initial radiographic study should be ultrasonography of the entire urinary tract. If all of these results are normal, then cystoscopy can be considered to localize the bleeding to the urethra, bladder, or one or both ureters. If these results are normal or suggest that only one kidney is the source of the bleeding, renal angiography should be considered to detect an arteriovenous malformation. Renal biopsy is seldom indicated for gross hematuria with no other signs or symptoms.
MICROSCOPIC HEMATURIA
429
Table 25-8. Differential Diagnosis of Hematuria with or
without Proteinuria* Proteinuria
No Proteinuria
2
20). Because urea is a breakdown product of protein, this ratio can be deceptively low in a child who has had poor protein intake. Appropriate fluid resuscitation increases the urine output and allows the BUN and creatinine levels to normalize. Although dehydration from gastrointestinal losses is the most common cause of prerenal azotemia in children, there are many other causes of prerenal azotemia (see Table 26-3). Volume depletion can be secondary to excessive urinary losses (see Chapter 62), skin losses or hemorrhage. Inadequate renal perfusion and secondary prerenal azotemia also occurs in patients with normal or even increased total body volume. A patient with heart failure may be grossly edematous but may nonetheless have inadequate renal perfusion (see Chapter 8). Similarly, intravascular volume depletion is a potential complication in patients with sepsis, nephrotic syndrome, cirrhosis, or postoperative third space fluid losses. Typically, renal compensatory mechanisms are adequate to maintain glomerular filtration until effective circulatory volume can be restored. However, a prolonged period of renal hypoperfusion or the addition of another insult may damage renal tissue, causing intrinsic renal azotemia. For example, in a child with dehydration, the administration of a nonsteroidal antiinflammatory drug (NSAID), which prevents prostaglandin synthesis, may adversely affect the autoregulatory ability of the kidneys to maintain GFR, precipitating intrinsic renal azotemia. Medications such as aminoglycosides or substances such as intravenous radiocontrast are more likely to cause intrinsic renal azotemia when the urine is highly concentrated as a result of prerenal azotemia.
Acute renal failure (ARF) is a rapid loss of normal renal function, typically associated with azotemia (elevation of serum urea and creatinine) and oliguria or anuria, although urine output is occasionally normal or elevated (Tables 26-1 and 26-2). Oliguria and azotemia may be the result of intravascular volume depletion, one of the more common causes of renal dysfunction in children. In this case, prompt fluid resuscitation often results in improved urine output, resolution of azotemia, and little or no kidney damage. In contrast, if hypoperfusion is persistent or severe, tubular damage may have occurred, leading to more prolonged renal dysfunction. In this instance, continued aggressive fluid resuscitation in an oliguric patient can have deleterious consequences. In the child with ARF, the initial challenge is to identify the underlying cause. For many patients, supportive care is the only treatment. In other patients, disease specific therapy is necessary to reverse the underlying ARF and prevent the potential development of chronic renal failure (CRF).
DIFFERENTIAL DIAGNOSIS The causes of renal failure in children are diverse, although a few causes account for most of the cases. The likely cause of renal failure at the time of presentation (e.g., hemolytic uremic syndrome or severe dehydration) differs from that of renal failure that develops during the course of hospitalization (e.g., after treatment with nephrotoxic agents or after surgery). Clinically, it is helpful to classify the causes of ARF into three categories on the basis of pathogenesis: prerenal azotemia, intrinsic renal azotemia, and postrenal or obstructive azotemia (Table 26-3). In addition, it is important to consider the possibility that a patient has CRF and is only now coming to medical attention.
INTRINSIC RENAL AZOTEMIA PRERENAL AZOTEMIA
Intrinsic renal azotemia is due to damage of the renal parenchyma. Intrinsic renal azotemia in children frequently occurs from prolonged prerenal azotemia, resulting in ischemic (hypotensive) acute tubular necrosis (ATN). The cause of ATN is often multifactorial; intravascular volume depletion is often associated with the administration of nephrotoxic medications. Many affected children are brought to the intensive care unit with multiorgan system failure. There are a large number of potential causes of intrinsic ARF that often overlap, although for diagnostic and therapeutic purposes, it is helpful to categorize the causes on the basis of the area of parenchymal damage: the tubules, glomeruli, interstitium, or vasculature (see Table 26-3). Damage to the renal vessels may occur in hypercoagulable states, as with renal vein thrombosis in the stressed neonate or renal infarction caused by indwelling umbilical arterial catheters. Damage to the renal microvasculature occurs with hemolytic uremic syndrome and vasculitis. Acute glomerular damage and renal failure may result from glomerulonephritis, as seen in postinfectious glomerulonephritis, rapidly progressive glomerulonephritis, or lupus nephritis (see Chapter 25). Treatment of some of these causes may
A common cause of prerenal azotemia is vomiting and diarrhea from acute gastroenteritis (see Chapter 15). Intravascular volume depletion is secondary to gastrointestinal losses and poor fluid intake. Physiologic compensatory mechanisms attempt to maintain adequate circulation and glomerular filtration. Renal autoregulatory mechanisms allow the glomerular filtration rate (GFR) to remain normal despite decreased renal perfusion pressure. The mechanisms that maintain GFR include glomerular afferent arteriolar vasodilatation, from the production of vasodilator prostaglandins and kallikreinkinins, and efferent arteriolar vasoconstriction from the effects of angiotensin II. Therefore, early in the course of dehydration, GFR is typically maintained in children with previously normal renal function. Increased tubular reabsorption of water and sodium helps maintain the intravascular volume and produces concentrated urine (high specific gravity and osmolality) with a very low concentration of sodium (decreased fractional excretion of sodium; see later discussion). The urine volume is low. The increased fluid reabsorption in the renal tubules decreases urea clearance because of passive tubular 433
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Table 26-1. Differential Diagnosis of Increased Blood
Urea Nitrogen and Creatinine Increased Blood Urea Nitrogen Decreased circulatory volume Renal insufficiency or failure Gastrointestinal bleeding Excessive protein intake Catabolic states (burns, infection, postsurgery) Medications: corticosteroids, nonsteroidal antiinflammatory agents, tetracyclines, β blockers, diuretics, angiotensinconverting enzyme inhibitors, and others Increased Creatinine Decreased circulatory volume Renal insufficiency or failure Muscle injury Drugs: cimetidine, trimethoprim, methyldopa, cephalosporins, and others
require aggressive use of immunosuppressive medications. Renal tubular damage and necrosis may be caused by renal ischemia, infection, or nephrotoxins, including medications or endogenous compounds such as myoglobin from rhabdomyolysis, hemoglobin from hemolytic anemia, or uric acid and cellular breakdown products with tumor lysis syndrome. Damage to the renal interstitium may occur as a consequence of the vascular, glomerular, or tubular diseases just noted, or it may be direct, as with interstitial nephritis caused by infection or medications, tumor infiltration, or granulomatous infiltration (e.g., sarcoidosis). The differential diagnosis of ARF includes undiagnosed CRF and global parenchymal damage progressing to end-stage renal disease. Renal tubular epithelial cell damage results in the release of vasoactive compounds, including angiotensin II, adenosine, and endothelin. The resultant afferent and efferent glomerular arteriolar vasoconstriction compromises renal perfusion and function, particularly in patients with decreased effective circulatory volume. Tubular cell breakdown causes accumulation of cell products (casts) in the renal tubules and intratubular obstruction. Renal vasoconstriction and intratubular obstruction contribute to oliguria and anuria seen in many patients. Damage to renal tubular epithelial cells is associated with loss of polarity of sodium-dependent adenosine triphosphatases that are critical for normal tubular reabsorptive processes. Loss of tubular cells and damage to basement membrane can result in “backleak” of filtrate into the circulation. Clinically, with intrinsic renal failure, oliguria may or may not occur, depending on the degree of renal vasoconstriction, the extent of tubular cell injury, and the degree of tubular obstruction. Renal
Table 26-2. Differential Diagnosis and Definitions of
Oliguria Differential Diagnosis Decreased fluid intake Decreased circulatory volume Renal or cardiac failure Syndrome of inappropriate secretion of antidiuretic hormone Urinary tract obstruction Definitions Premature infant Full-term infant Child Adolescent
5.5 Positive 7.45) occurs as a result of a primary increase in the serum HCO3−, which may occur as a result of (1) net loss of H+, (2) net gain of HCO3− (or its precursors), or (3) loss of fluid with more Cl− than HCO3−. Normally functioning kidneys can excrete large amounts of HCO3− and should offset any increase in serum HCO3− resulting from these causes. Therefore, factors that prevent the kidneys from excreting HCO3− also must be present to maintain the metabolic alkalosis. Factors Initiating Metabolic Alkalosis 1. The H+ can be lost externally, either through the gastrointestinal tract or through the kidneys. For every H+ lost at these sites, the body gains one HCO3− ion. This is because H+ production at both these sites (gastric parietal cell and renal tubular cells) is associated with generation of an equivalent number of HCO3− molecules. H+ can also be “lost” internally, by shifting into the intracellular compartment. This occurs in states of severe potassium depletion (H+ moves in, whereas K+ exits the cell, to maintain electroneutrality). 2. The administration of HCO3− or its precursors (such as lactate, citrate, and acetate), at a rate greater than normal metabolic production of acid can lead to net gain of HCO3− by the body.
Chapter 27 Acid-Base and Electrolyte Disturbances 3. External loss of fluid (gastric fluid) containing more Cl− than HCO3− raises the concentration of HCO3− in the body. One of the factors responsible for this type of alkalosis is the associated volume contraction, which leads to increased bicarbonate reabsorption by the proximal tubule of the kidney. Factors Responsible for Sustaining Alkalosis 1. Decrease in effective blood volume and kidney perfusion causes increased Na+ reabsorption, in both the proximal tubule (angiotensin II effect) and the distal renal tubule (mineralocorticoid effect), thereby increasing H+ excretion. 2. Increased mineralocorticoid directly increases H+ secretion in the outer medullary collecting duct. 3. Chloride depletion increases HCO3− reabsorption in the proximal tubule. This effect is independent of ECF volume status. 4. Potassium depletion stimulates ammonia genesis in the proximal tubular cells. Metabolic alkalosis and hypokalemia exist in a state of a vicious cycle and exacerbate each other. 5. Hypercapnia induces a state of intracellular acidosis, which increases H+ secretion. Although PCO2 increases as a normal compensatory response to metabolic alkalosis, the elevated PCO2 prevents the renal correction of alkalosis. Differential Diagnosis of Metabolic Alkalosis The causes of a metabolic alkalosis can be subdivided on the basis of the urinary chloride level and the patient’s blood pressure (Table 27-5). There is a small group of patients who do not fit into this classification scheme. Urinary Chloride Level Lower than 10 mEq/L Chloride-Deficient Diet. Although currently uncommon, the
ingestion of milk formula with low chloride content has been shown to result in hypochloremic metabolic alkalosis and failure to thrive in infants and to result in later neurodevelopmental abnormalities in childhood.
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Table 27-5. Differential Diagnosis of Metabolic Alkalosis
Urinary Chloride < 10 mEq/L Low chloride intake Gastric losses (e.g., vomiting, nasogastric suctioning) Intestinal losses (e.g., congenital chloride diarrhea, colonic adenoma) Diuretic therapy (prolonged) Contraction alkalosis Posthypercapnia Cystic fibrosis Urinary Chloride > 20 mEq/L With Hypertension High renin, high aldosterone Renal artery stenosis Renin-secreting tumors Low renin, high aldosterone Primary hyperaldosteronism (adenoma or hyperplasia) Dexamethasone suppressible hyperaldosteronism Low renin, low aldosterone Congenital adrenal hyperplasia variants 11-β-Hydroxylase deficiency 17-α-Hydroxylase deficiency Exogenous mineralocorticoids Liddle syndrome With Normal Blood Pressure Bartter syndrome Gitelman syndrome Diuretic therapy (recent) Miscellaneous Causes Gastrocystoplasty Excessive alkali administration with renal failure Hypoparathyroidism, hypercalcemia Massive blood transfusion Recovery from organic acidosis Glucose ingestion after starvation
Gastric Losses. The gastric fluid has a high H+ concentration; loss
of gastric fluid by vomiting or by nasogastric drainage leads to a net gain of HCO3− in the body. Although this is the initiating factor, the alkalosis is sustained by concomitant Cl− and K+ losses. Secondary hyperaldosteronism, resulting from volume contraction, promotes further urinary potassium and H+ excretion, worsening the hypokalemia and alkalosis. In fact, urine is the source of most of the potassium losses caused by emesis. The degree of metabolic alkalosis associated with vomiting is generally mild except in conditions in which gastric secretions are greatly stimulated (e.g., Zollinger-Ellison syndrome) or there is protracted vomiting (e.g., pyloric stenosis). Metabolic alkalosis can also be seen in newborns of mothers with eating disorders (bulimia). The baby reflects the electrolyte changes of the mother and sustains alkalosis because of the Cl− deficiency.
Posthypercapnia. Chronic hypercapnia, as seen in bronchopulmonary dysplasia or cystic fibrosis, leads to an elevated serum bicarbonate concentration from metabolic compensation. The increase in bicarbonate is balanced by a decrease in chloride. Affected patients have chloride depletion, which may be worsened by concomitant diuretic use. With resolution of the hypercapnia, the bicarbonate concentration remains high until the chloride depletion is corrected.
Chloride Diarrhea. This is a rare congenital syndrome characterized by a defect in small- and large-bowel chloride absorption that leads to a chronic diarrhea with high chloride losses in the stool. The ongoing chloride depletion leads to a sustained metabolic alkalosis.
Urinary Chloride Level Higher than 20 mEq/L with Hypertension
Diuretic Therapy. Loop and thiazide diuretics cause a metabolic
alkalosis. The alkalosis is sustained because of hypochloremia, hypokalemia, and volume contraction with resultant secondary hyperaldosteronism. The urinary Cl− may be high if the diuretics have been ingested recently. The metabolic derangements caused by
loop diuretics are virtually identical to those seen in Bartter syndrome.
Cystic Fibrosis. Metabolic alkalosis develops from marked losses
of Cl− in the sweat, which has relatively little HCO3−. The alkalosis is aggravated and sustained by accompanying volume depletion and possibly compensation of hypercapnia.
The disorders of mineralocorticoid excess are characterized by volume expansion and hypertension (see Table 27-5). The mineralocorticoid excess stimulates the renal excretion of H+ and K+, resulting in metabolic alkalosis and hypokalemia. The various causes can be differentiated by evaluating the renin-aldosterone axis. Treatment is aimed at removing or correcting the source of the mineralocorticoid excess.
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Urinary Chloride Level Higher than 20 mEq/L with Normal Blood Pressure Bartter Syndrome and Gitelman Syndrome. These
uncommon autosomal recessive disorders result from defects in various ion transporters within the nephron. Bartter syndrome is a severe disorder that is characterized by urinary chloride wasting, hypokalemia, metabolic alkalosis, and increased serum levels of aldosterone and renin. Hypercalciuria is also common and leads to nephrocalcinosis in some patients. Urinary prostaglandin levels are elevated, especially in the more severe neonatal Bartter syndrome. Affected patients present with a history of failure to thrive, polyuria, polydipsia, and an easy tendency for dehydration. In neonatal Bartter syndrome, there is usually a history of polyhydramnios and premature delivery. Gitelman syndrome, in contrast, is a milder disorder characterized by hypokalemia, metabolic alkalosis, and hypomagnesemia caused by urinary magnesium wasting; calcium excretion is normal. The growth retardation is not as severe. Children with Gitelman syndrome, however, are more prone to febrile seizures and tetanic episodes. Miscellaneous
Causes
of
Metabolic
Alkalosis.
Gastrocystoplasty, urinary bladder augmentation with part of the stomach, can result in metabolic alkalosis caused by acid secretion from the gastric mucosa and its loss in the urine. The administration of excessive alkali in the presence of renal failure when the kidneys are unable to excrete HCO3− can cause metabolic alkalosis. Hypercalcemia resulting from nonparathyroid causes (e.g., sarcoidosis, malignancy) can cause mild metabolic alkalosis by inhibiting parathyroid hormone secretion; hypoparathyroidism is another cause of metabolic alkalosis. Treatment of Metabolic Alkalosis Treatment focuses on correcting the underlying disorder and depends on the pathophysiologic mechanisms of the alkalosis. Patients with a chloride-responsive metabolic alkalosis (urine Cl− < 10 mEq/L) respond to volume repletion; both sodium and potassium chloride are necessary. In rare cases, if alkalosis persists despite chloride supplementation, the carbonic anhydrase inhibitor acetazolamide can be used to increase urinary bicarbonate losses. In patients undergoing persistent gastric drainage, administration of either an H2 blocker or H+ pump inhibitor can be beneficial by decreasing the gastric H+ secretion. Treatment of chloride-resistant metabolic alkalosis with hypertension (urinary Cl− > 20 mEq/L) generally mandates interference with the mineralocorticoid (or mineralocorticoid-like substance) that is maintaining renal H+ losses. This can sometimes be accomplished pharmacologically (e.g., with spironolactone or with other distal potassium-sparing diuretics such as amiloride). The management of Bartter syndrome involves potassium chloride supplementation, but this alone usually does not normalize serum potassium concentration, and addition of a potassium-sparing diuretic (i.e., spironolactone, amiloride, or triamterene) is usually necessary. Nonsteroidal antiinflammatory agents, because of their ability to decrease prostaglandin synthesis, are helpful in patients with Bartter syndrome and are the cornerstone of therapy in children with neonatal Bartter syndrome. In patients with Gitelman syndrome, potassium supplementation is invariably necessary. Magnesium supplementation may diminish urinary losses of sodium, potassium, and chloride. Amiloride and triamterene are also useful in these patients because they are potassium- and magnesium-sparing diuretics. When an elevated systemic pH becomes life-threatening because of the development of seizures and ventricular arrhythmias, rapid reduction in systemic pH may be accomplished by controlled mechanical ventilation or dialysis. Although administration of either HCl or its congeners (e.g., arginine chloride or ammonium chloride)
has historically been advocated to correct metabolic alkalosis, they must be used cautiously because of significant potential complications. RESPIRATORY ACIDOSIS Respiratory acidosis results when there is a primary increase in PCO2 that is secondary to impaired pulmonary ventilation. The nonbicarbonate intracellular buffers attenuate the initial decrease in pH. Renal compensation starts in 12 to 24 hours and reaches maximum in 3 to 5 days. The management of respiratory acidosis is directed toward improving alveolar ventilation and treating the underlying disorder (see Chapter 3). RESPIRATORY ALKALOSIS Respiratory alkalosis occurs when there is a primary decrease in PCO2 as a result of pulmonary hyperventilation. In a spontaneously breathing child, this can result from fever, sepsis, mild bronchial asthma, or central nervous system disorders. In the intensive care unit, the most common cause is mechanical overventilation of an intubated child. The initial alkalosis is acutely titrated by the intracellular buffers, and metabolic compensation by the kidneys returns pH toward normal within 1 to 2 days. Interestingly, this is the only simple acid-base disorder in which, at least in the adult, the pH may be completely normalized by the compensatory mechanisms. The treatment is management of the underlying process. MIXED ACID-BASE DISORDERS Mixed acid-base disorders occur when two or even three primary events act to alter the acid-base state at the same time. The deviations in pH are more marked when two primary events block the compensation of each other, such as the combination of a metabolic acidosis and a respiratory acidosis seen in a patient with shock and respiratory failure. In contrast, in the presence of two opposing primary events, the pH may be normal or only minimally abnormal, as can be seen with combined vomiting and diarrhea. A mixed acid-base disorder is commonly seen when neonates with respiratory acidosis caused by chronic lung disease also receive diuretics, which can cause a metabolic alkalosis. The diagnosis of mixed acid-base disorder should be suspected in the following situations: 1. if the compensation for the primary event is absent or is out of the expected range 2. if the deviation in anion gap and/or serum Cl− is out of proportion to the change in HCO3− 3. if the anion gap is significantly increased in the presence of a near-normal pH
POTASSIUM DISORDERS Potassium is the major intracellular cation; less than 2% is present in the ECF at a concentration of 3.5 to 5.5 mEq/L (during the early neonatal period, the upper limit of normal can be up to 6.0 mEq/L). The differential distribution of potassium between the intracellular (150 mEq/L) and extracellular compartments, sustained by the action of the Na+,K+-ATPase pump, is the chief determinant of the resting membrane potential. Not surprisingly, both hyperkalemia (serum K+ > 5.5 mEq/L) and hypokalemia (serum K+ < 3.5 mEq/L) have a profound effect on the excitability of the neuromuscular tissue, especially the cardiac tissue. As a result, fatal cardiac arrhythmias are possible sequelae of hypokalemia and hyperkalemia. Perturbations in serum K+ homeostasis also affect the smooth and striate muscles. In contrast, changes in the concentration of
Chapter 27 Acid-Base and Electrolyte Disturbances intracellular K+ do not result in significant alterations of excitability of neuromuscular tissue. Almost all dietary potassium is absorbed. The kidney is the major organ responsible for K+ excretion, eliminating more than 90% of the daily K+ intake. However, after an acute ingestion of K+, the kidneys excrete only half of it over the first 4 to 6 hours; the remainder is transiently redistributed intracellularly before the kidneys eventually excrete it. This intracellular redistribution has a very important role in offsetting acute changes in serum K+, but it has a limited capacity to do so. Redistribution of a very small fraction (1% to 2%) of intracellular K+ into the ECF can easily increase serum K+ to a dangerous level. A number of factors affect the distribution of K+ between the intracellular space and the ECF (Table 27-6). The colonic excretion of K+ is of no significance under normal conditions, but in patients with chronic renal failure, it becomes an important route of K+ elimination, when colonic excretion increases substantially. Because the kidney is the major route of potassium elimination from the body, a disturbance in renal potassium handling can be the cause of excessive loss or retention. RENAL POTASSIUM HANDLING The filtered K+ is extensively (up to 75%) reabsorbed in the proximal tubule, and the thick ascending limb reabsorbs another 15% of the filtered K+. Under normal circumstances, urinary K+ excretion is determined primarily by K+ secretion or reabsorption along the distal nephron. In the cortical collecting duct, active K+ secretion occurs, which at times can increase to the point at which the amount of K+ in the luminal fluid exceeds the amount that was originally filtered. Reabsorption of K+ is never complete; there is always an obligatory urinary loss of 4 to 5 mEq/L of K+ (this is in contrast to Na+, which can be almost completely reabsorbed). The principal cells secrete potassium in the distal nephron. Potassium from the blood enters the principal cells through the basolateral membrane via the Na+,K+-ATPase pump. The associated extrusion of Na+ results in a low intracellular Na+ concentration, which facilitates the inward movement of Na+ from the luminal fluid. This Na+ absorption, when unaccompanied by an anion, generates a negative charge in the lumen. The development of a negative charge in the lumen is necessary for K+ secretion and fails to develop if (1) the Na+ delivery to the distal nephron is decreased (e.g., because of low flow as observed during volume depletion), (2) the Na+ conductance channels in the luminal membrane are blocked (e.g., by a potassium-sparing diuretic such as amiloride), or (3) an equimolar or increased amount of anion accompanies Na+ reabsorption (e.g., as in excessive Cl− absorption, as seen in chloride shunt syndrome). Aldosterone or hyperkalemia increases K+ secretion by the principal cells. Anions other than Cl− (such as SO42− and HCO3−) in the distal nephron can greatly augment K+ losses. During a metabolic alkalosis, urinary K+ excretion increases because of increased Na+ and decreased Cl− delivery to the distal nephron. During an episode
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of metabolic acidosis, urinary K+ losses are usually decreased; the important exceptions are type I and type II RTA and DKA. Spironolactone, amiloride, and triamterene decrease K+ excretion. Whereas spironolactone is an aldosterone antagonist, amiloride and triamterene block the Na+ conductance channels present in the principal cell luminal membrane. The antimicrobial trimethoprim prevents K+ secretion by the same mechanism as amiloride. During evaluation of potassium disorders, it is important to determine the appropriateness of the renal response, because it aids in establishing the differential diagnosis of both hypokalemia and hyperkalemia. The appropriateness of the renal response can be checked by determining 24-hour potassium excretion (expected value < 15 mEq during hypokalemia and > 200 mEq during hyperkalemia), ratio of K+ to creatinine (expected value < 1 mmol/mmol during hypokalemia and > 20 mmol/mmol during hyperkalemia), and fractional excretion of K+ (expected values depend on GFR and require a nomogram). However, all these three methods have their drawbacks. The transtubular potassium gradient (TTKG) is currently regarded as the most useful test, because it is based on the physiologic processes of K+ excretion. The TTKG reflects the driving force for K+ secretion. Theoretically, it is the ratio of the K+ in the collecting duct (distal nephron) to the K+ in the peritubular vessels. None of these values can be directly measured. Collecting duct K+ is indirectly calculated from urine K+ and from serum and urine osmolalities: namely, collecting duct K+ = [K+]urine/(urine/plasma)osmolality. This calculation is permitted only when the urine osmolality is greater than the serum osmolality. This estimated collecting duct K+ is then divided by serum K+, which approximates peritubular vessel K+: TTKG = [K]urine/[K]plasma × (plasma osmolality/urine osmolality), where [K]urine is the urine potassium concentration and [K]plasma is the plasma potassium concentration. To calculate the TTKG, urine and blood samples for K+ and osmolality should be obtained simultaneously. The TTKG in a healthy person varies from 5 to 15. During hypokalemia of nonrenal origin, the expected TTKG should be lower than 2; a value higher than 6 indicates inappropriate renal potassium losses. During hyperkalemia of nonrenal origin, the expected TTKG should exceed 10; a value lower than 5 suggests inadequate renal potassium excretion. HYPOKALEMIA Hypokalemia (Table 27-7) may result from (1) increased renal losses, (2) increased extrarenal losses, (3) redistribution, or (4) prolonged decreased intake of potassium. When interpreting cases of hypokalemia, the clinician should pay careful attention to blood pressure and obtain laboratory data concerning acid-base status, electrolytes, osmolality of blood and urine, and the renin-aldosterone axis. These investigations should be done before any intervention is undertaken. Increased Renal Losses (TTKG > 6) with Hypertension
Table 27-6. Factors Affecting Potassium Distribution
between Extracellular Fluid and Intracellular Fluid Insulin Catecholamines Acid-base status Tissue injury
Excess causes hypokalemia Deficiency causes hyperkalemia β agonists cause hypokalemia β antagonists cause hyperkalemia Metabolic alkalosis causes hypokalemia Metabolic acidosis (especially inorganic) causes hyperkalemia Causes hyperkalemia
Mineralocorticoid Excess
The presence of excess mineralocorticoid hormone, regardless of its source, results in stimulation of potassium secretion by the distal tubular cells of the nephron. Mineralocorticoid excess can result from primary hyperaldosteronism, rare forms of congenital adrenal hyperplasia (17-α-hydroxylase or 11-β-hydroxylase deficiency), and Cushing syndrome. The hypokalemia in these conditions is associated with increased sodium chloride retention, causing hypertension. The expansion of the extracellular volume eventually leads to the suppression of Na+-retaining mechanisms, but the K+ losses continue unabated. Metabolic alkalosis develops as a result of
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Table 27-7. Differential Diagnosis of Hypokalemia
Increased Renal Losses (TTKG > 6) With Hypertension Mineralocorticoid excess Primary aldosteronism Congenital adrenal hyperplasia 17-α Hydroxylase deficiency 11-β Hydroxylase deficiency Hyperreninemic hyperaldosteronism Glucocorticoid-suppressible hyperaldosteronism Exogenous mineralocorticoid Cushing syndrome Liddle syndrome With Normal Blood Pressure With Acidosis Renal tubular acidosis Diabetic ketoacidosis With Alkalosis Vomiting Diuretics Congenital chloride diarrhea Bartter syndrome Gitelman syndrome Magnesium depletion Normotensive hyperaldosteronism With Normal Acid-Base Recovery from acute tubular necrosis Postobstructive diuresis Drugs (penicillins, amphotericin B) Extrarenal Losses (TTKG < 2) Diarrhea/GI fistulas Laxative abuse Profuse sweating Redistribution Alkalosis β-adrenergic agonists Barium intoxication Familial hypokalemic periodic paralysis GI, gastrointestinal; TTKG, transtubular potassium gradient.
enhanced proximal ammonium production secondary to potassium depletion. Liddle Syndrome
This is a rare cause of hypokalemia; it is characterized by a primary increase in sodium reabsorption in the collecting tubule and is usually associated with increased potassium secretion. The sodium reabsorption is increased through activation of the amiloridesensitive renal sodium channel. Because serum aldosterone levels are low, spironolactone is ineffective, but amiloride or triamterene, which block the sodium channel, decrease potassium losses and help ameliorate the hypokalemia and the hypertension. Increased Renal Losses (TTKG > 6) with Normal Blood Pressure The hypokalemia associated with Bartter syndrome, Gitelman syndrome, RTA, DKA, and vomiting are discussed in the section on acid-base disorders.
Hypomagnesemia of any cause can lead to K+ depletion, and correction of hypokalemia is not possible until magnesium balance is restored. These effects are believed to be secondary to magnesium’s affect on aldosterone secretion and K+ channels. Magnesium replacement in this situation should be done with magnesium oxide, because the sulfate ion of magnesium sulfate can increase the urinary K+ losses. The polyuric recovery phase of acute tubular necrosis and the postobstructive diuresis after relief of urinary tract obstruction are commonly encountered clinical conditions that may be associated with excess urine potassium losses. Penicillins can increase urinary K+ losses by increased delivery of sodium and nonabsorbable anions to the distal nephron. Amphotericin B enhances urinary K+ loss by increasing the tubular K+ permeability and also by causing type I RTA. Increased Extrarenal Losses (TTKG < 2) Diarrhea is a very common cause of hypokalemia in pediatric practice. Profuse sweating is a much less frequent cause of hypokalemia. Redistribution Alkalosis causes potassium to enter cells in exchange for H+ (this principle is utilized in the management of hyperkalemia; see later discussion). β-Adrenergic agonists increase intracellular movement of potassium. Familial hypokalemic periodic paralysis is a rare disorder characterized by recurring transient episodes of net K+ transfer from ECF to intracellular fluid (ICF). The autosomal dominant form manifests between the ages of 10 and 19 years. Another variant appears later in life (30 to 40 years) and is associated with thyrotoxicosis. The dominant finding is muscle weakness, which may advance to paralysis. Episodes typically occur after large carbohydrate-rich meals, strenuous exercise, or insulin administration. Therapy is largely symptomatic; empirical treatment with acetazolamide has yielded some results. Consequences of Hypokalemia Hypokalemia produces functional alterations in skeletal muscle, smooth muscle, and the heart. The cardiac effects are the most serious consequence of hypokalemia. The characteristic electrocardiographic (ECG) changes include flattening of the T wave with appearance of the U wave. Skeletal muscular weakness usually starts in the limbs before involving the trunk and respiratory muscles. Paralytic ileus and gastric dilatation reflect smooth muscle dysfunction. Rhabdomyolysis is a dramatic and serious complication of hypokalemia. Hypokalemia is particularly dangerous in patients taking digoxin. In the kidney, potassium deficiency may result in vacuolar changes in the tubular epithelium. The renal concentrating capacity is decreased, causing polyuria. Prolonged and sustained hypokalemia leads to systemic alkalosis. Treatment of Hypokalemia The immediate objective of potassium replacement is to prevent lifethreatening cardiac and muscular complications. The ultimate goal is to replenish total body potassium stores. There is no method of determining the potassium deficit, because there is no definite correlation between the plasma potassium concentration and body potassium stores. A decrease of 1 mEq/L in serum potassium concentration secondary to potassium loss generally corresponds to a loss of approximately 10% to 30% of body potassium. In conditions with associated acidosis and/or hyperosmolality (e.g., RTA, DKA), the plasma potassium concentration may underestimate potassium
Chapter 27 Acid-Base and Electrolyte Disturbances stores, and correction of acidosis with bicarbonate in these conditions may rapidly lower the serum potassium concentration. The safest route to administer potassium is by mouth, but in states of severe symptomatic hypokalemia or when there are gastrointestinal problems, potassium must be given intravenously. The usual concentration of potassium in intravenous fluid solutions is up to 40 mEq/L. Higher concentrations of up to 60 to 80 mEq/L can be given in a central vein under continuous ECG monitoring. Dextrose should be avoided in the initial fluids, because its administration with secondary increased insulin secretion may result in further lowering of the plasma potassium concentration. The choice of potassium salt depends on the clinical situation. Under most circumstances, when hypovolemia coexists, potassium chloride is appropriate. Potassium bicarbonate (or, more often, other salts such as citrate and acetate, which generate bicarbonate) can be given in the presence of coexistent metabolic acidosis. If there is an associated phosphate deficiency (as in DKA), potassium phosphate can be used. It is important to remember that correction of total body potassium deficits can take days to weeks. HYPERKALEMIA Moderate (6.1 to 7.0 mEq/L) to severe (>7.0 mEq/L) hyperkalemia, especially if it develops acutely, can lead to grave consequences and requires prompt treatment. Pseudohyperkalemia can occur as result of release of intracellular potassium (e.g., hemolysis caused by mechanical trauma during venipuncture), and it can also be seen in conditions with marked leukocytosis and thrombocytosis. It can be avoided by minimizing trauma and hand clenching during venipuncture, by rapidly separating red blood cells, and by using plasma rather than serum for potassium measurements. An unexpected elevated potassium level should be repeated. Hyperkalemia can be caused by (1) reduced urinary potassium excretion, (2) increased potassium intake, (3) release of intracellular potassium, and/or (4) impaired cellular potassium uptake (Table 27-8). Reduced Urinary Potassium Excretion (TTKG < 5) Renal potassium excretion decreases when the GFR is decreased or when there is a defect in tubular potassium excretion resulting from lack of aldosterone, medications, or a primary defect in tubular potassium excretion. Renal Failure
Potassium excretion is decreased in both acute and chronic renal failure. Severe hyperkalemia occurs more commonly in acute renal failure. In contrast, in patients with chronic renal failure, hyperkalemia does not occur unless the GFR is lower than 10 mL/minute or some other factor predisposing to hyperkalemia is present. In patients with chronic renal failure, potassium balance is maintained by increased K+ secretion per functioning nephron and also by enhanced excretion of K+ through the gastrointestinal tract. Hypoaldosteronism
Low levels or absence of aldosterone may result from a variety of conditions (Addison disease, congenital adrenal hyperplasia [deficiency of 21-hydroxylase], and hyporeninemic hypoaldosteronism). In pseudohypoaldosteronism there is a lack of response to aldosterone, despite high aldosterone levels. In addition to hyperkalemia, hyponatremia and hyperchloremic metabolic acidosis are the associated features in these disorders. The diagnosis can be confirmed by measurement of renin activity and aldosterone levels.
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Table 27-8. Differential Diagnosis of Hyperkalemia
Pseudohyperkalemia Hemolysis Thrombocytosis Leukocytosis Reduced Urinary Potassium Excretion (TTKG < 5) Renal Failure Acute Chronic Hypoaldosteronism Addison disease Hereditary adrenal enzyme defects 21-Hydroxylase deficiency Hyporeninemic hypoaldosteronism Pseudohypoaldosteronism Drugs ACE inhibitors Potassium-sparing diuretics Spironolactone Amiloride Triamterene Cyclosporine Trimethoprim Heparin Nonsteroidal antiinflammatory agents Primary Tubular Defects Postrenal transplantation Lupus nephritis AIDS RTA type IV (chloride shunt) Increased Intake/Tissue Release (TTKG > 10) Intravenous/oral administration Hemolysis (endogenous or transfused blood) Rhabdomyolysis Tumor lysis Redistribution Acidosis Insulin deficiency (diabetes) Familial hyperkalemic periodic paralysis Digitalis toxicity β-adrenergic blockade Succinylcholine ACE, angiotensin-converting enzyme; AIDS, acquired immunodeficiency syndrome; RTA, renal tubular acidosis; TTKG, transtubular potassium gradient.
Drugs
Several drugs are known to be associated with hyperkalemia; they can either impair renin-aldosterone secretion or action (angiotensinconverting enzyme inhibitors, spironolactone, cyclosporine, or heparin) or impair renal tubular potassium secretion (amiloride, triamterene, trimethoprim, or cyclosporine). Primary Tubular Defects
In some patients, hyperkalemia occurs as a result of low urinary K+ excretion despite normal renin and aldosterone levels. The presence of a selective defect in K+ secretion has been described in subjects with renal transplant rejection and lupus nephritis. A selective defect of K+ secretion is also seen in patients with chloride shunt syndrome.
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This syndrome is characterized by enhanced Cl− absorption in the distal nephron, which decreases the electrical gradient necessary for K+ secretion in the collecting duct (see previous discussion). Increased Potassium Intake/Tissue Release (TTKG > 10) Acute increases in potassium intake, usually through parenteral administration, may result in hyperkalemia. The hyperkalemia is typically transient, inasmuch as normal kidneys have a large capacity for excreting potassium. Sustained hyperkalemia is seen only when renal excretory mechanisms are impaired. In tumor lysis syndrome and rhabdomyolysis, massive amounts of K+ are released from the intracellular compartment, but hyperkalemia does not usually occur unless acute renal failure supervenes. Similarly, trauma, intravascular hemolysis, transfusion of stored blood, and catabolic states such as infection or high fever are associated with release of K+ from the cells; however, hyperkalemia is uncommon as long as renal function is normal and normal to high urine output is maintained with fluid therapy. Redistribution Acidosis and insulin deficiency result in egress of intracellular potassium (as discussed previously). Familial hyperkalemic periodic paralysis is a rare hereditary disorder characterized by episodes of muscular weakness and hyperkalemia (movement of K+ from ICF to ECF) resulting from mutations in cellular sodium channels. β2-Receptor blockers, digitalis (by inhibiting the Na+, K+-ATPase pump), and succinylcholine (by inhibiting cellular repolarization) cause hyperkalemia by impairing cellular potassium uptake.
Potassium can be shifted from the extracellular to the intracellular compartment by administration of sodium bicarbonate, glucose and insulin, and β2-adrenergic agonists, as detailed in Table 27-9. Although the intracellular shift of potassium can be accomplished rather quickly, this is only a temporary measure, and further steps should be taken to establish a negative potassium balance. Loop or thiazide diuretics increase renal potassium excretion. In patients with aldosterone deficiency, fludrocortisone increases renal potassium excretion. Alkalinizing the urine through systemic base administration can further enhance urinary potassium losses. Cation exchange resins actually remove potassium from the body and are effective in acute situations, particularly when poor renal function is present. Dialysis is needed in patients with severe hyperkalemia, especially in the presence of advanced renal failure or when accompanied by a hypercatabolic state or severe tissue necrosis. For urgent potassium removal, hemodialysis is more effective than continuous hemodiafiltration or peritoneal dialysis.
SODIUM DISORDERS Sodium is the principal cation of the ECF compartment, and total body sodium content is the major determinant of ECF volume. A normal ECF volume is essential for maintaining an adequate circulating blood volume. Being the chief determinant of ECF osmolality, the sodium concentration determines cell volume by directing water movement between the ECF compartment and the intracellular compartment. An increase in ECF osmolality causes water to move out of cells, and a decrease in ECF osmolality causes water to move into cells. Sodium homeostasis is coupled with water homeostasis; therefore, disorders of sodium homeostasis usually occur as a result of imbalances of both sodium and water rather than an isolated imbalance of either sodium or water.
Consequences of Hyperkalemia Overt clinical manifestations are uncommon with hyperkalemia, but cardiac arrhythmias are potentially life-threatening. Generalized muscular weakness and paralysis can occur. The characteristic ECG findings seen with increasing [K+] are tall, peaked T waves; widening of the QRS complex; decreased amplitude of the P wave; and fusion of the QRS complex with the T wave, forming a sine wave. This can be rapidly followed by atrioventricular dissociation and ventricular tachycardia or fibrillation. Cardiac arrest is more common with hyperkalemia than with hypokalemia. Treatment of Hyperkalemia The treatment of hyperkalemia depends on the magnitude of the hyperkalemia, the severity of ECG changes, and the anticipated future rise in [K+]. The specific therapy should always focus on the underlying cause. However, a plasma potassium concentration higher than 7.0 mEq/L or marked ECG changes are potentially lifethreatening and necessitate immediate treatment. A normal ECG result should not lead to a more casual approach, because significant ECG changes can appear over a short period of time. All potassium intake (parenteral nutrition, medications with potassium salt) and medications that cause hyperkalemia, such as potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and trimethoprim, should be discontinued. The treatment modalities usually belong to the following three categories: (1) antagonism of membrane excitability, (2) shifting of potassium into the intracellular compartment, and (3) elimination of excess potassium (Table 27-9). Calcium protects the heart from fatal arrhythmias caused by hyperkalemia by normalizing the difference between the resting and threshold potentials. This protective effect is quite rapid but relatively short-lived; therefore, other measures to reduce the concentration of serum potassium are necessary.
Table 27-9. Treatment of Hyperkalemia
Antagonism of Membrane Excitability Calcium gluconate 10% (elemental calcium, 0.45 mEq/mL), 0.5-1.0 mL/kg body weight (maximum = 10 mL), injected intravenously and slowly over 5-10 min, with continuous monitoring of heart rate) Shift of Potassium into the Intracellular Compartment Sodium bicarbonate, 1-2 mEq/kg body weight intravenously over 10-20 min; usefulness is limited in patients with volume expansion Glucose, 1 g/kg body weight, and insulin, 1 unit per every 4 g of glucose, intravenously over 20-30 min β2-Adrenergic agonists, such as albuterol, intravenously or by nebulizer or aerosol Elimination of Excess Potassium Loop/thiazide diuretics Fludrocortisone (0.05-0.1 mg/day); should be avoided or given with great caution to hypertensive patients Cation exchange resin, sodium polystyrene sulfonate, 1 g/kg body weight (maximum, 15 g/dose), administered orally or rectally in 20%-30% sorbitol or 10% glucose, 1 g resin/4mL (additional 70% sorbitol syrup may be given if constipation occurs) Peritoneal dialysis, hemodialysis, or hemodiafiltration Modified from Hellerstein S, Alon US, Warady BA: Renal impairment. In Ashcraft KW, Murphy JP, Sharp RJ, et al (eds): Pediatric Surgery, 3rd ed. Philadelphia, WB Saunders, 2000, pp 47-57.
Chapter 27 Acid-Base and Electrolyte Disturbances The kidneys are pivotal regulators of sodium and water balance. Sodium excretion, which is regulated by the renin-angiotensinaldosterone system and atrial natruretic peptide, increases in response to an expanded intravascular volume, as may occur with a high sodium intake. In response to a decreased intravascular volume, the urine can be made virtually sodium free. Osmolality is regulated by thirst and vasopressin production, which determines renal water excretion. A detailed history of the underlying disease, food and fluid intake, fluid losses in the form of stool, emesis, and urine should be obtained. The physical examination focuses on an evaluation of the patient’s volume status, including the nature and rate of peripheral pulses, blood pressure, fullness of the fontanelle, level of consciousness, dryness of mucous membranes, coolness of extremities, and capillary refill time. Urinary sodium concentration can provide valuable information regarding the child’s effective blood volume, but it can be misleading if the patient is receiving diuretics or has abnormal renal sodium handling. The clinical features associated with alterations in plasma osmolality are nonspecific. A low serum osmolality may produce lethargy and confusion, whereas a high serum osmolality may lead to irritability, a high-pitched cry, and a doughy skin texture. The determination of plasma osmolality requires a direct laboratory measurement or can be estimated from the following formula: Serum osmolality(mOsm) = 2[Na+]mEq/L + [glucose]mg/dL/18 + [urea] /2.8 mg/dL The ECF volume is the best indicator of body sodium balance, and the plasma osmolality reflects water balance.
459
HYPONATREMIA Hyponatremia (plasma sodium < 135 mEq/L) should be differentiated from pseudohyponatremia and factitious hyponatremia. Pseudohyponatremia occurs in the presence of excessive amounts of plasma proteins and lipids, which decrease the percentage of plasma water and thus artificially lower the plasma sodium concentration. The measured plasma osmolality of these patients is normal, inasmuch as lipids and proteins do not contribute significantly to osmolality because of their large size. Therefore, a gap between measured and calculated osmolalities can indicate pseudohyponatremia. Many clinical laboratories now measure the serum sodium concentration by using ion-selective electrodes, which are not affected by the presence of lipids and proteins and thus eliminate the possibility of pseudohyponatremia. Factitious hyponatremia results from high plasma concentrations of impermeable solutes such as glucose or mannitol that cause movement of water from the intracellular to the extracellular space. In contrast to pseudohyponatremia, the low plasma sodium concentration in these situations is a true value, and plasma osmolality is increased as a result of the presence of the extra solutes. The decrease in plasma sodium is approximately 1.6 mEq/L for every 100 mg/dL increase in the plasma glucose concentration. In true hyponatremia, the plasma osmolality is low ( water losses)
Euvolemic (modest ECF volume excess, no edema)
Extrarenal losses Renal losses Prematurity Gastrointestinal Recovery phase of ATN Vomiting Diuretics Diarrhea Osmotic diuresis Drains/fistulas Salt-wasting nephropathy Sweating (cystic fibrosis) Post-obstructive diuresis Third space losses Bicarbonaturia Pancreatitis Renal tubular acidosis Burns Metabolic alkalosis Muscle trauma Adrenal insufficiency Peritonitis Pseudohypoaldosteronism Effusions Cerebral salt-wasting syndrome Ascites
Excess ADH (SIADH) Reset osmostat Glucocorticoid deficiency Hypothyroidism Water intoxication IV therapy Tap water enema Psychogenic waterdrinking Infants fed excessive water
UNa > 20 mEq/L
UNa < 10 mEq/L
UNa > 20 mEq/L*
Isotonic saline
Isotonic saline
Water restriction
Hypervolemic (water excess > sodium excess)
Edema forming states Congestive heart failure Cirrhosis Nephrotic syndrome
Renal failure Acute Chronic
UNa < 10 mEq/L
UNa > 20 mEq/L✝
Salt and water restriction
Salt and water restriction
Figure 27-2. Classification, diagnosis and treatment of hyponatremic states. *In water intoxication the urine sodium is often 145 mEq/L) can occur as result of (1) loss of both body sodium and water (water losses exceeding those of sodium), (2) isolated loss of water, and (3) increase in body sodium. The development of hypernatremia is usually prevented by thirst and renal concentrating mechanisms. Thirst is so effective that even patients with complete diabetes insipidus (DI) avoid hypernatremia by drinking. Hypernatremia develops only when hypotonic fluid losses occur in combination with a disturbance in water intake, as a result of inadequate access (as in comatose, handicapped or very young patients), or as a result of a primary abnormality of thirst mechanism (e.g., hypothalamic adipsic syndrome). As is the case with hyponatremia, establishing the differential diagnosis of hypernatremia is aided by determining the patient’s ECF volume status (hypovolemia, euvolemia, or hypervolemia), as shown in Figure 27-3. Hypovolemic Hypernatremia Disorders associated with losses of both sodium and water but with a relatively greater loss of water lead to hypovolemic hypernatremia. Many of the common causes (e.g., diarrhea, diuretic use) are similar to those that cause hypovolemic hyponatremia. Hypernatremia in these situations develops because of failure to ingest water. Hypernatremic dehydration and failure to thrive often develop in neonates who nurse poorly, especially if the mother’s breast milk has not begun flowing. If the losses are extrarenal (e.g., through diarrhea, vomiting, profuse sweating), the urinary sodium concentration is less than 10 mEq/L. The renal causes are usually associated with a urine sodium concentration higher than 20 mEq/L. Euvolemic Hypernatremia Pure water losses do not lead to volume contraction unless the water losses are massive; these patients therefore appear euvolemic. In addition, hypernatremia develops only when the hypotonic losses are not accompanied by appropriate water intake. Although water loss can occur through the skin or the respiratory tract, the most important disorder in this group is DI. Patients with DI have a very low urine osmolality. Central DI is caused by a failure to secrete ADH; nephrogenic DI is secondary to a renal resistance to ADH. Acquired forms of central and nephrogenic DI are more common than the hereditary forms. Hereditary central DI can be either autosomal dominant or, less commonly, autosomal recessive. The autosomal recessive form occurs in association with diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome). The acquired causes of central DI include central nervous system trauma, infections, tumors, granulomatous infiltration, and vascular malformations. Congenital nephrogenic DI is a rare X-linked disorder affecting mainly boys, with variable penetrance in girls. The acquired form of nephrogenic DI can be seen in association with chronic renal diseases (e.g., polycystic disease, medullary cystic disease, ureteral obstruction), electrolyte disorders (e.g., hypokalemia, hypercalcemia),
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Hypernatremia
Hypovolemic (Water losses > sodium losses)
Renal losses Diuretics Osmotic diuresis Postobstructive diuresis Renal dysplasia
UNa > 20 mEq/L
Extrarenal losses
Gastrointestinal Vomiting Diarrhea Drains/fistulas Dermal Sweating Burns Radiant warmer
UNa < 10 mEq/L
Euvolemic (Isolated water deficit)
Renal losses Diabetes insipidus Central Nephrogenic Adipsic / hypodipsic
UNa variable
Iso- or hypotonic saline
Extrarenal losses Respiratory Dermal
UNa variable
Water replacement
Hypervolemic (Excessive sodium intake)
Increased intake Improper formulation Bicarbonate administration Hypertonic dialysis Hyperaldosteronism Cushing syndrome
UNa > 20 mEq/L
Diuretics and water replacement
Figure 27-3. Classification, diagnosis, and treatment of hypernatremic states. (Modified from Beri T, Schrier RW: Disorders of water metabolism. In Schrier RW [ed]: Renal and Electrolyte Disorders. Philadelphia, Lippincott-Raven, 1997.)
drugs (e.g., lithium, demeclocycline, amphotericin, foscarnet), and sickle cell disease/trait. Older children with DI have polyuria, polydipsia, and nocturia. The urine is hyposmolar and remains so even when these children develop dehydration and consequently increased serum osmolality. During infancy, DI can manifest with recurrent episodes of unexplained dehydration and fever. Repeated episodes of hypernatremic dehydration can lead to permanent neurologic sequelae. Performing a fluid deprivation test and then determining the response to injectable vasopressin can help diagnose DI and differentiate between the central and nephrogenic forms. Primary treatment should focus on the underlying cause if possible. Central DI is managed with hormonal replacement therapy with desmopressin (DDAVP). DDAVP is administered intranasally in a dosage ranging from 2.5 to 20 μg every 8 to 12 hours. Alternatively, the oral preparation can be administered (starting dosage, 0.05 mg b.i.d.). There is considerable individual variation in the required dosage, and it is important to allow patients to revert to mild polyuria before the next dose is given, to prevent excessive water accumulation. An intravenous form of antidiuretic hormone can be used in sick and comatose patients. Therapy for nephrogenic DI should ensure a sufficient intake of water to replace the large urinary losses. Because obligatory urinary water losses increase with increasing solute load, restriction of sodium intake reduces the urine output. Administration of diuretics, such as thiazides and amiloride, keeps these patients in a mildly dehydrated state, which leads to increased water reabsorption in the more proximal segments of the nephron, thereby decreasing urine output. Nonsteroidal anti-inflammatory drugs such as indomethacin also reduce polyuria and may be used in combination with diuretics. Careful attention should be paid to the fluid balance in these patients
when they are sick and cannot drink on their own, because they require large quantities of water replacement. Frequent monitoring of serum electrolytes is mandatory during these periods. Adipsic/hypodipsic hypernatremia (essential hypernatremia; reset osmostat) characterizes a group of patients who have persistent hypernatremia, absence or attenuation of thirst, and often-partial DI. Many patients are obese as a result of polyphagia. These patients require regimental intake of fluids; they may need supplementation with DDAVP. Hypervolemic Hypernatremia This is the least common type of hypernatremia. Most of the causes are iatrogenic (administration of improperly formulated oral rehydration solution, administration of intravenous fluids, excessive bicarbonate administration during resuscitative efforts, inadvertent dialysis against a high sodium concentration dialysate, and seawater drowning). Other causes include primary hyperaldosteronism and Cushing syndrome. Consequences of Hypernatremia Hypernatremia causes intracellular dehydration by movement of water from the intracellular to the extracellular compartment. The consequences of intracellular dehydration are particularly marked in the brain and manifest with irritability, altered sensorium, lethargy, and hyperreflexia and eventually seizures, coma, and death. Brain hemorrhages can result from tearing of small blood vessels when the brain shrinks as a result of intracellular dehydration. Hypernatremia and dehydration may predispose to dural sinus thrombosis. During chronic hypernatremia, the brain cells adapt to the increased ECF
Chapter 27 Acid-Base and Electrolyte Disturbances osmolality by accumulating “idiogenic osmoles” (which are mostly amino acids, particularly taurine). They increase intracellular osmolality, consequently restoring intracellular volume. This protective response has significant implications for therapy and the speed with which hypernatremia should be corrected (see later discussion). Treatment of Hypernatremia The treatment of hypernatremia is guided by its severity, its chronicity, and the ECF volume status of the patient. It is important to realize that patients with hyperosmolality maintain the ECF space at the expense of the ICF compartment, and, therefore, the degree of sodium and fluid losses may be profound before clinical signs of hypovolemia develop. As a consequence, large volumes of isotonic crystalloid may be necessary to replace the fluid deficit. Once initial fluid resuscitation has been performed, the serum sodium concentration should be restored slowly over a minimum period of 48 hours. The total water deficit can be estimated as follows: Free water deficit (in liters) = ([PNa (mEq/L)/140] − 1) × 0.6 × weight (kg) Hypernatremia is corrected especially slowly when it is more severe and chronic. The rate of fall in plasma sodium concentration should be less than 1 mEq/L/hour. During the correction of hypernatremia, the idiogenic osmoles that brain cells produce to prevent cellular dehydration dissipate slowly. If hypernatremia is corrected too rapidly, the increased intracellular osmolality from the idiogenic osmoles can lead to cerebral edema. In patients with hypervolemic hypernatremia, the first line of therapy is restriction of salt intake, followed by administration of diuretics.
SUMMARY AND RED FLAGS Acid-base and electrolyte disturbances have many causes that reflect abnormalities of regulation or compensation of these systems. For many acid-base or electrolyte disturbances, the underlying condition needs to be treated before consideration of the disturbance. This is true in all causes of shock, such as dehydration, adrenal crisis, or hemorrhage. The circulating blood volume must be quickly reestablished; this is usually performed as part of the resuscitation phase of treating dehydration. Thereafter, specific acid-base or, more often, electrolyte abnormalities can be attended to during the replacement phase to correct electrolyte deficits. In general, electrolyte disturbances can and often must be corrected slowly. This is particularly true for sodium abnormalities. The major exceptions are hyperkalemia and acute hypercarbic respiratory acidosis, which must be treated immediately. Hyperkalemia can cause life-threatening arrhythmias (see Chapter 7) and cardiac arrest, whereas acute respiratory acidosis signifies impending respiratory failure and respiratory arrest (see Chapter 3). Each of the discussed acid-base and electrolyte disturbances are red flags, but hyperkalemia remains the one of most concern and the most dangerous. Anuria, hypotension, weight loss, seizures, coma, hypoglycemia or hyperglycemia, apnea, and arrhythmias are additional red flags. Moreover, the clinician must remain vigilant in identifying the primary reason or reasons for any of these acid-base or electrolyte disturbances. REFERENCES Acid-Base Disorders Adrogue HJ, Madias NE: Management of life-threatening acid-base disorders. New Engl J Med 1998;338:26.
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Batlle D, von Riotte A, Schlueter W: Urinary sodium in the evaluation of hyperchloremic metabolic acidosis. New Engl J Med 1987;316:144. Benaron DA, Yorgin PD, Lapuk S, et al: Alkalemia in a newborn infant. J Pediatr 1992;120:489. Bergstein JM: Renal tubular acidosis. In Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics. Philadelphia, WB Saunders, 2000. Bettinelli A, Bianchetti MG, Girardin E, et al: Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 1992;120:38. Brewer ED: Disorders of acid-base balance. Pediatr Clin North Am 1990;37:429. Fall PJ: A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med 2000;107:249. Hanna JD, Scheinman JI, Chan JCM: The kidney in acid-base balance. Pediatr Clin North Am 1995;42:1365. Izraeli S, Rachmel A, Frishberg Y, et al: Transient renal acidification defect during acute infantile diarrhea: The role of urinary sodium. J Pediatr 1990;117:711. Lorenz JM, Kleinman LI, Markarian K, et al: Serum anion gap in the differential diagnosis of metabolic acidosis in critically ill newborns. J Pediatr 1999;135:751. Mingin GC, Stock JA, Hanna MK: Gastrocystoplasty: Long-term complications in 22 patients. J Urol 1999;162:1122. Paces R: Long-term follow-up in distal renal tubular acidosis with sensorineural deafness. Pediatr Nephrol 2000;15:63. Rodriguez-Soriano J, Garcia-Fuentes M, Vallo A, et al: Hypercalcemia in neonatal distal renal tubular acidosis. Pediatr Nephrol 2000;14:354. Shapiro JI, Kaehny WD: Pathogenesis and management of metabolic acidosis and alkalosis. In Schrier RW (ed): Renal and Electrolyte Disorders. Philadelphia, Lippincott-Raven, 1997. Zelikovic I: Molecular pathophysiology of tubular transport disorders. Pediatr Nephrol 2001;16:919. Potassium Disorders Alon US: Renal tubular acidosis. In Finberg L (ed): Saunders Manual of Pediatric Practice. Philadelphia, WB Saunders, 1998, p 694. Carlisle EJF, Donnelly SM, Ethier JH, et al: Modulation of the secretion of potassium by accompanying anions in humans. Kidney Int 1991;39:1206. Chacko M, Fordtran JS, Emmett M: Effect of mineralocorticoid activity on transtubular potassium gradient, urinary [K]/[Na] ratio, and fractional excretion of potassium. Am J Kidney Dis 1998;32:47. Halperin ML, Kamel K: Potassium. Lancet 1998;352:135. Hellerstein S, Alon US, Warady BA: Renal impairment. In Ashcraft KW (ed): Pediatric Surgery. Philadelphia, WB Saunders, 2000. Mandal AK: Hypokalemia and hyperkalemia. Med Clin North Am 1997;81:611. Perazella MA: Drug-induced hyperkalemia: Old culprits and new offenders. Am J Med 2000;109:307. Peterson LN, Levi M: Disorders of potassium metabolism. In Schrier RW (ed): Renal and Electrolyte Disorders. Philadelphia, Lippincott-Raven, 1997. Rodriguez-Soriano J, Ubetagoyena M, Vallo A: Transtubular potassium concentration gradient: A useful test to estimate renal aldosterone bioactivity in infants and children. Pediatr Nephrol 1990;4:105. Wilson FH, Disse-Nicodeme S, Choate KA, et al: Human hypertension caused by mutations in WNK kinases. Science 2001;293:1107. Sodium Disorders Abrahm WT, Schrier RW: Renal sodium excretion, edematous disorders, and diuretic use. In Schrier RW (ed): Renal and Electrolyte Disorders. Philadelphia, Lippincott-Raven, 1997. Ball SG, Vaidja B, Baylis PH: Hypothalamic adipsic syndrome: Diagnosis and management. Clin Endocrinol 1997;47:405. Berl T, Schrier RW: Disorders of water metabolism. In Schrier RW (ed): Renal and Electrolyte Disorders. Philadelphia, Lippincott-Raven, 1997. Berry PL, Belsha CW: Hyponatremia. Pediatr Clin North Am 1990; 37:351. Cadnapaphornchai MA, Schrier RW: Pathogenesis and management of hyponatremia. Am J Med 2000;109:688. Conley SB: Hypernatremia. Pediatr Clin North Am 1990;37:365.
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Ganong CA, Kappy MS: Cerebral salt wasting in children. The need for recognition and treatment. Am J Dis Child 1993;147:167. Hall RT, Simon S, Smith MT: Readmission of breastfed infants in the first 2 weeks of life. J Perinatol 2000;20:432. Harris HW Jr: Diabetes insipidus. In Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics. Philadelphia, WB Saunders, 2000. Haycock GB: The syndrome of inappropriate secretion of antidiuretic hormone. Pediatr Nephrol 1995;9:375.
Jakobsson B, Berg U: Effect of hydrochlorothiazide and indomethacin treatment on renal function in nephrogenic diabetes insipidus. Acta Pediatr 1994;83:522. Manganaro R, Mami C, Marrone T, et al: Incidence of dehydration and hypernatremia in exclusively breast-fed infants. J Pediatr 2001;139:673. Trachtman H: Sodium and water homeostasis. Pediatr Clin North Am 1995;6:1343.
28
Acute and Chronic Scrotal Swelling
Jack S. Elder
temperature of the testes being 2° to 3° F below core body temperature, which allows for normal spermatogenesis.
The most serious causes of acute scrotal swelling are testicular torsion and incarcerated or strangulated inguinal hernia, both of which necessitate immediate surgical correction. Consequently, a prompt, careful approach to a painful or inflamed scrotum is essential. The differential diagnosis of scrotal swelling is extensive and varies depending on age of the patient (Tables 28-1 and 28-2). Optimal treatment requires an expeditious diagnosis. If there is any ambiguity regarding the diagnosis, a pediatric urologist should be consulted.
TESTIS The testes are the male reproductive organs and are suspended in the tunica vaginalis of the scrotum by the spermatic cords. The epididymis, attached to the testis posteriorly, consists of the caput (upper pole), corpus (body), and cauda (tail) (Fig. 28-2). The cauda epididymis is attached to the vas deferens, which can be palpated as a small, rubbery structure in the spermatic cord. The epididymis is responsible for sperm maturation and storage. Each testis relies on three arteries for its blood supply: the testicular artery, the cremasteric artery, and the deferential artery. Each enters the scrotum through the spermatic cord. The testicle receives both sympathetic and parasympathetic innervation. These autonomic nerves carry impulses that, with testicular stimulation, produce symptoms of deep visceral pain and associated nausea.
SCROTAL AND INGUINAL ANATOMY INGUINAL REGION All abdominal muscles and their aponeuroses contribute to the inguinal ligament and canal. The inguinal canal runs obliquely between the external and the internal inguinal rings. The anterior wall of the canal is formed by the external oblique aponeurosis; the floor, by the inguinal ligament; the roof, by arching fibers of the internal oblique and transversus abdominis muscles; and the posterior wall by the conjoined tendon, by the internal oblique and transversus abdominis muscles. The oblique direction of the inguinal canal allows for the posterior and anterior walls to coapt with increases in intraabdominal pressure.
DIAGNOSTIC STRATEGIES HISTORY A detailed history is critical in evaluating a boy with acute or chronic scrotal swelling. If there is painful testicular or scrotal swelling, knowledge of the following characteristics is helpful:
TESTIS DESCENT
1. Onset of pain: Testicular torsion and torsion of an appendix testis often occur after exercise or minor genital injury. Pain caused by these conditions may also awaken the patient from sleep. 2. Duration of pain: number of hours or days since onset of symptoms. 3. Evolution of pain: Testicular torsion tends to occur abruptly, whereas torsion of an appendix testis and epididymitis typically have an insidious onset. 4. Associated/radiation of pain: Inguinal discomfort suggests inguinal pathologic processes such as a hernia. If there is radiation of pain from the flank, then renal or ureteral pathologic processes, such as an obstructing ureteral calculus, should be considered in the differential diagnosis. Pain, with or without swelling of the scrotum, has a large differential diagnosis (Table 28-3).
The testes develop in the lumbar region of the abdominal cavity between the peritoneum and the transversalis fascia at approximately 7 weeks of gestation. By the eighth week of gestation, the gubernaculum extends from the caudal end of the epididymis through the inguinal canal to insert on the internal wall of the scrotum. The processus vaginalis, a finger-like outpouching of the peritoneum, extends adjacent to the gubernaculum to form the inguinal canal. As the processus vaginalis descends into the scrotum, it carries extensions of the abdominal wall layers. The testis normally descends through the inguinal canal into the scrotum before birth. As the testis and the spermatic cord descend through the inguinal canal, they are covered by the three concentric layers of the anterior abdominal fascia (Fig. 28-1). When the testis reaches the scrotum, the processus vaginalis is patent, leaving a connection between the scrotum and the peritoneal cavity. Normally, the processus vaginalis becomes obliterated, leaving a residual tunica vaginalis surrounding the testis. Typically, 1 to 2 mL of clear fluid is in the tunica vaginalis.
Although sometimes nonspecific, associated manifestations are also important: 1. General systemic: Fever, chills, or rigors suggest an infectious cause. 2. Abdominal signs/symptoms: Nausea, vomiting, and abdominal or inguinal pain suggest testicular torsion or, on occasion, epididymitis. Some patients with testicular torsion initially experience severe abdominal pain as well as testicular pain. 3. Urologic signs/symptoms: Dysuria, urinary frequency, hematuria, or penile discharge suggests a urinary tract infection, urethritis, or epididymitis in a sexually active boy or man.
SCROTUM The scrotum has two separate compartments, each containing a testis, epididymis, and distal spermatic cord. It comprises multiple layers that are continuous with the superficial layers of the anterior abdominal wall. The external location of the scrotum results in the 465
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Table 28-1. Differential Diagnosis of Scrotal Masses in
Young and Adolescent Boys Painful
Painless*
Testicular torsion Torsion of testicular appendage Epididymoorchitis Trauma: testicular rupture, hematocele Inguinal hernia (incarcerated or strangulated) Mumps orchitis
Hydrocele Inguinal hernia (reducible) Varicocele Spermatocele Testicular tumor Paratesticular tumor Idiopathic scrotal edema Henoch-Schönlein purpura
*Occasionally associated with discomfort.
4. Unusual rashes: Henoch-Schönlein purpura may result in vasculitis of the spermatic cord with associated scrotal pain and swelling. In addition, a thorough medical history is imperative. Significant questions include the following: 1. History of urinary tract infections, sexually transmitted diseases, or renal calculi. 2. History of any surgical procedures on the groin, scrotum, or abdomen. Often an orchiopexy performed for an undescended testis places the testis in a dartos pouch, which would prevent testicular torsion in the future. 3. History of any previous episodes of testicular pain. Previous intermittent severe pain in the same testis may be secondary to intermittent torsion of the testis. 4. Obstructive voiding pattern, such as slow, intermittent stream or incomplete bladder emptying predisposes to urinary infection, which could cause epididymitis. 5. Lower urinary tract pathologic processes, such as posterior urethral valves, urethral stricture (after trauma or hypospadias repair), or neuropathic bladder, may predispose to urinary infection, which could cause epididymitis. PHYSICAL EXAMINATION Examination of the scrotal contents should be routine in any boy presenting with abdominal, inguinal, or scrotal pain. Inspection, palpation, and transillumination of any mass are integral parts of a thorough physical examination.
Figure 28-1. Diagram illustrating the inguinal canal and the origin of the layers of the spermatic cord. The drawing demonstrates the eight layers of the abdominal wall, the scrotal wall, and the spermatic cord. The external spermatic fascia is derived from the external oblique aponeurosis; the cremaster muscle and cremasteric fascia are derived from the external oblique and its fascia; and the internal spermatic fascia is derived from the transversalis fascia. R, rectus abdominis; T, testis; TV, tunica vaginalis. (From Moore KL: Clinically Oriented Anatomy, 2nd ed. Baltimore, Williams & Wilkins, 1985.)
Scrotal Skin Changes and Fixation. Erythema suggests an
underlying inflammatory process but is nonspecific. Fixation of skin over the testis is suggestive of testicular necrosis.
Pubertal Development. Testicular torsion is much less common
than torsion of the appendix testis in a prepubertal child (Table 28-4). Conversely, in an adolescent, testicular torsion and epididymitis (if the patient is sexually active) are most common. Scars in the Inguinal Region. Scars imply previous surgery for hernia, hydrocele, undescended testis, or varicocele.
Table 28-2. Differential Diagnosis of Scrotal Swelling in
Newborns Hydrocele Inguinal hernia (reducible) Inguinal hernia (incarcerated)* Testicular torsion* *May be associated with scrotal inflammation.
Scrotal hematoma Testicular tumor Meconium peritonitis Epididymitis*
Testis Position within the Scrotum. An inflamed testis positioned high in the scrotum is suggestive of testicular torsion. Palpation provides information about intrascrotal structures. The testis should be evaluated for size and consistency (soft, firm, or hard) and compared with the testis on the contralateral side. Accurate localization of pain and swelling to the testis or epididymis, or both, is important. The consistency, size, and relationship to the testis of a paratesticular mass should be noted, along with its reducibility. Any scrotal soft tissue swelling should be evaluated by transillumination. The cremasteric reflex is stimulated by gently scratching the ipsilateral medial thigh; cremasteric muscle contraction causes the scrotum to retract. The presence of a symmetric cremasteric reflex makes testicular torsion unlikely; absence of the reflex is a nonspecific finding.
LABORATORY DATA Basic laboratory data for evaluation of acute and chronic swelling of the testis include urinalysis, urine culture, and tests for chlamydia
Chapter 28 Acute and Chronic Scrotal Swelling
Paradidymis - Organ of Giraldes
467
and gonorrhea if the patient is sexually active (see Chapters 23 and 29). A complete blood cell or white blood cell count is generally not useful in establishing a diagnosis. IMAGING STUDIES
Appendix epididymis
Appendix testis
Superior Vas aberrans of Haller Inferior Figure 28-2. Lateral view of the testis showing posterior location of epididymis and appendix testes. The appendix testis is present in almost all boys, the appendix epididymis is present approximately 50% of boys, and the other appendages are rarely present. (From Kelalis PP, King LR, Belman AB [eds]: Clinical Pediatric Urology, 2nd ed. Philadelphia, WB Saunders, 1985.)
Table 28-3. Causes of Acute Scrotal Pain
Common Testicular torsion Torsion of testicular appendage Epididymitis (gonorrhea, chlamydial infection in sexually active adolescents)* Trauma* Scrotal edema (Henoch-Schönlein purpura) Pain referred to scrotum (nephrolithiasis, ureteropelvic junction obstruction, appendicitis, spinal cord tumor, immunoglobulin A [IgA] nephropathy) Less Common Orchitis (mumps, varicella, coxsackievirus, dengue)* Abscess Infarction Malignancy: primary testicular neoplasm (e.g., seminoma), embryonal cell (usually painless mass) Leukemia: primary or relapse (usually painless swelling)* Uncommon Granulomatous orchitis* Drug-induced epididymitis (amiodarone)* Behçet disease Sarcoidosis Polyarteritis nodosa* Epididymitis (tuberculosis, brucellosis, actinomycosis, leprosy, Salmonella infection, fungal infection, parasitic infestation, Nocardia infection) Orchitis (rickettsial, Nocardia infections; toxoplasmosis; cytomegalovirus) Testicular pyocele Fournier gangrene* *Bilateral involvement possible.
Imaging studies are often helpful in determining the cause of acute and chronic testicular or scrotal swelling. They should not be substituted for a thorough history and careful physical examination performed by a surgical specialist. The conditions necessitating immediate surgical treatment include testicular torsion, incarcerated inguinal hernia, and testicular rupture secondary to trauma; testicular tumor mandates urgent surgical attention. Although the diagnosis of incarcerated hernia usually is straightforward, testicular torsion can be easily confused with several conditions that can be managed nonoperatively, including epididymitis and torsion of the appendix testis. The two diagnostic studies most frequently utilized are color Doppler ultrasonography and the radionuclide scrotal (testicular flow) scan. These studies assess whether blood flow is normal or increased, observed with epididymitis and torsion of the appendix testis, or whether blood flow is absent or reduced, observed with testicular torsion. Unfortunately, neither imaging study is 100% accurate. If the clinician strongly suspects that the patient has testicular torsion, then prompt surgical exploration is recommended, without confirmation by an imaging study. If the clinician seems certain of the diagnosis (e.g., torsion of the appendix testis, simple hydrocele), then it is unnecessary to obtain the study. Ordering a color Doppler ultrasonographic study or testicular flow scan is recommended in the following situations: 1. when the clinician is relatively certain that the child does not have testicular torsion and desires confirmation. 2. if acute scrotal pain and swelling have been present for more than 48 hours, in which case the likelihood of testicular salvage with ischemia-producing testicular torsion is low. 3. if the diagnosis cannot be made with certainty from the history and physical examination. 4. if there is a hydrocele that prevents palpation of the testis (on occasion, a testis tumor may be present). Color Doppler Ultrasonography Sonography provides a relatively accurate image of the testis and epididymis, and color Doppler imaging assesses blood flow. It is performed by examining the normal testis first and adjusting the color flow settings to detect normal flow. The affected testis is then examined for decreased or absent flow in comparison with the normal testis. Color flow Doppler imaging is able to distinguish between the increased collateral blood flow within the scrotal skin and the decreased blood flow to the testis in patients with testicular torsion. Sonography also can differentiate testicular rupture from a scrotal hematoma. Color flow Doppler imaging is nearly 100% accurate in demonstrating increased flow resulting from torsion of the appendix testis or epididymitis, but it is usually unable to distinguish these two entities. If a tumor is present (usually the mass is hypoechoic), sonography can demonstrate that the mass arises from the testis. There are a few benign localized testicular tumors that can be excised, with sparing of the remainder of the testis. The test is quick, easy to perform, and noninvasive. Accuracy rates of this modality are at least 95%, which compares favorably with those of scrotal scintigraphy. In addition, it is performed more rapidly than scintigraphy and is less expensive. There are several limitations of color Doppler imaging: 1. In boys with testicular torsion of short duration and if the torsion is less than 360 degrees, there may be venous congestion without impairment of testicular blood flow; color Doppler imaging may demonstrate normal flow.
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Table 28-4. Differentiation of Acute Painful Scrotal Swelling in Childhood Spermatic Cord Torsion
Epididymoorchitis
Usually perinatal and 10-18 yr, but any age possible Abrupt onset; there may have been previous similar episodes Localized to the testis and may radiate to groin and lower abdomen
Usually adolescence, but any age possible Gradual onset
Fever Vomiting Dysuria Physical examination
Rare Common Rare Testis may be high riding, swollen, exquisitely tender; scrotal erythema may be present; cremasteric reflex is absent
Common Rare Common Testis and epididymis are firm, tender, swollen; scrotal erythema may be present; cremasteric reflex present
Pyuria, urinary infection Blood flow (color Doppler study; isotope scrotal scan)
Rare Diminished or absent
Common Increased
Age Symptoms and signs Pain
2. In the prepubertal testis, blood flow may be difficult to demonstrate, even when the testis is normal, and absence of flow may be misinterpreted for testicular torsion. 3. The color Doppler aspect of the study is user dependent.
Localization to epididymis; may involve entire testis after 24 hr
Torsion of Appendix Testis
2-12 yr Gradual onset Localization to upper pole of testis; may involve entire testis after 24 hr Rare Rare Rare Testis is normal or enlarged; firm mass may be seen or felt at upper pole, distinct from epididymis; scrotal erythema may be present; cremasteric reflex present Rare Normal or increased
DIFFERENTIAL DIAGNOSIS (See Tables 28-3 and 28-4) TESTICULAR TORSION
Testicular Flow Scan The technetium 99m–pertechnetate testicular flow scan can distinguish between inflammatory and ischemic conditions of the testis. After intravenous injection of the radionuclide, both flow studies and static images of the testes are obtained. Typically, the study takes 20 to 30 minutes. Testicular torsion appears as a “cold spot” of radionuclide deficiency secondary to diminished blood flow. In contrast, inflammatory conditions, such as epididymitis or torsion of the appendix testis, produce normal or increased uptake of 99mTc. If the testicle has been torsed for longer than 48 hours, there is often a hyperemic rim of tissue surrounding a cold spot, referred to as the “vascular rim.” Accuracy rates of scrotal scintigraphy are 90% to 95%. There are several limitations to the testicular flow scan: 1. The test is not available at all hospitals. 2. A false-positive scan (incorrectly interpreted as reduced flow, suggestive of torsion) can result from a hernia, hydrocele, or spermatocele, which may falsely decrease the radionuclide counts in the region of the testis. A false-negative scan (torsion is present but scan is read as normal) may occur in boys with latephase testicular torsion, in which hyperemia of the scrotal wall is misinterpreted as flow to the testis. 3. If the extent of testicular torsion is 180 to 360 degrees, the scan may suggest normal flow. 4. If the patient has torsion-detorsion syndrome with only partial detorsion, the scan may demonstrate normal testicular flow. 5. No anatomic information regarding the scrotal contents is provided. 6. Although many institutions can rapidly arrange this study during weekday hours, considerable time delays may be encountered in arranging scans at night or on weekends.
Testicular torsion is a surgical emergency because of the risk of gonadal loss. The likelihood of testicular survival depends on the duration and severity of torsion. Consequently, testicular survival depends on accurate diagnosis and expedient management. The incidence of spermatic cord torsion is 1 in 4000 among boys and men younger than 25 years. The peak ages for testicular torsion are 10 to 18 years and the neonatal period. The pathogenesis of torsion and presentation in these two age groups are different. In testicular torsion, the testis and spermatic cord rotate or twist within the tunica vaginalis (termed “intravaginal”), resulting in obstruction of venous drainage, followed by compromise of arterial flow and subsequent infarction (Fig. 28-3). In many older boys with torsion, there is a predisposing anatomic abnormality that increases the likelihood that the testis can rotate on the spermatic cord, termed the “bell-clapper” abnormality. The “bell-clapper” refers to horizontal positioning of the testis that results from a redundant tunica vaginalis or from an abnormal insertion of the epididymis to the testis (Fig. 28-4). The likelihood of irreversible testicular damage depends on the severity and duration of torsion. If the testicular torsion exceeds 360 degrees, then the testis may become necrotic within 6 to 12 hours. However, if testicular torsion is less than 360 degrees, then there may be continued arterial perfusion for 24 to 48 hours. Patients typically experience the sudden onset of severe testicular pain and swelling. The event often occurs after minor trauma or exercise and may awaken the patient from sleep. Although the pain is usually localized to the affected hemiscrotum, there can be pain referred to the ipsilateral groin, and some patients also report abdominal pain. Associated symptoms may include nausea and vomiting. Thirty percent to 50% of patients describe previous episodes of severe scrotal pain that have resolved spontaneously. Patients do not have irritative voiding symptoms.
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Figure 28-3. A to C, Mechanism of testicular torsion associated with the bell-clapper deformity. (From Fleisher GR, Ludwig S: Textbook of Pediatric Emergency Medicine, 3rd ed. Baltimore, Williams & Wilkins, 1993.)
On examination, the scrotum is erythematous and edematous, and the testis is enlarged and extremely tender. The relationship between the testis and the epididymis depends on the degree of testicular torsion; often the epididymis is posterior, as in normal male genitalia. If the patient has been experiencing pain for more than 24 hours, there may be too much inflammation to delineate the
Figure 28-4. Anomalies of suspension associated with intravaginal testicular torsion. A, Normal. B, Envelopment by the tunica vaginalis. C, Inversion of the epididymis. D and E, Horizontal lie. Bell-clapper deformity is shown in B through E. (From Kelalis PP, King LR, Belman AB [eds]: Clinical Pediatric Urology, 2nd ed. Philadelphia, WB Saunders, 1985.)
scrotal contents. The cremasteric reflex is nearly always absent. The testis may be high in the scrotum. Urinalysis results are negative. In most cases, the diagnosis of testicular torsion can be made from the history and physical examination. If torsion is the likely diagnosis, scrotal exploration should proceed immediately. Imaging studies such as color Doppler ultrasonography and radionuclide testicular flow scan typically demonstrate absence of blood flow. Because excessive time spent obtaining diagnostic studies can result in significant delay in therapy, these studies should be reserved for cases in which torsion is not suspected. If the duration of symptoms is less than 4 to 6 hours, manual detorsion can be attempted. After administration of intravenous morphine (0.1 mg/kg body weight), manual detorsion can be attempted by lifting the scrotum and rotating the testis on its vascular pedicle. Usually, torsion occurs in a medial direction; therefore, the testis should be rotated outward toward the thigh. Successful detorsion is indicated by both relief of pain and a lower testicular position within the scrotum. Although successful manual detorsion may obviate emergency surgery, surgical fixation must be performed promptly because of the risk of recurrence. Some boys present with a history of severe testicular pain that resolved in the emergency room or on the way to the hospital. In these cases, torsion-detorsion syndrome should be suspected, and scrotal orchiopexy should be considered. If testicular torsion has been present more than 48 hours, the scrotum typically is severely enlarged, edematous, and erythematous, and the testis is an enlarged indurated mass. Color Doppler imaging in this situation typically reveals hyperemia in the scrotal wall with absence of testicular flow. The most appropriate term for this situation is late-phase torsion. Some clinicians use the inappropriate term “missed torsion.” Late-phase torsion refers to a testis that has been torsed for a prolonged period of time and is necrotic. Surgical management of testicular torsion consists of exploration, detorsion, and evaluation of testicular viability. An infarcted testicle is removed. If the testis is viable, it is fixed to the scrotal wall with nonabsorbable suture; this procedure is termed scrotal orchiopexy.
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Contralateral scrotal orchiopexy is necessary because there is a significant risk of contralateral torsion. If torsion is detected and treated within 4 hours of the onset of symptoms, the salvage rate approaches 100%; at 8 to 12 hours, it falls to 20%; and after 24 hours, infarction is the rule. Testicular torsion can also occur in the fetus and neonate. In these cases, torsion results from incomplete attachment of the gubernaculum to the scrotal wall and is “extravaginal.” When torsion occurs in utero, often the testis is nonpalpable because it has become atrophic. If torsion occurs just before birth, the testis is typically large, firm, and nontender. Usually the ipsilateral hemiscrotum is ecchymotic. In these cases, the testis always is nonviable because torsion was a remote event. On occasion, extravaginal testicular torsion occurs after delivery, and the baby is at risk until 30 days beyond term; in these cases, the infant becomes irritable, the testis enlarges, and the scrotum becomes erythematous. Color Doppler ultrasonography in the neonate is fairly reliable in distinguishing testicular torsion from scrotal hematoma and testicular tumor. However, testicular flow scanning is unreliable. Although testicular salvage in neonates with in utero torsion is highly unlikely, urgent exploration is recommended to confirm the diagnosis and to perform a contralateral scrotal orchiopexy to protect the solitary testis. If there is a possibility that torsion occurred after birth, there is a chance of saving the testis, and immediate exploration is therefore warranted. TORSION OF APPENDIX TESTIS The appendix testis is a vestigial remnant of the müllerian (mesonephric) ductal system that is attached to the upper pole of the testis. Some boys and men also have an appendage attached to the epididymis. When these appendages are long and pedunculated, they have a tendency to twist at their base, which results in ischemia and eventual infarction. This entity is most common in boys between 2 and 12 years of age and is uncommon in adolescents. Torsion of the appendix testis results in progressive inflammation and swelling of the epididymis and testis. The onset of testicular pain and swelling is typically gradual. Usually affected boys walk into the emergency room and appear comfortable. Constitutional symptoms are usually less severe than with testicular torsion, but pain referred to the lower abdomen, nausea, and vomiting can occur. Physical examination reveals an erythematous and edematous scrotum with underlying testicular enlargement. Palpation of the testis should reveal a 3- to 5-mm tender, indurated mass on the upper pole. In some cases, the torsed appendix testis may be visible through the scrotal skin; this is termed the blue dot sign. As the duration of inflammation becomes longer, the cremasteric reflex is less likely to be present. Later in its clinical course, differentiation from testis torsion becomes increasingly difficult because there is associated reactive enlargement of the testis and epididymis (epididymoorchitis). A clinical diagnosis of torsion of the appendix testis should not be made unless the appendix testis is palpated or visualized. The natural history of torsion of the appendix testis is for the inflammation to resolve gradually after infarction of the appendage. In general, the process is complete within 10 days from the onset of symptoms. Management includes bed rest for 24 to 48 hours and nonsteroidal antiinflammatory medication (e.g., ibuprofen) for 5 days to reduce inflammation and pain. The patient should be instructed to return promptly to the emergency room or physician’s office if the pain worsens, because it may be an indication of testicular torsion. Scrotal exploration and excision of the torsed appendage for pain control is unnecessary. If the likely diagnosis is torsion of the appendix testis but the clinician desires confirmation, color Doppler sonography or a testicular flow scan may be ordered. Either of these studies should demonstrate hyperemia to the testis. However, if there is any ambiguity
regarding the diagnosis, emergency scrotal exploration should be performed to be certain that the child does not have testicular torsion. EPIDIDYMOORCHITIS Epididymitis refers to an inflammatory process that involves the epididymis and usually results from a urethral infection that passes in a retrograde manner through the vas deferens to the epididymis (Fig. 28-5). Epididymal inflammation without infection also may be a secondary reaction to torsion of the appendix testis. Frequently, scrotal sonography in a prepubertal boy with testicular pain and swelling shows epididymal swelling indicative of a diagnosis of epididymitis, but usually it is not secondary to infection and does not necessitate antibiotic therapy. Some clinical reviews of boys with testicular pain include many with epididymitis, whereas the true origin in many of those cases is torsion of the appendix testis. Epididymitis secondary to infection is most common during adolescence; it is rare before puberty. In most postpubertal boys, epididymitis results from a sexually transmitted disease (see Chapter 29), unless there is a preexisting abnormality of the lower genitourinary tract (neuropathic bladder, urethral stricture). Organisms responsible include Chlamydia species, Mycoplasma species, and Neisseria gonorrhoeae. In prepubertal boys, in contrast, epididymitis is most frequently secondary to a structural abnormality of the lower genitourinary tract, including ectopic ureter, ectopic vas deferens, rectourethral fistula associated with imperforate anus, urethral stricture, or dysfunctional voiding. If the condition is diagnosed and treated early, the testicle is not involved. In many cases, however, the inflammatory process also involves the testis and is termed epididymoorchitis. If the infection is bacterial (e.g., Escherichia coli or other gram-negative uropathogen) and is not treated for 1 to 2 weeks, testicular infarction can occur. Epididymitis typically causes testicular pain and swelling that is insidious in onset. There may be symptoms of urinary tract infection, including dysuria, urgency, and frequency, as well as urethral discharge. Some patients report transient inguinal pain secondary to inflammation of the spermatic cord before the onset of testicular symptoms. On physical examination, fever is common, as is scrotal erythema. The epididymis is tender, enlarged, indurated, and posterior to the testis. Often the testis is also enlarged and tender. The cremasteric reflex is frequently absent. A reactive hydrocele may be present and obscures the testicular examination. If there is fixation of skin over the testis, the testis may be nonviable. For sexually active adolescents, diagnosis focuses on Chlamydia trachomatis and N. gonorrhoeae. These patients should have a
Figure 28-5. Epididymitis in a 6-year-old boy. Note the reactive orchitis as well as significant enlargement of the epididymis.
Chapter 28 Acute and Chronic Scrotal Swelling nucleic acid amplification test on either an intraurethral swab or a first-void urine sample for N. gonorrhoeae and C. trachomatis. Alternatively, a culture of intraurethral exudate can be obtained. A Gram stain smear of urethral exudate or intraurethral swab specimen confirms the diagnosis of urethritis (more than 5 polymorphonuclear leukocytes per field) and may suggest gonococcal infection (intracellular gram-negative diplococci). If the urethral Gram stain result is negative, then a culture and Gram stain test should be obtained from a first-void uncentrifuged urine specimen. Testing for syphilis and human immunodeficiency virus should be performed (see Chapter 29). In prepubertal boys, the most important laboratory study is the urinalysis, which often shows pyuria or bacteriuria, or both (see Chapter 23). The urine should be subjected to culture. Not all prepubertal boys with epididymitis have an abnormal urinalysis result; in rare cases, boys with testicular torsion may have evidence of infection. If there is a urethral discharge, a specimen of urethral fluid should be obtained for Gram stain and culture. After treatment, these young boys should undergo voiding cystourethrography and renal ultrasonography as part of the evaluation for an underlying anatomic abnormality. If the diagnosis is not definitive or if testicular torsion is suspected, color Doppler ultrasonography or a testicular flow scan may be helpful by showing blood flow to the testis. Sonography may also show evidence of an abscess. Empirical treatment for sexually acquired epididymitis should include coverage for N. gonorrhoeae (ceftriaxone, 250 mg intramuscularly in a single dose) and Chlamydia species (doxycycline, 100 mg orally b.i.d. for 10 days) (see Chapter 29). Supportive measures include an ice pack, scrotal support, nonsteroidal antiinflammatory medication for analgesia, and bed rest for 48 hours. In non–sexually active children, E. coli is the most common cause. The patient should initially receive empirical treatment with a broad-spectrum antibiotic (gentamicin or cefotaxime). All patients should be reexamined periodically until the inflammatory process resolves completely. Approximately 15% of individuals with a testis tumor are initially treated for epididymitis. Surgical management is reserved primarily for cases in which there is ambiguity regarding the diagnosis and testicular torsion is suspected or if there is a suspected abscess.
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Orchitis as an isolated infection is uncommon in boys. Most often, it results from extension of an epididymal inflammatory process. Mumps orchitis occurs most frequently in postpubertal boys. The onset of orchitis usually occurs 4 to 6 days after the parotitis. As many as 33% of patients with orchitis develop testicular atrophy. Treatment of orchitis includes broad-spectrum antibiotics until the urine culture result is available. If the primary infection is obviously viral, only symptomatic therapy (nonsteroidal antiinflammatory drugs, scrotal support, ice pack) is necessary. TRAUMA AND HEMATOCELE Blunt scrotal trauma can result in a spectrum of injuries ranging from testicular contusion to rupture of the testis (Fig. 28-6). Testicular injuries usually result from a fall, kick, or direct blow from a blunt object. A detailed history of the nature of the injury aids in recognizing the likelihood of serious testicular injury. With disruption of the tunica albuginea (capsule) of the testis, there is such significant painful scrotal swelling that the testis cannot be palpated. Often there is associated erythema or ecchymosis of the scrotal wall. In most cases of suspected testicular injury, scrotal ultrasonography is performed to assess the integrity of the testis. In many boys with testicular torsion or torsion of the appendix testis, there is often, inexplicably, a history of recent mild scrotal trauma. Although there is no evidence that these disorders can result from blunt trauma, these diagnoses should be considered if there is not an obvious significant testicular injury, but the scrotal examination is abnormal. Treatment of scrotal trauma is determined by the extent of the injury. Boys with a small, nonexpanding hematocele and a normal testis are managed nonoperatively with bed rest, scrotal support, and ice packs. In contrast, a ruptured testis associated with a large hematocele necessitates urgent surgical exploration and repair. VARICOCELE A varicocele is an abnormal dilation of the veins of the pampiniform plexus in the scrotum. Approximately 10% of adolescent boys and 15% of men have a varicocele; 15% of these men are infertile.
Figure 28-6. A, Appearance in an 8year-old boy kicked in the scrotum while performing karate with his brother. Note right scrotal swelling. An ultrasound study showed scrotal hematoma and a ruptured testis. B, Scrotal exploration shows a nonviable testis. Orchiectomy was performed.
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A varicocele is the most common surgically correctable cause of infertility in men. Infertility is thought to result from the effect of elevated temperature on the testis. Varicoceles are rare in boys younger than 10 years of age. The increased prevalence among adolescents is secondary to the increased testicular blood flow that occurs with puberty. More than 95% of cases involve the left testis; this involvement is secondary to multiple factors, including the long length of the left internal spermatic vein in comparison with that of the right and the absence of a venous valve at the insertion of the left internal spermatic vein into the renal vein. A varicocele manifests as a painless, paratesticular mass often described as a “bag of worms.” On occasion, patients describe a chronic, dull ache in or adjacent to the testis. Physical examination of the patient in both the supine and the upright positions, with and without the Valsalva maneuver, facilitates the diagnosis. Typically, the varicocele is decompressed when the patient is supine and prominent when standing. Varicocele size may be graded: grade I means barely palpable; grade II, easily palpable but not visible in the standing position; and grade III, easily visible in the standing position. Measurement of the volume of both testicles is important to document differences in the size of the testis. Calipers or an orchidometer may be used to assess testicular size; scrotal ultrasonography may also be used. Approximately 33% of affected boys have an associated volume loss of the left testis. If a varicocele is detected in a boy younger than 10 years old or on the right side (both red flags), abdominal ultrasonography is indicated to ascertain whether an abdominal mass is present. Histologic studies have demonstrated pathologic testicular changes in some adolescent boys and men with varicoceles, including degeneration of germinal centers, interstitial fibrosis, and impaired spermatogenesis. The goal in treatment of a varicocele is preservation and restoration of spermatogenesis. Because the majority of testicular volume is composed of seminiferous tubules, if the left testis is significantly smaller than the right, the clinician may presume that the varicocele has affected testicular growth. Typically, after varicocelectomy in an adolescent, the testis shows catch-up growth and ultimately is similar in size to the contralateral testicle.
Indications for varicocelectomy in boys and adolescents include significant disparity in testicular size, pain, and diseased or absent contralateral testis. Surgical repair should also be considered for very large varicoceles and if bilateral testicular growth arrest is suspected. Varicocelectomy is accomplished by ligating the dilated veins of the pampiniform plexus through a low inguinal incision or by ligating and dividing the internal spermatic vein through a high transverse inguinal incision or by a laparoscopic approach. All of these techniques may be performed on an ambulatory basis. INGUINAL HERNIA Hernias and hydroceles result from incomplete obliteration of the processus vaginalis. Indirect inguinal hernias result from a patent processus vaginalis that allows a loop of bowel, omentum, or other abdominal organ to pass through the internal inguinal ring. Patients usually present with nontender groin, scrotal swelling, or both, which reduce with minimal pressure (Fig. 28-7). A hernia that cannot be reduced is called an incarcerated hernia. A strangulated hernia, in which the vascular supply of the herniated bowel is compromised, is a surgical emergency. Physical signs of incarceration include inguinal or scrotal erythema, pain, signs of bowel obstruction, and inability to reduce the hernia. Infants with an incarcerated hernia have a 10% incidence of ipsilateral testicular infarction secondary to increased pressure on the spermatic cord. If an incarcerated hernia is suspected, the child is admitted and sedated, and manual reduction of the hernia is attempted. Most hernias can be reduced successfully and should be repaired promptly. Children with an easily reducible hernia should also undergo herniorrhaphy within a reasonable time to reduce the possibility of incarceration or strangulation. Neonates and small infants with an incarcerated hernia may present with painful scrotal swelling without an inguinal mass, but this manifestation is unusual in older children. Surgical correction involves dissection and high ligation of the hernial sac through a small inguinal incision. Elective herniorrhaphy
Figure 28-7. Diagrams of sagittal sections of the inguinal region. A, Incomplete indirect inguinal hernia, resulting from persistence of the proximal processus vaginalis. B, Indirect inguinal hernia into the scrotum, resulting from persistence of the entire processus vaginalis. Note the presence of an undescended testicle, which is a commonly associated malformation. C, Hydrocele of the cord, derived from an unobliterated portion of the processus vaginalis. D, Communicating hydrocele, resulting from peritoneal fluid passing through a patent processus vaginalis. (From Moore KL: Clinically Oriented Anatomy, 2nd ed. Baltimore, Williams & Wilkins, 1993, p 299.)
Chapter 28 Acute and Chronic Scrotal Swelling is usually performed as an ambulatory surgical procedure when the infant is 5 to 6 months of age. HYDROCELE A hydrocele is an accumulation of fluid within the tunica vaginalis. Approximately 1% to 2% of newborn boys have a hydrocele. In most of these cases, which are noncommunicating hydroceles, the fluid disappears by 1 year of age. Communicating hydroceles, defined by a patent processus vaginalis (see Fig. 28-7), tend to persist. Typically, affected boys have progressive scrotal swelling over the course of the day that decreases by morning as the hydrocele fluid returns to the abdomen during sleep. In infants who are not walking, the hydrocele usually does not change in size. In an older boy, a noncommunicating hydrocele can result from an inflammatory condition within the scrotum (testicular torsion, torsion of the appendix testis, epididymitis, testis tumor). Communicating hydroceles and hernias differ by the anatomy and contents of the processus vaginalis. In communicating hydroceles, the diameter of the processus vaginalis is much smaller in relation to a hernia, allowing only fluid to pass into the scrotum. On examination, hydroceles are smooth and nontender and can be associated with thickening of the cord structures. Bright transillumination of the scrotum confirms the fluid-filled nature of the mass. If compression of the fluid-filled mass eliminates the hydrocele, then the patent processus vaginalis is large, and the boy can be considered to have an inguinal hernia. Because hydroceles can be associated with testicular neoplasms, the testis should be palpated to document that it is normal. If the diagnosis is uncertain with regard to the mass, scrotal ultrasonography is advised. A severe form of the hydrocele is the abdominoscrotal hydrocele, in which the hydrocele sac is tense with fluid and extends from the scrotum proximally through the inguinal canal into the abdominal cavity. On examination, these hydroceles are palpable in the inguinal canal, and an abdominal mass is often present. These hydroceles do not resolve and may cause extrinsic testicular compression; consequently, repair is recommended. Treatment depends on several factors. Most hydroceles resolve by 12 months of age after reabsorption of the hydrocele fluid. If the hydrocele is large and tense, however, early surgical correction is recommended for two reasons: (1) It is often impossible to verify that the child does not have a hernia, and (2) large hydroceles rarely disappear spontaneously. Hydroceles persisting beyond the age of 12 to 18 months are usually communicating and thus rarely regress; hence, these hydroceles should be surgically repaired. If left untreated, most eventually progress to an inguinal hernia. Parents should be advised to watch for more severe inguinal or scrotal swelling, or both, which indicates that a hernia has developed. Surgical repair of hydroceles is essentially identical to a herniorrhaphy. Through an inguinal incision, the spermatic cord is identified, the hydrocele fluid is drained, and a high ligation of the processus vaginalis is performed. TESTICULAR TUMORS Although testicular and paratesticular tumors are uncommon, they can occur at any age, even in the newborn. In men, 98% of testicular tumors are malignant. In children, however, only 35% are malignant; they include yolk sac carcinoma, rhabdomyosarcoma, and, in rare cases, leukemias. Most manifest as a painless, hard testicular or paratesticular mass that does not transilluminate. Ten percent to 15% are associated with a hydrocele. Scrotal ultrasonography should be performed to confirm the finding of a testicular mass and may help delineate the type of testicular tumor. Serum tumor markers (α−fetoprotein and human chorionic gonadotropin) should be evaluated before surgical intervention. Definitive therapy includes surgical exploration through an inguinal incision. Radical orchiectomy involves ligation of the
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spermatic cord, followed by removal of the testis and spermatic cord. If the ultrasound study or surgical exploration suggests the presence of a benign tumor, such as a teratoma or epidermoid cyst, with a significant amount of normal testicular parenchyma, excision of the mass only (testis-sparing surgery) may be performed. If the tumor is malignant, a metastatic workup, including abdominal and chest computed tomographic scan, is obtained to evaluate the most common sites of metastatic disease: the retroperitoneum and lung. MECONIUM PERITONITIS Antenatal peritonitis may result from intestinal perforation. Although the intestinal perforation may heal, the intraabdominal meconium may track down the patent processus vaginalis into the scrotum, resulting in the formation of an inflammatory mass. This condition can manifest as bilateral neonatal hydroceles, which eventually regress into firm, nodular masses involving either or both testicles. Scrotal sonography demonstrates multiple areas of echogenic foci suggestive of calcification. In addition, a plain film of the scrotum shows calcification. SCROTAL WALL SWELLING Henoch-Schönlein Purpura Henoch-Schönlein purpura is a systemic vasculitis of unknown origin that involves the skin, gastrointestinal tract, joints, and kidneys. Most affected patients are younger than 7 years. Genitourinary manifestations may include glomerulonephritis (see Chapter 25), ureteritis, renal pelvic bleeding, and acute swelling of the scrotum and spermatic cord. Scrotal wall and testicular involvement has been reported in up to 33% of affected patients. A maculopapular purpuric rash (palpable purpura) often begins in the lower extremities and buttock region. Later the rash may spread to the scrotum. The initial manifestation may, however, be a scrotal rash. With testicular involvement, which is relatively uncommon, there is mild to moderate swelling and tenderness of the testes. Differentiation from testicular torsion can be made if the characteristic rash and associated symptoms develop before the acute enlargement of the scrotum. These two conditions can coexist; therefore, if there is any uncertainty regarding the diagnosis, color Doppler ultrasonography or scrotal scintigraphy should be performed. Acute Idiopathic Scrotal Wall Edema Acute idiopathic scrotal wall edema is an uncommon entity that accounts for 2% to 5% of acute scrotal swelling. The average patient is between 4 and 7 years of age. Patients typically present with the sudden onset of unilateral or bilateral scrotal wall edema associated with mild tenderness. The overlying skin is erythematous, and the edema may extend anteriorly onto the abdominal wall or posteriorly into the perineum. The testicles are easily palpable, normal in size, and nontender. The origin of this syndrome is unknown, but allergic causes have been implicated. Therapy consists of bed rest and parental reassurance. Although treatment with antibiotics, antihistamines, and corticosteroids has been proposed, most children experience improvement within 48 to 72 hours regardless of therapy. Idiopathic Fat Necrosis Idiopathic fat necrosis causes acute painful swelling of the scrotum secondary to necrosis of intrascrotal fat. Examination of the underlying testis may be hampered by inflammation within the scrotal wall. The cause of this problem is unknown but may be related to
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trauma with physical activity. Sonography may help differentiate this entity from an intrascrotal process. Treatment is supportive if the diagnosis is made nonoperatively. Fournier Gangrene Fournier gangrene of the scrotum usually affects adults but occasionally afflicts infants and children. In children, it occurs primarily in those with severe diaper rash, in those with insect bites, after circumcision, or in those with perianal skin abscess. Other predisposing factors include diabetes mellitus, trauma, instrumentation, urethral stricture, and inguinal or perineal surgery. Symptoms of this life-threatening infection include acute scrotal swelling with tenderness, erythema, and systemic manifestations of fever, chills, and septicemia. The most common organisms identified include Staphylococcus aureus, Streptococcus species, Bacteroides fragilis, E. coli, and Clostridium welchii. Treatment involves emergency débridement with the patient under anesthesia; copious irrigation; and broad-spectrum parenteral antibiotics. In some cases, hyperbaric oxygen therapy is beneficial. Despite aggressive treatment, mortality rates approach 50%.
RED FLAGS Because testicular torsion is a surgical emergency, acute scrotal pain should be evaluated promptly. Physical examination findings suggesting testicular torsion include marked tenderness, high-riding testis, and absent cremasteric reflex. A varicocele before puberty or on the right side is a red flag; abdominal ultrasonography is indicated.
Testicular Torsion Barada JH, Weingarten JL, Cromie WJ: Testicular salvage and age-related delay in the presentation of testicular torsion. J Urol 1989;142:746. Cornel EB, Karthaus HF: Manual detorsion of the twisted spermatic cord. BJU Int 1999;83:672. Cuckow PM, Frank JD: Torsion of the testis. BJU Int 2000;86:349. Dunne PJ, O’Loughlin BS: Testicular torsion: Time is the enemy. Aust N Z J Surg 2000;70:441. Pinto KJ, Noe HN, Jerkins GR: Neonatal testicular torsion. J Urol 1997; 158:1196. Van Glabeke E, Philippe-Chomette P, Gall O, et al: Spermatic cord torsion in the newborn: Role of surgical exploration. Arch Pediatr 2000;7:1072. Epididymoorchitis Beard CM, Benson RC, Kelalis PP, et al: The incidence and outcome of mumps orchitis in Rochester, Minnesota, 1935 to 1974. Mayo Clin Proc 1977;52:3. Bukowski TP, Lewis AG, Reeves D, et al: Epididymitis in older boys: Dysfunctional voiding as an etiology. J Urol 1995;154:762. Siegel A, Snyder H, Duckett JW: Epididymitis in infants and boys: Underlying urogenital anomalies and efficacy of imaging modalities. J Urol 1987; 138:1100. Inguinal Hernia Puri P, Guiney EJ, O’Donnell B: Inguinal hernia in infants: The fate of the testis following incarceration. J Pediatr Surg 1984;19:44. Stoker DL, Spiegelhalter DJ, Singh R, et al: Laparoscopic versus open inguinal hernia repair: Randomised prospective trial. Lancet 1994; 343:1243. Other Diagnoses
REFERENCES Diagnostic Strategies Burgher SW: Acute scrotal pain. Emerg Clin North Am 1998;16:781. Galeis LE: Diagnosis and treatment of the acute scrotum. Am Fam Phys 1999;59:817. Hawtrey CE: Assessment of acute scrotal symptoms and findings. A clinician’s dilemma. Urol Clin North Am 1998;25:715. Kadish HA, Bolte RG: A retrospective review of pediatric patients with epididymitis, testicular torsion, and torsion of testicular appendages. Pediatrics 1998;102:73. Kass EJ, Lundak B: The acute scrotum. Pediatr Clin North Am 1997;44:1251. Lewis AG, Bukowski TP, Jarvis PD, et al: Evaluation of acute scrotum in the emergency department. J Pediatr Surg 1995;30:277. Marcozzi D, Suner S: The nontraumatic acute scrotum. Emerg Clin North Am 2000;19:547. Imaging Allen TD, Elder JS: Shortcomings of color Doppler sonography in the diagnosis of testicular torsion. J Urol 1995;154:1508. Baker LA, Sigman D, Mathews RI, et al: An analysis of clinical outcomes using color Doppler testicular ultrasound for testicular torsion. Pediatrics 2000;105:604. Dogra VS, Sessions A, Mevorach RA, et al: Reversal of diastolic plateau in partial testicular torsion. J Clin Ultrasound 2001;29:105. Kravchick S, Cytron S, Leibovici O, et al: Color Doppler sonography: Its real role in the evaluation of children with highly suspected testicular torsion. Eur Radiol 2001;11:1000. Paltiel HJ, Connolly LP, Atala A, et al: Acute scrotal symptoms in boys with an indeterminate clinical presentation: Comparison of color Doppler sonography and scintigraphy. Radiology 1998;207:223. Weber DM, Rosslein R, Fliegel C: Color Doppler sonography in the diagnosis of acute scrotum in boys. Eur J Pediatr Surg 2000;10:235.
Anzai AK: Fournier’s gangrene: A urologic emergency. Am Fam Phys 1995; 52:1821. Corman JM, Moody JA, Aronson WJ: Fournier’s gangrene in a modern surgical setting: Improved survival with aggressive management. BJU Int 1999;84:85. Dayanir YO, Akdilli A, Karaman CZ, et al: Epididymoorchitis mimicking testicular torsion in Henoch-Schönlein purpura. Eur Radiol 2001; 11:2267. Diamond DA, Paltiel HJ, DiCanzio J, et al: Comparative assessment of pediatric testicular volume: Orchidometer versus ultrasound. J Urol 2000; 164:1111. Ioannides AS, Turnock R: An audit of the management of the acute scrotum in children with Henoch-Schönlein purpura. J R Coll Surg Edinb 2001; 46:98. Kaplan GW: Acute idiopathic scrotal edema. J Pediatr Surg 1977;12:647. Kass EJ, Stork BR, Steinert BW: Varicocele in adolescence induces left and right testicular volume loss. BJU Int 2001;87:499. Levy DA, Kay R, Elder JS: Neonatal testis tumors: A review of the prepubertal testis registry. J Urol 1994;151:715. Nemoy NJ, Rosin S, Kaplan L: Scrotal panniculitis in the prepubertal male patient. J Urol 1977;118:492. Ross J, Kay R, Elder J: Testis sparing surgery for pediatric epidermoid cysts of the testis. J Urol 1993;149:353. Rushton HG, Belman AB, Sesterhenn I, et al: Testicular sparing surgery for prepubertal teratoma of the testis. J Urol 1990;144:726. Sayfan J, Siplovich L, Koltun L, et al: Varicocele treatment in pubertal boys prevents testicular growth arrest. J Urol 1997;157:1456. Thomas JC, Elder JS: Testicular growth arrest and adolescent varicocele: Does varicocele size make a difference? J Urol 2002;168:1689. Vasavada S, Ross J, Nasrallah P, et al: Prepubertal varicoceles. Urology 1997;50:774. Walsh C, Rushton HG: Diagnosis and management of teratomas and epidermoid cysts. Urol Clin North Am 2000;27:509. Yeh ML, Chang CJ, MU SC: Neonatal idiopathic scrotal hemorrhage: Patient reports. Clin Pediatr 2000;39:493.
29
Sexually Transmitted Diseases
Gale R. Burstein*
the assault must be documented, because such activities may interfere with specimen collection. Clinical symptoms that should specifically be noted include vaginal or rectal discharge, odor, pruritus, or pain; sore throat; local bleeding; dysuria, urgency, or frequency; abdominal pain; warts; and abnormal menstrual bleeding. A history of any known STD, voluntary sexual relationships, or previous sexual assault and relevant medical treatment should be obtained. Although most STDs are asymptomatic among both boys and girls, certain symptoms should raise clinical suspicion. Symptomatic girls may present with vaginal discharge, genital lesions, abdominal pain, dysuria, or menstrual spotting. Boys may complain of dysuria, genital lesions, testicular pain, urethral discharge, or scrotal swelling. A variety of rashes may be noted with STDs and may be the reason for seeking medical attention. Constitutional symptoms may include fever, malaise, lymphadenopathy, and, less often, arthritis. If the patient has any constitutional symptoms, the examiner should inquire about weight loss, appetite, sleep patterns, energy level, headaches, and weakness. Vaginal discharge in the adolescent girl is a nonspecific symptom, but its presence should lead to the consideration of bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), trichomoniasis, chlamydia, and gonorrhea. BV and VVC are not sexually transmitted. In the prepubescent girl with acute onset of vaginal irritation or discharge, an Escherichia coli or streptococcal infection is likely, whereas nonspecific, mixed bacterial vulvovaginitis is the most likely cause of chronic vaginal symptoms in this younger age group. Male patients who seek medical attention for a urethral discharge or urethritis may be infected with Neisseria gonorrhoeae or Chlamydia trachomatis. However, the proportion of urethritis cases caused by these organisms has been declining since the early 1990s. Boys and girls who describe genital lesions may have ulcers, vesicles, papules, or warts (Table 29-3). Patients presenting with systemic complaints such as arthralgias, weight loss, headache, or fever may have an infection with HIV, syphilis, herpes simplex virus (HSV), disseminated gonorrhea infection, or reactive arthritis.
Adolescents represent an age group at high risk for acquisition and transmission of sexually transmitted diseases (STDs). Most STDs are asymptomatic and are diagnosed by screening asymptomatic sexually active individuals. A national survey of high school students demonstrated that 46% have engaged in sexual intercourse, with an increase to 61% of 12th graders. Seven percent initiated sexual intercourse before 13 years of age, and 36% had had a sexual encounter within the previous 3 months. Adolescents are likely to have multiple sexual partners over relatively short periods of time, fail to recognize the symptoms of STDs, and use condoms inconsistently. Adolescents who engage in sex for money, who are homeless, or who are involved with the juvenile justice system are at especially high risk for acquiring STDs. Young men who have sex with men are at very high risk for human immunodeficiency virus (HIV) infection, as well as other STDs.
HISTORY The adolescent seeking medical care for evaluation of any sexual health issue, including STDs, may complain of vague symptoms and avoid discussing the actual concern. Providers should suspect a “hidden agenda” from an adolescent patient who presents for a check-up. The majority of STDs in adolescents are asymptomatic or manifest symptoms that are not recognized. Therefore, providers miss most infections by testing only patients presenting with suggestive symptoms. The sexual history should be obtained from the adolescent patient confidentially. Interviewing the adolescent in the room alone (i.e., without a parent present) for at least a portion of the visit is the standard of care for all adolescent health care visits. The terms of a confidential visit should be explained to the adolescent (and parent, if present); all information disclosed by the adolescent remains confidential, unless he or she reveals a risk of rendering harm to himself or herself or to others, such as with suicidal or homicidal ideation. Tables 29-1 and 29-2 detail important points from the history that should be discussed with the patient who is sexually active. It is critical that the provider perform a thorough history in a nonjudgmental and nonthreatening manner. Because many patients infected with STDs may be asymptomatic, gaining insight into sexual activity and orientation is most important. A history of a previous STD places the patient at high risk for future STDs. Questions about victimization and abuse are part of the sexual history, regardless of age or gender. If the patient has been a victim of assault, a description of the assault should be obtained, and the sites of attempted or successful penetration should be noted. If possible, the offender should be identified. The time interval between the assault and evaluation is important. Any bathing, douching, urinating, defecating, tooth brushing, or gargling since the time of
PHYSICAL EXAMINATION A complete physical examination and laboratory evaluation are necessary to evaluate a symptomatic patient for STDs. Table 29-4 is a brief listing of general physical examination findings that must be sought. Tables 29-5 and 29-6 review the physical examination procedures that should be followed for a comprehensive STD evaluation in adolescent boys and girls. The complete rectal examination may not be necessary if the patient reports no anal sex or symptoms. Table 29-3 should assist the clinician in distinguishing genital lesions associated with some of the more common infectious agents. Table 29-7 offers an approach to the physical examination in the prepubertal girl who presents with vaginal irritation or discharge. If the clinician suspects that a prepubertal child has been sexually abused, a careful general examination is performed. Anatomic
*This chapter is an updated and edited version of the chapter by Trina M. Anglin that appeared in the first edition. The points of view expressed in this chapter are the author’s and do not necessarily reflect the opinion of the Centers for Disease Control and Prevention.
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Table 29-1. Approach to Clinical Evaluation of Sexually
Transmitted Diseases: Sexual History Age at coitarche Date of most recent sexual encounter Duration of relationship with current partner Numbers of current, recent (within past 3-6 months), and lifetime partners Condom usage (overall consistency) Contraceptive usage Vaginal intercourse Oral intercourse Anal intercourse Dyspareunia Gender of partners Involuntary sexual encounters (abuse, rape) Partner’s sexually transmitted disease symptoms and relevant sexual history (i.e., other sex partners)
abnormalities (trauma, lacerations, erythema, scarring) of the external genitalia and the anorectal area should be documented; colposcopic magnification and photography are standard (see Chapter 36).
LABORATORY TESTING Adolescents who present with one STD are at high risk for having another STD. Table 29-8 provides a template for the basic diagnostic laboratory evaluation for treatable STDs that should be performed on all sexually active adolescents, regardless of presenting symptoms. Additional laboratory tests may be indicated, depending on the clinical scenario (see later discussion). Pregnancy testing is indicated when an adolescent girl presents with symptoms of an STD. The test results may influence the treatment plan. Table 29-9 lists the circumstances in which HIV counseling, testing, and referral should be considered for adolescents.
SEXUALLY TRANSMITTED DISEASE SYNDROMES GENITAL ULCER DISEASE
Table 29-2. Approach to Clinical Evaluation of Sexually
Transmitted Diseases: Symptoms and General Health Symptoms (Duration, Intensity, Course) Urinary (dysuria, urgency, frequency, hematuria) Vaginal discharge (quantity, color, odor, consistency, pruritus, burning) Urethral discharge (character, quantity, when it occurs) Anorectal discharge (character, quantity, when it occurs; bowel movements) Local pain (character; location: mucosal, abdominal, testicular, inguinal, anal) Genital lesions (onset, quantity, appearance, pain, pruritus) Self-Treatment Over-the-counter medication Douching Antibiotic usage Reproductive Health History Sexually transmitted diseases Pregnancies Menstruation Last menstrual period (date, duration, quantity, associated pain or cramping, comparison with usual menses) Spotting or intramenstrual bleeding Review of Systems Skin (rash, pruritus, lesions) Joints (pain, swelling, redness) Bowel changes (diarrhea, bleeding) Constitutional (fever, weight loss, night sweats, malaise, cough, depression) General Health Medical problems Medication usage/allergies Travel Substance Abuse Alcohol and illicit drug usage (self and partner) Needle injection (self and partner)
Table 29-3 describes the clinical manifestations of various causes of genital ulcer disease. Pustules and vesicles atop an erythematous base are most often a result of HSV. Fluid from these vesicles may be sent for herpes culture. Antigen detection tests do not distinguish HSV type 1 (HSV-1) from HSV type 2 (HSV-2). Material from the ulcer or chancre associated with syphilis can be examined via darkfield microscopy for the presence of the treponeme, or the material can be air-dried on a slide and a direct fluorescent antibody test for Treponema pallidum can be performed (highly sensitive and specific). Lymphogranuloma venereum and chancroid are rarely seen in the United States. Laboratory evaluation of an ulcer caused by syphilis, lymphogranuloma venereum, and chancroid is complicated and usually not performed in the primary care office setting. Consultation with an infectious diseases specialist or the local health department STD clinic is recommended for these evaluations. Two noninfectious causes of genital ulcers that can be confused with infection include inflammatory bowel disease and Behçet syndrome. Inflammatory bowel disease usually manifests with intestinal symptoms, deeper ulcers, and a longer duration of ulcerative lesions. Behçet syndrome may manifest with lesions of other mucous membranes as well as ocular, central nervous system, and joint manifestations. If the clinical diagnosis is not definitive, viral culture of the lesions is recommended. GENITAL WARTS Human papillomavirus (HPV) types 6 and 11 are most commonly associated with genital warts. The clinical manifestations are described in Table 29-3. Although all the HPV types causing genital warts are not likely to cause cervical cancer, they often produce abnormalities on Papanicolaou (Pap) smears, and patients may be infected simultaneously with multiple types of HPV. Annual cervical cancer screening with a Pap smear of adolescent females should begin 3 years after the onset of sexual activity. The majority of cervical cancers are associated with specific serotypes of HPV. Patients with genital warts usually present with complaints of bumps or growths on their genitalia. On occasion, patients may complain of itching, burning sensation, pain, or bleeding. Genital warts can appear on the penis, urethral meatus, scrotum, and perianal areas in boys and on the vulvar skin and mucosa, vagina, cervix, and perianal area in girls. In general, HPV is a multifocal disease. The entire genitalia should be inspected for warts because more than one lesion and lesions on different sites are usually present.
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Table 29-3. Diagnostic Characteristics of Genital Lesions
Syndrome
Herpes Syphilis Lymphogranuloma venereum Human papillomavirus Lice or nits Chancroid
Appearance
Number of Lesions
Pain
Vesicles and superficial ulcers on erythematous base (1-2 mm) Papule and superficial or deep ulcer (5-15 mm) Ulcer (2-10 mm), resolves quickly
Multiple
Often
Single
No
Single
Yes
Anogenital exophytic warts; may resemble cauliflowers or be papular with projections Tiny (≤1 mm) insects or eggs adherent to hair shaft; excoriations Deep, purulent ulcers (2-20 mm)
Single or multiple
No
Multiple
No but pruritic Yes
The four morphologic types of genital warts are 1. condylomata acuminata (cauliflower-like appearance) 2. papular warts (flesh-colored, dome-shaped papules, usually 1-4 mm in diameter) 3. keratotic warts (resemble common skin wart with thick, crustlike layer) 4. flat-topped papules (macular, slightly raised) The differential diagnosis for genital warts includes 1. Anatomic structures: skin tags, pearly penile papules, vestibular papillae, sebaceous glands, melanocytic nevi 2. Acquired lesions: molluscum contagiosum, Crohn disease, seborrheic keratosis, lichen planus, lichen nidus, and condyloma latum. Clinical diagnosis of exophytic condylomata caused by HPV is usually straightforward. However, it is important to distinguish them from the lesions of secondary syphilis (condylomata lata). A nontreponemal syphilis test should be performed in patients presenting with genital warts. Condylomata lata are more rounded, and the patient has a strongly positive (i.e., titer > 1:16) nontreponemal serologic syphilis test result. The lesions of molluscum contagiosum are smooth, firm, dome-shaped, and umbilicated. In rare cases, nongenital HPV types that cause common warts on the hands and feet can cause warts in the genital region. Females with cervical lesions should be referred for colposcopy; males and females with recurrent perianal lesions, for anoscopy; and males with lesions at the distal urethral meatus and terminal hematuria or an abnormal urinary stream, for urethroscopy. Use of mild
Table 29-4. Sexually Transmitted Disease Evaluation:
General Physical Examination Vital signs Skin (rash; excoriations; location of lesions, especially palms, soles, face, trunk, extremities) Oropharynx (inflammation, lesions, exudates, enanthem) Nodes Abdominal tenderness Back (costovertebral angle tenderness) Joints (tenderness, swelling, erythremia, warmth)
Multiple
Adenopathy
Occurrence in the United States
Bilateral; inguinal; firm; movable; tender Bilateral; inguinal; firm; movable; nontender Unilateral; inguinal; fluctuant; may suppurate; tender None
Frequent
None
Common
Unilateral; inguinal; fluctuant; may suppurate; tender
Rare
Uncommon Rare Frequent
acetic acid solution to detect subclinical disease is not recommended because of its poor sensitivity and specificity. The primary goal of treatment of visible genital warts is their removal. Without treatment, visible genital warts may resolve, remain unchanged, or increase in size or number. Treatment of warts does not eradicate the virus or its infectivity, nor does it affect the development of cervical cancer that may result from simultaneous infection with high-risk HPV types. Treatment should be guided by patient preference, provider experience, and treatment availability.
Table 29-5. Comprehensive Physical Examination of the
Adolescent Female External Genitalia Pubic hair sexual maturation rating Lice and nits Mucosal estrogenization Erythema Edema Lesions (erythema, ulcers, warts, fissures, excoriation) Bartholin and Skene (periurethral) glands Urethra Discharge at introitus Trauma Speculum Examination (see Chapter 30) Vagina (erythema, lesions, quantity/color/consistency/odor of vaginal pool) Cervix (conformation, bleeding, erythema, friability, character of mucus, lesions) Bimanual Examination Uterus (size, position, mobility, tenderness, consistency) Adnexa (tenderness, enlargement, mass) Cervical motion tenderness Rectal Examination Lesions of perianal skin or anal verge Sphincter tone Ampulla (mass, tenderness, feces) Stool character and Hematest
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Table 29-6. Comprehensive Physical Examination of the
Table 29-7. Approach to the Physical Examination in
Adolescent Male
Prepubertal Females with Vaginal Irritation or Discharge
External Genitalia Sexual maturation ratings (pubic hair and genitalia) Lice and nits Skin lesions (penis, foreskin, scrotum, inguinal region, and medial thighs; ulcers, warts, papules, nodules, erythema, or excoriation) Urethral meatus (erythema, lesions, tenderness) Urethral discharge (quantity, color, consistency) Scrotum/testes (tenderness, mass, edema)
General Physical Examination Skin for evidence of viral exanthem, atopic or seborrheic dermatitis, and other lesions Evidence of acute respiratory, pharyngeal, or gastrointestinal illness Chronic disease Inspection of underpants for discharge
Rectal Examination Lesions of perianal skin or anal verge Sphincter tone Ampulla (mass, tenderness, feces) Stool character and Hematest
Table 29-10 lists patient-applied and provider-administered treatment regimens recommended by the Centers for Disease Control and Prevention (CDC) for genital warts. All of these regimens are comparably effective. URETHRAL DISCHARGE IN THE ADOLESCENT MALE Urethritis, inflammation of the urethra, is more commonly diagnosed in older adolescent males and young men. N. gonorrhoeae and C. trachomatis are the clinically important bacterial pathogens of adolescent urethritis that warrant diagnostic evaluation. Nongonococcal urethritis is urethritis caused by pathogens other than N. gonorrhoeae. Because the proportion of cases of nongonococcal urethritis caused by C. trachomatis has been declining since the early 1990s, many diagnostic workups for nongonococcal urethritis do not yield an identifiable pathogen. Objective clinical or laboratory evidence of urethral inflammation must be demonstrated to make a diagnosis of urethritis (Table 29-11). Patient complaints without objective examination or laboratory findings do not fulfill diagnostic requirements. In a patient with symptoms, stripping the urethra from the base to the meatus three or four times and examination after a long interval without voiding (i.e., at least 2 hours) increases the likelihood of a positive finding. However, highly sensitive nucleic acid amplification tests (NAATs) identify STD pathogens in boys who do not meet the diagnostic criteria for urethritis. The CDC recommends gonorrhea and chlamydia testing of all boys who meet the diagnostic criteria for urethritis. NAATs, the most sensitive combination gonorrhea and chlamydia diagnostic test, can be performed on a single urine or urethral specimen. Tables 29-12 and 29-13 summarize advantages and disadvantages of various laboratory diagnostic tests for gonorrhea and chlamydia. Treatment should be provided as soon as possible after diagnosis of a pathogen (Table 29-14). Empirical gonorrhea and chlamydia treatment of symptomatic patients without documentation of urethritis by examination or laboratory is recommended for males who are unlikely to return for a follow-up evaluation. Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Patients who have persistent or recurrent urethritis should be re-treated with the initial regimen if noncompliance or reexposure from an untreated partner is a possibility. If this is unlikely, a test for Trichomonas vaginalis should be performed, and patients should be treated for recurrent/ persistent urethritis (Table 29-15).
Visualization of External Genitalia and Perianal Area Supine, lithotomy, or modified lithotomy position (includes labial separation and traction): Inflammation and lesions of skin and vulva mucosa Evidence of poor toilet hygiene Signs of excoriation Presence of discharge at introitus Presence of pinworms (Enterobius vermicularis) Degree of estrogenization Hymenal configuration Evidence of recent or past trauma Ectopic urethra Congenital anomalies Evidence of scabies Visualization of Vagina and Cervix Knee-chest position with traction on buttocks and use of otoscope as light source Vaginal Specimen Collection Saline-moistened cotton/Dacron-tipped nasopharyngeal or urethral swabs or “catheter within a catheter” technique to aspirate specimen Normal saline preparation for microscopic examination Potassium hydroxide preparation Cultures for Neisseria gonorrhoeae, Chlamydia trachomatis, Candida species, group A streptococci, anaerobes, and gram-negative enteric bacteria Request that laboratory identify and quantify all predominant isolates Tape test (nonfrosted cellophane tape) for pinworms (best performed by parent before child arises in the morning; specimen of tape then applied to microscope slide and brought to laboratory) Rectoabdominal Examination Lithotomy or modified lithotomy position Tenderness Expression of vaginal discharge Palpation of mass or firm foreign body through rectovaginal wall
VAGINAL DISCHARGE IN THE ADOLESCENT FEMALE An adolescent girl presenting with complaints of vaginal discharge may have mucopurulent cervicitis (MPC), vaginitis, or both. An evaluation for both conditions should be performed. Mucopurulent Cervicitis MPC is characterized by mucopurulent discharge from an inflamed cervix. A test for C. trachomatis and N. gonorrhoeae should be performed. However, an infectious cause is often not identified. The adolescent with MPC may present with complaints of vaginal discharge; vaginal itching; irregular vaginal bleeding, especially after
Chapter 29 Sexually Transmitted Diseases Table 29-8. Laboratory Evaluations for Treatable
Table 29-10. Treatment Regimens for Genital Warts
Sexually Transmitted Diseases in Adolescents Disease
Gonorrhea Chlamydia Vulvovaginal candidiasis Bacterial vaginosis Trichomoniasis Syphilis Human immunodeficiency virus infection
Males
Females
X X
X X X X X X X
X X
Patient-Applied Treatments Podofilox, 0.5% solution or gel* Patients may apply with a cotton swab or finger to visible genital warts twice a day for 3 days, followed by 4 days of no therapy Cycle should be repeated as needed up to four times Provider should apply first treatment to demonstrate proper application technique and to identify which warts should be treated Imiquimod, 5% cream* Patients may apply with a finger at bedtime three times per week for up to 16 weeks The treatment should be washed with mild soap and water 6-10 hr after application
sexual intercourse; and dyspareunia. Pelvic inflammatory disease (PID) must be considered if there is a history of lower abdominal pain. Purulent or mucopurulent discharge from the cervical os, easily induced endocervical bleeding (friability), and edema and erythema of the zone of ectopy on the cervix are found on examination. The presence of yellow mucopus collected from the endocervix and evident on a white swab is indicative of MPC. Friability alone does not constitute MPC. Diagnoses to consider with findings of an inflamed cervix on examination include vaginitis; endometritis; PID; inflammation of an ectropion secondary to allergies; trauma; and presence of a foreign body, such as a tampon. The “gold standard” for laboratory diagnosis of MPC is an NAAT. Tables 29-12 and 29-13 summarize advantages and disadvantages of various laboratory diagnostic tests for gonorrhea and chlamydia.
Provider-Administered Treatments Cryotherapy with liquid nitrogen or cryoprobe Applications should be repeated every 1-2 weeks Podophyllin resin, 10%-25% in compound tincture of benzoin* Patients apply a small amount to each wart and allow to air dry Patients wash off 1-4 hr after application Applications may be repeated weekly if necessary Trichloroacetic acid (TCA) or bichloracetic acid (BCA), 80%-90% Patients apply a small amount only to warts and allow to dry, at which time a white “frosting” develops; patients powder with talc, sodium bicarbonate, or liquid soap preparations to remove unreacted acid if an excess amount is applied Patients may repeat weekly if necessary Surgical removal by tangential scissor excision, tangential shave excision, curettage, or electrosurgery
Table 29-9. Adolescents Who Should Receive Human
Immunodeficiency Virus Prevention Counseling, Testing, and Referral • All sexually active adolescents in settings serving populations at increased behavioral or clinical HIV risk, e.g., adolescent or school-based health clinics with high STD rates, juvenile detention centers, drug or alcohol prevention and treatment programs, homeless shelters, clinics serving men who have sex with men, freestanding HIV test sites, or STD clinics • Individual clients in setting with 1%† HIV prevalence • All pregnant females Adapted from Centers for Disease Control and Prevention: Revised guidelines for HIV counseling, testing, and referral. MMWR Morb Mortal Wkly Rep 2001;50:1-57. *Or lower than other settings in the community. †
Or higher than other settings in the community.
HIV, human immunodeficiency virus; STD, sexually transmitted disease.
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Recommended Treatments by Wart Location Cervical warts Consult with an expert; high-grade squamous intraepithelial lesions must be excluded before treatment is begun Vaginal warts Cryotherapy with liquid nitrogen (use of cryoprobe in vagina is not recommended because of risk for vaginal perforation) TCA or BCA, 80%-90% Urethral meatal Podophyllin resin, 10%-25% in warts† compound tincture of benzoin* Cryotherapy with liquid nitrogen Anal warts Management of warts on rectal mucosa should be referred to an expert Cryotherapy with liquid nitrogen TCA or BCA, 80%-90% Surgical removal Oral warts Cryotherapy with liquid nitrogen Surgical removal Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-84. *Safety of use during pregnancy has not been established. †
Some specialists recommend podofilox and imiquimod for the treatment of distal meatal warts in certain patients.
Although no infection is identified for many cases of MPC, the CDC recommends empirical treatment for C. trachomatis and N. gonorrhoeae in populations such as adolescents that are at high risk for infection and unlikely to follow up for test results (see Table 29-14).
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Table 29-11. Diagnostic Criteria to Demonstrate
Urethral Inflammation Observation of mucoid or purulent urethral discharge Positive leukocyte esterase test on first-void urine Gram stain findings of ≥5 White blood cells per high-powered field or Gram-negative intracellular diplococci Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
Vaginitis Vaginitis is inflammation of the squamous epithelial tissues lining the vagina. Three conditions cause most cases of adolescent vaginitis: VVC, BV, and trichomoniasis. All three treatable conditions can be diagnosed by examination of vaginal secretions during an office visit. The presence of sexual activity influences the differential diagnosis; trichomoniasis and BV are more common in sexually experienced adolescents. In non–sexually active girls, VVC is the major cause of vaginal complaints and inflammation. Local chemical or allergic irritants, bacterial infections caused by Streptococcus or Staphylococcus species, trauma, and secondary infections from foreign bodies, may also cause vaginitis. Rare causes of vaginitis include ulcerating conditions of the mucous membranes, such as toxic shock and Stevens-Johnson syndromes. The physical examination is an important part of the diagnostic workup (Table 29-16). Thick, adherent cottage cheese–like discharge is suggestive of VVC. The clinician may also find erythema, edema, and excoriation of the vagina in a girl with VVC. Thin, homogeneous, gray-white, foul-smelling discharge is suggestive of BV. Purulent, profuse, irritating, frothy green-yellow discharge often accompanies trichomoniasis. Table 29-16 summarizes the diagnostic workup for vaginitis. The evaluation includes description of the vaginal discharge, measurement of vaginal pH, performance of a whiff test, and microscopic examination. Care should be taken to obtain a vaginal swab that is not contaminated with alkaline cervical secretions. Rubbing the specimen over a pH paper strip and matching the resulting color to the color chart determines the vaginal pH. Diluting a sample in a drop of 10% potassium hydroxide (KOH), referred to as the whiff test, produces a “fishy” odor with BV and sometimes with trichomoniasis.
Microscopy is critical in the diagnostic process (see Table 29-16). On the wet preparation, the clinician should look for (1) an excessive number of white blood cells, which is evidence of the inflammation often found with trichomoniasis and VVC; (2) vaginal “clue cells,” which are typical of BV (Fig. 29-1); (3) motile or static trichomonads (Fig. 29-2), which are diagnostic of trichomoniasis; and (4) budding yeast and pseudohyphae (Fig. 29-3), which are diagnostic of VVC. Warming the solution to body temperature may improve identification of trichomonads and pseudohyphae. Because normal vaginal bacteria may be confused with yeast forms, the clinicians should look for pseudohyphae to help identify true yeast. Adding 10% KOH solution to the vaginal fluid lyses other cells and bacteria and often improves pseudohyphae visualization. Alternative diagnostic strategies can aid or substitute for the conventional etiologic workup. For BV, the FemExam pH and Amines TestCard and the PIP Activity TestCard (Quidel Corp, San Diego, California) can substitute for the pH paper, the whiff test, and microscopic examination on a vaginal specimen by detecting an elevated vaginal pH, trimethylamines generated by BV associated anaerobic bacteria, and an enzyme produced by Gardnerella vaginalis. Although rarely performed as part of an office-based vaginitis evaluation, a Gram stain of vaginal fluid can provide a quantitative assessment (Nugent score) of BV-associated organisms. For trichomoniasis, the InPouch TV test (BioMed Diagnostics, San Jose, California) is an office-based self-contained culture kit. The clinician inoculates a culture medium–filled pouch with a vaginal fluid specimen from girls or sediment from a spun first-void urine specimen from boys and examines its contents for trichomonads by microscopy. The clinician can incubate and repeatedly examine the transparent culture pouch under the microscope for up to 5 subsequent days. The InPouch TV test can be a valuable adjunct because most clinical laboratories do not perform the standard culture technique with Diamond medium. For offices without microscopy, a professional laboratory that offers the Affirm VP III Microbial Identification Test (Becton Dickinson, Sparks, Maryland) provides a diagnostic option. The Affirm VP III, a DNA probe performed on vaginal fluid specimens, offers the advantage of diagnosing BV, VVC, and trichomoniasis. Correlating results of this test with clinical symptoms and elevated vaginal pH is recommended. VAGINAL DISCHARGE AND IRRITATION IN THE PREPUBERTAL FEMALE Nonsexually transmitted vulvovaginitis in infants and prepubertal girls is common. In prepubertal girls, the vulvar mucosa is thin and susceptible to inflammation from chemicals and mechanical irritation. Because the labia are not well developed, the vulvar mucosa is
Table 29-12. Diagnostic Laboratory Test Performances for Neisseria gonorrhoeae Test
Culture
DNA probe Gram stain Nucleic acid amplification
Advantages
Sensitivity ≈ 85% Specificity ≈ 100% Inexpensive, not labor intensive Not technically difficult Can determine antimicrobial susceptibility Sensitivity = 85% Inexpensive Easy transport Inexpensive Easy transport Sensitivity = 95% for urethral specimens Sensitivity/specificity = 80%-90% Urine specimens
Disadvantages
Transport in CO2 medium Requires urethral or cervical specimens
Requires urethral or cervical specimens Requires urethral or cervical specimens Sensitivity = 55% for cervical specimens High cost
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Table 29-13. Diagnostic Laboratory Test Performances for Chlamydia trachomatis Test
Advantages
Disadvantages
Cell culture
Specificity ≈ 100%
ELISA immunoassay
Inexpensive Not technically difficult Sensitivity = 65% Inexpensive Easy transport Sensitivity/specificity = 85% Urine specimens
DNA probe Nucleic acid amplification
Sensitivity = 70% Complicated transport medium Requires urethral or cervical specimens High cost Labor intensive Technically difficult Sensitivity = 60% Requires urethral or cervical specimens Requires urethral or cervical specimens High cost
Adapted from Centers for Disease Control and Prevention (CDC): Take action on HEDIS. http://www.cdc.gov/nchstp/dstd/Reports_Publications/ HMOletter.pdf. Accessed on August 26, 2002.
not anatomically shielded and is thus vulnerable to irritation. In addition, a girl’s hymenal configuration may predispose to vaginitis: A high, small opening may interfere with vaginal drainage, whereas a wide, gaping hymen (e.g., “posterior rim” configuration or after episodes of sexual abuse) permits easy contamination of the vagina by urine and feces. In the majority of cases, vulvovaginitis in prepubertal girls is a mixed, nonspecific bacterial infection secondary to contamination
Table 29-14. Treatment for Uncomplicated Genital Chlamydia trachomatis and Neisseria gonorrhoeae Infections in Adolescents* Pathogen
C. trachomatis
N. gonorrhoeae†
Treatment
Azithromycin, 1 g orally in a single dose or Doxycycline, 100 mg orally twice daily for 7 days Cefixime,§ 400 mg orally in a single dose or Ciprofloxacin,‡ 500 mg orally in a single dose or Ofloxacin,‡ 400 mg orally in a single dose or Levofloxacin,‡ 250 mg orally in a single dose or Ceftriaxone, 125 mg intramuscularly in a single dose plus Treatment for C. trachomatis if indicated†
Adapted from the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-84. *8 years of age or older. †
Centers for Disease Control and Prevention recommend treating persons with a positive gonorrhea test result for both gonorrhea and chlamydia unless a negative result has been obtained with a sensitive chlamydia test. ‡
Fluoroquinolones have not been recommended for persons younger than 18 years because they damage articular cartilage in juvenile animal models. However, among children treated with fluoroquinolones, no joint damage attributable to therapy has been observed. Quinolones should not be used to treat gonorrhea infections acquired in Asia or the Pacific islands, including Hawaii. §
Cefixime is no longer produced in the USA; availability is limited.
by urine and feces. The responsible bacteria are usually normal flora: diphtheroids, α-hemolytic streptococci, lactobacilli, and E. coli. Other organisms include nonhemolytic streptococci, groups B and D streptococci, β-hemolytic group A streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella species, Pseudomonas species, Proteus species, and G. vaginalis. Anaerobes, Candida species, Mycoplasma hominis, and Ureaplasma urealyticum have also been found. Bloody vaginal discharge in young girls may be caused by Shigella species or group A streptococcal infections, a foreign body, neoplasm (such as rhabdomyosarcoma), or trauma. Retained toilet paper is a common foreign body. It can usually be flushed out of the vagina with normal saline. Several vulvar skin disorders can be confused with vulvovaginitis. Lichen sclerosus manifests as white patches on the glabrous skin that are thinned and atrophic and are easily traumatized with resultant bullae (which may be blood-filled) in the vulvar region. Seborrheic dermatitis may manifest with inflammation and secondary infection of the intertriginous areas; the face and scalp may be involved as well. Labial or vulvar agglutination may be noted and can be secondary to previous vulvovaginitis of unestrogenized epithelia. Other etiologic factors in premenarchal vulvovaginitis include infection (fungi, pinworms, scabies), irritation (soap, shampoo, detergent, bubble bath), systemic illness (Stevens-Johnson syndrome), and trauma (abuse, play, tight clothing, masturbation). Finally, some young girls with emotional or behavioral problems (occasionally caused by sexual abuse) may complain of vulvar symptoms in the absence of any findings on examination. Most cases of prepubertal nonspecific vaginitis can be managed with hygiene and 10 to 14 days of antibiotics, topical premarin vaginal cream (b.i.d.), and Phisohex liquid antibacterial soap in the bath water 1 to
Table 29-15. Centers for Disease Control and
Prevention Recommended Treatment for Recurrent/Persistent Urethritis Metronidazole, 2 g orally in a single dose plus Erythromycin base, 500 mg orally 4 times a day for 7 days or Erythromycin ethylsuccinate, 800 mg orally 4 times a day for 7 days
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Table 29-16. Clinical and Laboratory Features of Vaginitis Infection
Symptoms
Bacterial vaginosis
Foul smelling discharge, ↑ after intercourse
Trichomoniasis
Frothy, foul smelling discharge, pruritus, dysuria
Vulvovaginal candidiasis
Pruritus, burning, discharge
Vaginal Discharge
Whiff Test
Microscopic Findings
pH
Enhanced Diagnosis
Thin Homogenous Gray-white Purulent, profuse, irritating, frothy, green-yellow
Positive
>20% clue cells
>4.5
Gram stain Affirm VP III
Variably positive
↑ WBCs Trichomonads
>4.5
Thick Adherent White
Negative
↑ WBCs Budding yeast Pseudohyphae
4-4.5
Diamond media culture Inpouch TV test Affirm VP III Affirm VP III
WBC, white blood cell. ↑, increased.
2 times per week. The treatment of vulvovaginitis in prepubertal girls is summarized in Tables 29-17 and 29-18.
EVALUATION AND MANAGEMENT OF SEXUALLY TRANSMITTED DISEASES AMONG SEXUALLY ABUSED CHILDREN AND ADOLESCENTS The prevalence of STDs among prepubertal victims of sexual assault has been reported as 5%, and it is generally accompanied by symptoms. Because the STD risk is low and the risk of imparting psychological and physical discomfort with the specimen collection procedures is high, many experts recommend reserving STD screening of prepubertal children for the situations listed in Table 29-19.
Figure 29-1. Bacteria clinging to the sides of a vaginal epithelial cell (“clue cell”). This occurrence is significant in bacterial vaginosis. (Reproduced by courtesy of Dr. Herman L. Gardner. From Huffman JW: Genitourinary infections. In Feigin RD, Cherry JD [eds]: Textbook of Pediatric Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1992, p 570.)
The examination should be performed in compliance with expert recommendations by an experienced clinician. Table 29-20 lists recommended STD tests. Because children can acquire an STD through vertical transmission, autoinoculation, or sexual contact, STD screening should focus on likely anatomic sites. Table 29-21 lists the likelihood of an STD as evidence of sexual assault and suggested action. Because sexually experienced adolescents may have an asymptomatic infection unrelated to the alleged event and the risk of complications of an untreated STD are high, most experts recommend empirical STD screening and treatment of postpubertal victims. STD screening should focus on likely anatomic sites. The timing of the examination depends on the history of the assault. When the alleged assault has occurred within the previous 72 hours or when there is bleeding or acute injury, the examination should be performed immediately, and specific protocols to collect forensic evidence should be followed. To allow sufficient time for concentrations of organisms to reach detectable levels, clinicians may recommend a follow-up visit 2 weeks after the most recent sexual exposure for a repeat examination and collection of additional specimens. If syphilis,
Figure 29-2. Trichomonas vaginalis is a triflagellated protozoan that, when motile, is easily identified in wet smears of the vaginal discharge. (From Huffman JW: Genitourinary infections. In Feigin RD, Cherry JD [eds]: Textbook of Pediatric Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1992, p 568.)
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Table 29-18. Oral Treatment of Non–Sexually Transmitted Causes of Vulvovaginitis in Prepubertal Females
β-Hemolytic Group A Streptococci Clindamycin, 30 mg/kg/day ÷ t.i.d. for 10-14 days or Penicillin VK, 25-50 mg/kg/day ÷ t.i.d. for 10-14 days or Erythromycin, 40 mg/kg/day ÷ t.i.d. for 10-14 days or Cephalexin, 25-100 mg/kg/day ÷ q.i.d. for 10-14 days Streptococcus pneumoniae Penicillin VK, 25-50 mg/kg/day ÷ t.i.d. for 10-14 days or Erythromycin, 40 mg/kg/day ÷ t.i.d. for 10-14 days or Cephalexin, 25-100 mg/kg/day ÷ q.i.d. for 10-14 days
Figure 29-3. Hyphae of Candida albicans discovered on wet smear of vaginal discharge. (From Huffman JW: Genitourinary infections. In Feigin RD, Cherry JD [eds]: Textbook of Pediatric Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1992, p 564.)
HIV, or hepatitis B virus transmission is of concern, another visit in 12 weeks may be necessary to collect sera for specific antibodies. Presumptive STD treatment for children who have been sexually assaulted or abused is not routinely recommended. However, if patients or parents/guardians are concerned about the possibility of infection, providers may choose to presumptively treat after all specimens for
Table 29-17. Treatment of Nonspecific Vulvovaginitis in
Young Females Toilet Hygiene Wipe in an anterior-to-posterior direction with supervision Diaper wipes are useful Urinate with knees spread apart Clothing Choose white cotton underpants Wear loose-fitting clothing Bathing Take sitz baths in clear water up to four times a day Wash gently with unperfumed soap Do not use bubble bath or wash hair in bath Rinse perineum with clear water, dry gently with towel Take baths with Phisohex liquid antibacterial soap in bathwater once or twice per week for 10-14 days Management of Inflammation and Pruritus Premarin vaginal cream topically twice daily for 10-14 days Hydroxyzine, 0.5-1 mg/kg/dose orally q.i.d. as needed or Diphenhydramine, 1.25 mg/kg/dose orally q.i.d. as needed
Staphylococcus aureus Dicloxacillin, 25 mg/kg/day ÷ q.i.d. for 10-14 days or Amoxicillin plus clavulanate, 25-45 mg/kg/day ÷ b.i.d. for 10-14 days or Cefpodoxime proxetil, 10 mg/kg/day daily or ÷ b.i.d. for 10-14 days or Cephalexin, 25-100 mg/kg/day ÷ q.i.d. for 10-14 days or Clindamycin, 30 mg/kg/day ÷ t.i.d. for 10-14 days or Cefuroxime, 30 mg/kg/day ÷ b.i.d. for 10-14 days or Clarithromycin, 15 mg/kg/day ÷ b.i.d. for 10-14 days Haemophilus influenzae Erythromycin ethylsuccinate/sulfisoxazole, 50 mg/kg/day ÷ q.i.d. for 10-14 days or Trimethoprim/sulfamethoxazole, 8-10 mg/kg/day ÷ b.i.d. for 10-14 days or Amoxicillin/clavulanate, 25-45 mg/kg/day ÷ b.i.d. for 10-14 days or Clarithromycin, 15 mg/kg/day ÷ b.i.d. for 10-14 days or Cefixime, 8 mg/kg/day daily or ÷ b.i.d. for 10-14 days* Shigella Trimethoprim/sulfamethoxazole, 8-10 mg/kg/day ÷ b.i.d. for 10-14 days Candida Nystatin vaginal cream, apply topically b.i.d. for 10-14 days Enterobius vermicularis Mebendazole, 100 mg as a single dose for patient and all household members, then repeated in 2 weeks b.i.d., twice per day; t.i.d., three times per day; q.i.d., four times per day. *Cefixime production was discontinued in the United States in July 2002; availability is limited.
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Table 29-19. Sexually Transmitted Diseases Screening
Table 29-21. Implications of Commonly Encountered Sexually Transmitted Infections for Diagnosis and Reporting of Suspected Sexual Abuse of Infants and Prepubertal Children
Indications for Sexually Victimized Children The child has signs or symptoms of a sexually transmitted disease (STD), including genital pain, vaginal or urethral discharge, pruritus or odor, urinary symptoms, or genital ulcers or lesions. A suspected sex offender is known to have an STD or to be at high risk for STDs A sibling or another child or adult in the household or child’s immediate environment has an STD The patient or parent requests testing Evidence of genital, oral, or anal penetration or ejaculation
Sexually Transmitted/ Associated Infection Confirmed
Gonorrhea* Syphilis* Human immunodeficiency virus‡ Chlamydia* Trichomonas vaginalis
Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
relevant diagnostic tests are collected. Adolescent sexual assault victims should be offered prophylactic treatment for STDs and pregnancy prevention. Table 29-22 lists recommended presumptive treatment. HIV postexposure assessment and prophylaxis should be considered for abused children on a case-by-case basis, depending on the likelihood of HIV infection among the assailant or assailants (Table 29-23).
Condylomata acuminata* (anogenital warts) Genital herpes Bacterial vaginosis
Evidence for Sexual Abuse
Suggested Action
Diagnostic Diagnostic Diagnostic
Report† Report† Report†
Diagnostic Highly suspicious Suspicious
Report† Report†
Suspicious Inconclusive
Report†§ Medical follow-up
Report†
Adapted from the American Academy of Pediatrics Committee on Child Abuse and Neglect Guidelines for the evaluation of sexual abuse of children. Pediatrics 1999;103:186-191. Correction published in Pediatrics 1999;103:1049. *If not likely to be perinatally acquired. †
Table 29-20. Recommended Sexually Transmitted
Diseases Testing in a Prepubertal Child when Sexual Abuse Is Suspected Organism/Syndrome
Neisseria gonorrhoeae Chlamydia trachomatis Syphilis
Trichomonas vaginalis Bacterial vaginosis Hepatitis B virus Human papillomavirus Pediculosis capitis Human immunodeficiency virus
Reports should be made to the agency in the community mandated to receive reports of suspected child abuse or neglect.
‡
If not likely to be perinatally or transfusion acquired.
§
Unless there is a clear history of autoinoculation.
Specimens
Rectal, throat, urethral, and/or vaginal culture(s)* Rectal and vaginal cultures† Darkfield examination of chancre fluid, if present; blood for serologic tests at time of abuse and 6, 12, and 24 weeks later Wet mount and culture of vaginal discharge Wet mount and culture of vaginal discharge Serum hepatitis B surface antigen test‡ Biopsy of lesion Identification of eggs, nymphs, and lice with naked eye or by using hand lens Serologic test of abuser; serologic test of child at time of abuse and 12, and 24 weeks later if indicated
SYSTEMIC DISEASE The STDs and their sequelae that are most often associated with systemic symptoms include HIV, syphilis, HSV, hepatitis B, PID, reactive arthritis, and disseminated gonorrhea infection. See later discussion for relevant disease presentations and management.
DIAGNOSTIC AND THERAPEUTIC CONSIDERATIONS BACTERIAL VAGINOSIS BV is a noninflammatory disturbance of the normal vaginal ecosystem and is one of the most common causes of vaginal discharge in adolescents. Although not considered to be an STD, BV occurs
Table 29-22. Postexposure Prophylaxis for Sexually
Transmitted Diseases* after Sexual Assault in Adolescents Adapted from American Academy of Pediatrics. Sexually transmitted diseases in adolescent and children. In Pickering LK (ed): 2003 Redbook: Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 159-167. *Cervical specimens are not recommended. A meatal discharge specimen is an adequate substitute for an intraurethral specimen. Only standard culture systems should be used for prepubertal females. †
A meatal specimen should be obtained if urethral discharge is present in prepubertal boys. Urethral specimens are not recommended among asymptomatic boys. Only standard culture systems should be used. Expert opinion suggests nucleic acid amplification tests (NAATs) may be an alternative only if confirmation is available but culture systems for C. trachomatis are unavailable. Confirmation tests should consist of a second U.S. Food and Drug Administration–approved NAAT that targets a different molecule from the initial test.
‡
Test abuser. Test victim at initial visit and at 12-week follow-up visit if there is no history of immunization.
Ceftriaxone, 125 mg intramuscularly in a single dose plus Metronidazole, 2 g orally in a single dose plus Azithromycin, 1 g orally in a single dose or doxycycline, 100 mg orally twice daily for 7 days Post-exposure hepatitis B virus immunization if no previous immunization; follow-up doses should be administered at 1-2 months and 4-6 months Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. *Excluding human immunodeficiency virus infection.
Chapter 29 Sexually Transmitted Diseases Table 29-23. Recommendations for Human Immunodeficiency Virus (HIV) Postexposure Assessment of Children and Adolescents within 72 Hours of Sexual Assault
Review HIV/AIDS local epidemiology and assess risk of HIV infection in assailant Evaluate circumstances of assault that may affect risk of HIV transmission Consult with specialist in HIV treatment if postexposure prophylaxis is considered If the victim appears to be at risk of HIV transmission from the assault, discuss antiretroviral prophylaxis, including toxicity, and unknown efficacy with patient (or guardian) If the victim is (or if guardian chooses for the child) to receive antiretroviral postexposure prophylaxis, provide enough medication until the return visit at 3-7 days after initial assessment to reevaluate patient and to assess tolerance of medication; pediatric dosages should not exceed adult doses HIV antibody test at original assessment, 6 weeks, 3 months, and 6 months Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. AIDS, acquired immunodeficiency syndrome.
more frequently among sexually active females. BV is thought to result from the replacement of the normal H2O2-producing vaginal flora with organisms such as G. vaginalis, M. hominis, Mobiluncus species, Bacteroides species, and other anaerobes. BV is asymptomatic in almost 50% of females diagnosed with this disorder. Usual symptoms include vaginal odor and vaginal discharge. BV is diagnosed by the presence of a gray-white, malodorous (fishy), homogenous, nonviscous vaginal discharge. The clinical diagnosis of BV is made by the presence of at least three of the four criteria listed in Table 29-24 or by more sophisticated laboratory techniques listed in Table 29-16. Treatment is recommended for all symptomatic patients. Options for treatment include oral and vaginal regimens (Table 29-25). Abstinence from alcohol during treatment with metronidazole and for 24 hours afterward should be stressed because of the disulfiramlike effect of that drug. No treatment of the sexual partner is indicated. VULVOVAGINAL CANDIDIASIS Candida species are common microbes that can be isolated from the vagina in 10% to 55% of asymptomatic, healthy women of reproductive age. It is probably a commensal organism that becomes an
Table 29-24. Amsel Criteria for Diagnosis of Bacterial
Vaginosis Vaginal discharge: thin, homogenous, white, uniformly adherent Vaginal pH > 4.5 Positive result of whiff test: fishy odor after mixing discharge with 10% KOH >20% clue cells on microscopic examination: bacteria-coated squamous epithelial cells, where both the periphery (cell membrane) and cytoplasm have a granular, irregular, “moth-eaten” appearance KOH, potassium hydroxide.
485
Table 29-25. Treatment Regimens for Bacterial
Vaginosis Nonpregnant Females Metronidazole, 500 mg orally twice daily for 7 days or Metronidazole gel, 0.75%, one full applicator (5 g) intravaginally once a day for 5 days or Clindamycin cream, 2%, one full applicator (5 g) intravaginally once a day for 7 days Pregnant Females Metronidazole, 250 mg orally three times daily for 7 days or Clindamycin, 300 mg orally twice daily for 7 days Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-84.
invasive pathogen under certain circumstances. Increased rates of infection are noted in pregnant girls and women, especially during the third trimester; in some oral contraceptive users; in patients with poorly controlled diabetes mellitus; in patients with high-calorie, high-carbohydrate, and high-fiber diets; and in patients who are taking corticosteroids or broad-spectrum antibiotics. Most vaginal yeast infections (85% to 90%) are caused by Candida albicans. Other candidal species and Torulopsis glabrata infections are increasing in frequency. Acute pruritus and vaginal discharge are the main complaints of symptomatic patients. The odorless discharge may be watery or thick and sometimes resembles cottage cheese. At times, the patient may also complain of vulvar burning sensation, vaginal soreness, external dysuria, or dyspareunia. On examination, the labia can be edematous and erythematous; pustulopapular lesions may exist peripherally. The vaginal mucosa may be erythematous, but the cervix is normal. Table 29-16 describes the diagnostic features of VVC. VVC is easily treated with many topical azole antifungal preparations whose active agent is clotrimazole, miconazole, butoconazole, terconazole, or tioconazole. Clinical and microbiologic cure rates are 80% to 90% for most regimens. Oral fluconazole, in a 150-mg single dose, is as effective as the topical treatments. A longer duration of treatment (10 to 14 days) may be needed for severe and recurrent infections. TRICHOMONIASIS T. vaginalis is a sexually transmitted, unicellular, flagellated, anaerobic protozoan that exists as an extracellular parasite in the human lower genitourinary tract (see Fig. 29-2). females appear to have more acute manifestations than do males. Many girls and women have no symptoms, but vaginal discharge, abnormal vaginal odor, vulvar pruritus, dyspareunia, dysuria, and lower abdominal discomfort are the usual findings. In males who are symptomatic, urethral discharge has been noted. Table 29-16 lists diagnostic techniques. Trichomoniasis is easily treated in about 85% to 95% of infected patients with metronidazole in a 2-g single dose accompanied by concurrent partner treatment with the same regimen. Abstinence from alcohol for 24 hours should be stressed because of the disulfiramlike effect of metronidazole. Topical treatments are not effective. Nonresponders should be retreated with a 7-day course of 500 mg of metronidazole twice daily. If this regimen fails, a third alternative is 2 g of metronidazole daily for 3 to 5 days. However, a partner’s nonadherence to treatment should be explored because this is a common cause of reinfection. A single 2-g dose of metronidazole is recommended during pregnancy.
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CHLAMYDIA INFECTION C. trachomatis is the most common reported pathogen among adolescents. Chlamydia is frequently asymptomatic in both sexes. Most sexually active adolescents are unaware of their risk for chlamydia infection. Although often asymptomatic, chlamydia can manifest as various STD syndromes, depending on the site of infection. Affected patients of both sexes may develop urethritis. Females may develop MPC. Sequelae of uncomplicated chlamydia infection can be devastating for females. Infection can ascend into the pelvis, causing PID. Chlamydia screening and treatment of adolescent girls consequently reduces the incidence of PID. Females with a prior chlamydia infection are also at increased risk of infertility, ectopic pregnancy, and chronic pelvic pain. Chlamydia sequelae are rare among males. The incidence of epididymitis among males is much lower than the incidence of PID among females. There is no evidence of a causal association between chlamydial and gonorrheal urethritis and male infertility. Exudative STDs involving mucosal surfaces, such as chlamydia, can result in sequelae among patients of both sexes. Reactive arthritis, a postinfectious inflammatory arthritis, can follow a localized genitourinary chlamydia infection. Like other exudative STDs, chlamydia can facilitate both HIV transmission and acquisition. Diagnostic options are presented in Table 29-13. The CDC’s recommended treatment options are listed in Table 29-14 and Table 29-26. All sexual partners should be evaluated and treated. Abstinence should be recommended for at least 7 days after initiation of therapy for both infected patients and sex partners. A “test of cure” is not routinely recommended after treatment of adolescent chlamydia infection. However, providers should consider advising all with chlamydia infection to be rescreened 3 to 4 months after treatment. Some experts recommend testing adolescents for chlamydia every 6 months because the risk of repeat infection is high. GONORRHEA INFECTION Adolescent females aged 15-19 years have the highest reported rate of gonorrhea in the United States. In addition to age, other demographic risk factors for gonorrhea include African American race, lower socioeconomic status, early onset of sexual activity, single marital status, and prior gonorrhea infection. N. gonorrhoeae infections can manifest as various STD syndromes. Both males and females may develop urethritis, proctitis, or pharyngitis. Females
Table 29-26. Treatment for Pediatric* Uncomplicated
Genital Chlamydia trachomatis and Neisseria gonorrhoeae Infections Pathogen
C. trachomatis
N. gonorrhoeae§
Treatment
Erythromycin base or ethylsuccinate, 50 mg/kg/day orally divided into 4 doses daily for 14 days† or Azithromycin, 1 g orally in a single dose‡ Ceftriaxone, 125 mg intramuscularly in a single dose§
Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. *Younger than 8 years. †
For children weighing 45 kg.
§
Children weighing >45 kg should be treated with a regimen recommended for adults.
may develop MPC. Sensitive NAATs have shown that gonorrhea infection can be asymptomatic in both sexes. As in chlamydia infections, females may develop PID as a sequela and males in rare cases develop epididymitis. Both sexes are at risk of developing disseminated gonorrhea infection. Gonorrhea facilitates HIV transmission and acquisition. Diagnostic options are presented in Table 29-12. The CDC’s recommended treatment options are listed in Tables 29-14 and 29-26. Some providers prescribe azithromycin for treatment of gonorrhea infection. However, a single 1-g azithromycin dose produces suboptimal gonorrhea cure rates. A single 2-g dose provides adequate therapy, but a high frequency of gastrointestinal side effects and its high cost prohibit its use. Cefixime is currently not available in the United States. Fluoroquinolones have not been recommended for persons younger than 18 years because they damage articular cartilage in juvenile animal models. However, among children treated with fluoroquinolones, no joint damage attributable to therapy has been observed. Quinolones should not be used to treat gonorrhea infections acquired in Asia or the Pacific, including Hawaii and California, because of documented resistance in those areas.
GENITAL HERPES SIMPLEX VIRUS INFECTIONS Genital herpes, caused by HSV-1 and HSV-2, is the most common cause of genital ulcers in the United States. An estimated 1.5% of all adolescents aged 12-19 years are infected with HSV-2. Demographic and behavioral risk factors include female gender, nonwhite race, and greater number of lifetime sex partners. Clinical disease develops with approximately a third of HSV-2 infections; a large proportion of genital herpes infections go unrecognized. Although HSV-2 is responsible for most genital herpes infections, the frequency of HSV-1 genital infections is rising. A prior HSV-1 infection appears to be protective against development of symptoms with HSV-2 infection but not protective against infection with HSV-2 virus. HSV-infected patients can present with a primary infection, which can be asymptomatic; a first clinical episode, which may not necessarily occur during the primary infection; or a recurrent episode. Usually first clinical episodes are more painful and prolonged than are subsequent ones. Recurrent episodes occur less frequently with a genital HSV-1 infection and with intervals between episodes becoming longer. Symptomatic primary genital herpes infection is characterized by prolonged systemic and local symptoms. Systemic symptoms typically develop a week after exposure to infection and last for about a week. Systemic symptoms, more common among females, manifest as fever, headache, malaise, and myalgias. Local symptoms typically develop a week after exposure to infection, reach their maximum intensity 7 to 10 days after onset of symptoms, and gradually recede over the following week. Local symptoms include pain, itching, dysuria, vaginal or urethral discharge, and tender bilateral inguinal adenopathy. Painful lesions usually begin as papules or vesicles that rapidly spread over the genital area. Multiple small pustular lesions coalesce into large areas of ulcerations, eventually crusting over and reepithelializing. Crusting does not occur over mucosal surfaces. Lesions typically do not leave scars. New lesions commonly develop during the end of the first week of symptoms. Viral shedding usually continues for 2 weeks. An episode, from onset of lesions to complete resolution, can last up to 3 weeks. Primary HSV infection can cause other conditions, including nongenital lesions, cervicitis, urethritis, cystitis, proctitis, and pharyngitis. Systemic complications such as hepatitis, pneumonia, thrombocytopenia, and monoarticular arthritis may occur. Recurrent genital herpes imparts a less severe and shorter duration of local and systemic symptoms. Females usually develop more severe episodes than do males. Typically, patients develop prodromal
Chapter 29 Sexually Transmitted Diseases symptoms, which can vary from mild tingling sensations to shooting pains in the buttocks or lower extremities, before the appearance of lesions. The lesions of recurrent infections are usually unilateral (80% to 95%) and involve a much smaller area. The average number of lesions is five in females and eight in males. Most patients experience pain for 4 to 6 days. Some patients may experience dysuria or tender adenopathy. The mean time to heal is 10 days, and the mean duration of viral shedding is 4 days. Considerable variability exists in the clinical manifestation and frequency of recurrent episodes. Therefore, herpes should be considered in the evaluation of all genital lesions. Complications of genital herpes include central nervous system disease such as aseptic meningitis, autonomic dysfunction, and transverse myelitis; extragenital lesions, most commonly located in the buttocks, groin, or thigh area; disseminated infection; vertical transmission, resulting in neonatal herpes; and facilitation of HIV infection. Asymptomatic viral shedding is common with genital HSV infection. Clinicians need to stress to infected patients that they may be contagious during the prodrome and during the symptom-free periods, and clinicians should offer strategies to decrease risk of transmission to sexual partners. The clinical diagnosis of genital herpes should be confirmed by laboratory testing to distinguish between virus types. Because recurrences are usually less frequent after initial episodes of HSV-1 infection, knowledge of virus type helps determine the prognosis. HSV isolation by cell culture is the preferred virologic test for patients who present with open genital ulcers or other mucocutaneous lesions. HSV antigen detection tests do not distinguish between HSV-1 and HSV-2. Tzanck preparations and cervical Pap smears are insensitive and nonspecific for diagnosis of HSV infection. For serologic testing of HSV, the serologic type-specific glycoprotein G (gG)–based assays should be specifically requested. A test using an assay for HSV antibodies must be based on the HSVspecific glycoprotein G2 for the diagnosis of HSV-2 infection and the glycoprotein G1 for diagnosis of HSV-1 infection. Older assays that do not accurately distinguish between HSV-1 and HSV-2 antibodies, despite claims, remain on the market. U.S. Food and Drug Administration–approved gG-based type-specific assays include POCkit HSV-2 Rapid Test (Diagnology, Belfast, Northern Ireland), and HerpeSelect-1 ELISA IgG, HerpeSelect-2 ELISA IgG, and HerpeSelect 1 and 2 Immunoblot IgG (Focus Technologies, Herndon, Virginia). The reported sensitivities range from 80% to 98%, and specificities are reported to be higher than 96% for detection of HSV-2 antibodies. False-negative results may occur early after infection, and false-positive results can occur in patients with a low likelihood of HSV infection. HSV is a manageable but not curable chronic infection. Although systemic antiviral medication partially controls signs and symptoms of clinical episodes, it does not eradicate latent virus or affect the frequency or severity of recurrences after the drug is discontinued. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission, such as consistent condom use and abstinence during clinical episodes, is an important component of clinical management. Table 29-27 lists CDC-recommended regimens for first clinical episodes of genital herpes. Most patients presenting with first episodes should receive antiviral therapy despite mild manifestations because therapy can prevent progression to severe and prolonged symptoms. Duration of treatment may be extended if healing is incomplete after 10 days of therapy. Table 29-28 lists episodic therapy that can be used for recurrent HSV disease. Effective episodic treatment of recurrent herpes decreases the duration of symptoms and viral shedding by 1 to 2 days. The patient can be provided with a prescription for the medication and instructions to self-initiate treatment immediately when symptoms begin because effective episodic treatment requires initiation of therapy during the prodromal period or within 1 day of lesion onset.
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Table 29-27. Treatment Regimens for First Clinical
Genital Herpes Episode Acyclovir, 400 mg orally three times a day for 7-10 days or Acyclovir, 200 mg orally five times a day for 7-10 days or Famciclovir, 250 mg orally three times a day for 7-10 days or Valacyclovir, 1.0 g orally twice a day for 7-10 days Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
Table 29-29 lists CDC-recommended suppressive therapy for recurrent HSV disease. Suppressive therapy reduces the frequency of genital herpes recurrences by 70% to 80% among patients experiencing frequent recurrences (i.e., >6 episodes per year). Patients with less frequent recurrences may also benefit from suppressive therapy. Patients should understand that suppressive therapy reduces but does not eliminate subclinical viral shedding. Because the frequency of recurrent outbreaks typically diminishes over time, continuation of therapy should be periodically reassessed (e.g., once a year). HUMAN IMMUNODEFICIENCY VIRUS INFECTION HIV infection is increasing among adolescents in the United States, and sexual contact is the most common cause of new infections in adolescents. Over 50% of new adolescent cases occur in females, the majority from heterosexual infection. HIV transmission in adolescent males occurs most commonly via male-to-male sex. There is an increased prevalence of HIV infection among African American and Hispanic adolescents. Most adolescents are asymptomatic, and thus HIV testing is necessary to identify infected patients. Indications for HIV testing are listed in Table 29-9. Adolescents need to be informed about the importance of testing. Diagnosis allows early initiation of therapy and decreases transmission to others. State laws regarding adolescent consent for HIV counseling and testing vary. Adolescents with sexually acquired HIV infection frequently have additional STDs and high levels of sexual activity. Acute retroviral syndrome, a mononucleosis-like illness, frequently develops within a few weeks of primary infection with HIV. Signs and symptoms may include fever, sweats, malaise, myalgias, anorexia, nausea, diarrhea, pharyngitis, truncal exanthem, and lymphadenopathy. Possible neurologic manifestations range from aseptic meningitis to Guillain-Barré syndrome or encephalitis. Acute opportunistic
Table 29-28. Treatment Regimens of Episodic Therapy
for Recurrent Genital Herpes Acyclovir, 400 mg orally three times a day for 5 days or Acyclovir, 200 mg orally five times a day for 5 days or Acyclovir, 800 mg orally twice a day for 5 days or Famciclovir, 125 mg orally twice a day for 5 days or Valacyclovir, 500 mg orally twice a day for 3-5 days or Valacyclovir, 1.0 g orally once a day for 5 days Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
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Table 29-29. Treatment Regimens of Suppressive
Therapy for Recurrent Genital Herpes* Acyclovir, 400 mg orally twice a day or Famciclovir, 250 mg orally twice a day or Valacyclovir, 500 mg orally once a day or Valacyclovir, 1.0 g orally once a day Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. *Continuation of suppressive therapy should be periodically reassessed (e.g., once a year).
infections occasionally occur. Peripheral lymphocyte counts are low; transaminase elevation is common. If acute HIV infection is suspected, a serologic test for HIV should be performed, but the result is likely to be negative because antibodies are not yet present. An HIV polymerase chain reaction test is usually positive at this stage. Such patients should be referred to an HIV clinic for early antiretroviral therapy. There is substantial variation in the rate of progression from HIV infection to acquired immunodeficiency syndrome (AIDS) in untreated patients. Because the median time to develop AIDS is about 10 years, most infected adolescents are asymptomatic at the time of diagnosis. Clinical manifestations of AIDS are protean and can affect virtually every organ system (Table 29-30). Treatment of adolescents with HIV infection is best done at an HIV clinic or by a pediatric infectious disease specialist. High HIV plasma RNA (viral load) and a low CD4 T cell count are related predictors of disease progression and risk of opportunistic infections. Therapy includes antiretroviral medications and prophylaxis against
Table 29-30. Organ-Specific Manifestations of Acquired Immunodeficiency Syndrome
Immune Lymphadenopathy Hepatosplenomegaly Lymphopenia Opportunistic infections (bacterial sepsis, recurrent otitis media, Mycobacterium avium complex or Mycobacterium kansasii, Mycobacterium tuberculosis, histoplasmosis, cryptococcosis, Salmonella species, Nocardia species, coccidioidomycosis, CMV) Constitutional Fever Weight loss, failure to thrive Fatigue Night sweats Malaise Muscle and Nervous Systems Aseptic meningitis Developmental delay or regression after reaching milestones Encephalopathy Progressive multifocal leukoencephalopathy Dementia (cognitive impairment) Peripheral neuropathy Bell palsy Ataxia Myelopathy Headache Depression Spasticity Paresis Lymphoma (primary CNS) Seizures Strokes Polymyositis/pyomyositis Opportunistic infections (toxoplasmosis) Pulmonary Lymphoid interstitial pneumonia Opportunistic pneumonias (Pneumocystis carinii, CMV) Cardiac Cardiomyopathy Opportunistic infections (myocarditis) CMV, cytomegalovirus; CNS, central nervous system; HSV, herpes simplex.
Gastrointestinal Parotitis Hairy leukoplakia Gingivitis Periodontitis Oral ulceration Oral and esophageal thrush Esophagitis Gastritis Hepatitis Cholecystitis Cholangitis Diarrhea (enterocolitis) Pancreatitis Opportunistic infections (HSV, Candida species, CMV, cryptosporidiosis, isosporiasis) Ocular Retinitis Opportunistic infections (CMV) Cutaneous Seborrhea dermatitis Psoriasis Atopic dermatitis Ichthyosis Opportunistic infections (HSV, zoster, varicella, Bartonella species causing bacillary angiomatosis, Norwegian scabies) Hematologic Thrombocytopenia Anemia Leukopenia Lymphopenia Malignancies Lymphomas Leiomyosarcomas Kaposi sarcoma Cervical cancer Renal Nephropathy
Chapter 29 Sexually Transmitted Diseases opportunistic infection. Identification and treatment of HIV-infected pregnant adolescents substantially decreases the risk of motherto-child HIV transmission. Compliance with medical therapy is a major problem in adolescent patients, with unstable living situation the most significant risk factor for poor adherence. HUMAN PAPILLOMAVIRUS ANOGENITAL INFECTIONS Genital HPV infection is probably the most prevalent STD in the United States. Adolescent females have almost a 50% risk of acquiring an HPV infection. Most HPV infections are transient. Repeat HPV tests become negative in most female adolescents within 24 months. However, HIV-infected patients are more likely to have persistent HPV infection. Genital warts and cervical squamous intraepithelial lesions are clinical manifestations of HPV that are important to diagnose. Genital warts have already been discussed in this chapter. The majority of cervical cancer is caused by persistent HPV infection. HPV may cause cytologic abnormalities on Pap smear. However, most abnormal Pap smears in adolescents are not associated with high-grade cervical dysplasia. Cervical cancer screening among adolescents should begin 3 years after the onset of vaginal intercourse or by age 21 years. SYPHILIS Syphilis is caused by the spirochete T. pallidum. Syphilis prevalence rates among adolescents are much lower than those of other STDs. Adolescent prevalence rates are highest among African Americans. Syphilis is more common in the southern United States than any other U.S. region. The disease is most readily transmitted during sexual contact by organisms living in open lesions of the genital and anal skin or mucosa. Organisms can also be transmitted by oral contact. After inoculation of T. pallidum, the incubation period averages 21 days, with a range of 10 to 90 days. Primary syphilis begins with a papule which progresses to an ulcer over 1 to 3 weeks. More than one lesion can be present. The typical ulcer (chancre) can range in size from 2 to 20 mm. Unless it is secondarily infected, it has a clean base with rounded borders that feel rubbery to palpation. The ulcer is usually painless but can be tender to palpation. The ulcer heals gradually within a few weeks. Almost 50% of patients have bilateral, usually nontender, nonsuppurative, regional lymphadenopathy that can persist for months. Secondary syphilis represents disseminated infection and develops 6 to 24 weeks after inoculation, or about 3 to 6 weeks after the appearance of a chancre. Multiple organ systems can be involved, including the skin, lymphatics, gastrointestinal tract, bones, kidneys, eyes, and central nervous system. Most patients have symptoms of fever, malaise, anorexia, weight loss, pharyngitis, laryngitis, arthralgia, and lymphadenopathy. Epitrochlear nodes are suggestive of syphilis. Most patients have a rash that manifests as macular, maculopapular, papular, papulosquamous, or, in rare cases, pustular lesions. Vesicles are not present. The lesions occur on the trunk at first and may be pruritic. Different types of lesions can occur simultaneously. Two thirds of patients have lesions on their palms and soles. Occasional patients may have a temporary patchy alopecia or loss of eyebrow hair. These closed skin lesions are relatively noninfectious but may persist for months. If a squamous component of the rash is present, it may resemble pityriasis rosea, psoriasis, or lichen planus. Other types of mucocutaneous lesions are highly infective because they contain large numbers of spirochetes. The plaques of condylomata lata occur in warm, moist intertriginous locations, such as the vulva, scrotum, anal verge, inner thighs, and axillary folds. Mucous patches may occur in the mouth, pharynx, vulva, vagina, cervix, glans penis, and anal canal.
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Asymptomatic involvement of the central nervous system can occur in 8% to 40% of untreated patients; cerebrospinal fluid (CSF) samples demonstrate elevated protein levels and lymphocyte counts. Symptoms of aseptic meningitis develop in only 1% to 2% of untreated patients. Anterior uveitis is rare. Other rare manifestations of secondary syphilis include glomerulonephritis, nephrotic syndrome, hepatitis, arthritis, and periostitis. Latent syphilis infection lacks clinical manifestations. A latent infection is detected by serologic testing. Latent syphilis acquired within the preceding year is referred to as early latent syphilis. All other cases of latent syphilis are considered late latent syphilis or latent syphilis of unknown duration. Identifying the organism from exudate or tissue through darkfield examination or direct fluorescent antibody tests makes the definitive diagnosis of primary or secondary syphilis. These techniques are technically difficult, and consultation with an STD specialist or the health department is recommended. A presumptive syphilis diagnosis can be made by using a nontreponemal test (i.e., Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin) and confirming positive results with a treponemal test (i.e., fluorescent treponemal antibody absorbed and T. pallidum particle agglutination). Nontreponemal test antibody titers are usually correlated with disease activity; treponemal test antibody titers are not. A fourfold change in a nontreponemal test titer (e.g., from 1:16 to 1:4) is considered necessary to demonstrate a clinically significant difference between the same two serologic nontreponemal test results. Treponemal test antibody titers usually are poorly correlated with disease and should not be used to assess treatment response. Nontreponemal test results usually become nonreactive sometime after treatment, whereas most reactive treponemal tests remain reactive throughout the life of the patient. Although rapid plasma reagin and VDRL are equally valid assays, quantitative results from the two tests cannot be compared. Therefore, providers should consistently use the same nontreponemal test for an individual patient. Providers should consult with an STD specialist or the health department for evaluation of neurosyphilis and for interpreting syphilis test results for an HIV-infected patient. All patients diagnosed with syphilis should be tested for HIV infection. Syphilis-infected patients who have symptoms or signs suggesting neurologic disease should have an evaluation that includes a CSF analysis. Consultation with an infectious diseases specialist or the health department is recommended. Syphilis during pregnancy places the fetus at risk for congenital syphilis. All pregnant females should be screened for syphilis. Pregnant females in populations in which syphilis is known to be a public health problem should be screened again during the third trimester and at delivery. Consultation with the health department is recommended for management and follow-up of pregnant patients diagnosed with syphilis. Children diagnosed with syphilis after the newborn period should have birth and maternal records reviewed to assess whether the child has congenital or acquired disease. Acquired disease should be reported to child-protection services. In addition, a CSF examination to detect asymptomatic neurosyphilis should be performed. All cases of syphilis should be reported to the health department to assist with follow-up and partner notification. The treatment of all stages of syphilis is best achieved with parenteral penicillin G. Preparation and dosage depends on the disease stage and clinical manifestations. Table 29-31 shows CDC-recommended syphilis treatment regimens. Providers should consult with an STD specialist or the health department for managing treatment and follow-up for patients with a diagnosis of neurosyphilis and for HIV-infected patients with a diagnosis of syphilis. Patients should be followed up at 6 and 12 months after treatment for clinical and laboratory evaluation. Patients should be retested with the same nontreponemal test used at diagnosis. Patients with persistent or recurrent signs or symptoms and those with a sustained fourfold increase in the nontreponemal test titer should be re-treated
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Table 29-31. Treatment Regimens for Syphilis
Primary and Secondary Syphilis Adults Children* Penicillin allergy
Early Latent Syphilis Adults Children*
†
Table 29-32. Diagnostic Criteria for Pelvic
Inflammatory Disease Benzathine penicillin G, 2.4 million U IM in a single dose Benzathine penicillin G, 50,000 U/kg IM, up to 2.4 million U, in a single dose Doxycycline, 100 mg orally twice daily for 14 days or Tetracycline, 500 mg four times daily for 14 days
Benzathine penicillin G, 2.4 million U IM in a single dose Benzathine penicillin G, 50,000 U/kg IM, up to 2.4 million units in a single dose
Late Latent Syphilis or Latent Syphilis of Unknown Duration Adults Benzathine penicillin G, 7.2 million U total, administered as 3 doses of 2.4 million U IM each at 1-week intervals Children* Benzathine penicillin G, 50,000 U/kg IM, up to 2.4 million U administered as 3 doses at 1-week intervals Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. *Children beyond the neonatal period. † Some specialists recommend ceftriaxone, 1 g IV or IM daily for 8-10 days or azithromycin, 2 g orally in a single dose.
IM, intramuscularly.
and reevaluated for HIV infection. A CSF analysis should be performed in suspected cases of treatment failure.
COMPLICATIONS OF SEXUALLY TRANSMITTED DISEASES
Minimum Criteria Uterine or adnexal tenderness (unilateral or bilateral) or Cervical motion tenderness Additional Criteria to Increase Specificity of Minimum Criteria Abnormal cervical or vaginal mucopurulent discharge Presence of WBCs on saline microscopy of vaginal secretions Oral temperature > 38.3° C (101° F) Elevated erythrocyte sedimentation rate or C-reactive protein Laboratory evidence of Neisseria gonorrhoeae or Chlamydia trachomatis at cervix Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. WBC, white blood cell.
PID is a polymicrobial infection. Sexually transmitted organisms, particularly C. trachomatis and N. gonorrhoeae, are often implicated. The altered vaginal flora that occurs with BV can often be found in the upper genital tract of women diagnosed with PID, which implicates BV as an important cofactor in the development of PID. In many PID cases, no pathogen is identified. The diagnostic criteria and differential diagnosis of PID are presented in Tables 29-32 and 29-33. Most girls and women with PID have mucopurulent cervical discharge or evidence of white blood cells on a microscopic evaluation of a vaginal fluid saline preparation. If the cervical discharge appears normal and if there are no white blood cells noted on the wet preparation, PID is unlikely to be the disease, and alternative causes of pain should be sought. When the diagnosis is suspected, the following laboratory studies improve the specificity of the diagnosis: saline wet preparation of vaginal fluid for evidence of inflammation, complete blood cell count with differential, erythrocyte sedimentation rate or C-reactive protein measurement, urinalysis, urine culture, and diagnostic tests for N. gonorrhoeae and C. trachomatis. An HIV antibody test should be offered, and counseling should be performed after the patient has clinically improved. A sensitive pregnancy test should be performed routinely in patients with suspected PID. This excludes the diagnosis of ectopic pregnancy and guides antibiotic treatment. Ultrasonography may be helpful if the diagnosis is in question, if ectopic pregnancy is a strong consideration, or if a tuboovarian abscess is considered.
PELVIC INFLAMMATORY DISEASE PID is an acute clinical syndrome caused by microorganisms ascending from the lower female genital tract through the endometrium to the level of the fallopian tubes. It may involve contiguous structures, including the ovaries, pelvic peritoneum, and pelvic cavity. It involves endometritis, salpingitis, tuboovarian abscess, and pelvic peritonitis. It has a broad clinical spectrum that includes the following manifestations: acute, silent, atypical, a residual or chronic syndrome, and postpartum or postabortal occurrence. Unless a diagnostic procedure such as laparoscopy or ultrasonography is performed, it is difficult to enhance clinical specificity. Adolescence is the age group with the highest rates of PID. Short-term complications include perihepatitis (Fitz-Hugh-Curtis syndrome, inflammation of the liver capsule) and tuboovarian abscess. Long-term consequences from tubal scarring and occlusion include infertility, ectopic pregnancy, and chronic pelvic pain.
Table 29-33. Differential Diagnosis for Pelvic
Inflammatory Disease Ectopic pregnancy Ovarian cyst (with or without torsion) Acute appendicitis Endometriosis Pyelonephritis Septic or incomplete abortion Pelvic thrombophlebitis Functional pain Psoas-pelvic abscess Mesenteric adenitis Pelvic adhesions Chronic intestinal disease (e.g., inflammatory bowel disease)
Chapter 29 Sexually Transmitted Diseases Antibiotic treatment regimens for PID are generally empirical and must be broad in spectrum. All regimens should be effective against N. gonorrhoeae and C. trachomatis, even when endocervical tests are negative. Providing coverage against anaerobes and other gram-negative organisms is also important. Treatment should be initiated as soon as a presumptive diagnosis is made. Table 29-34 lists CDC-recommended antibiotic treatment regimens for PID. Addition of metronidazole or clindamycin to the oral doxycycline regimen improves anaerobic coverage at the risk of decreasing compliance. PID is often treated in the outpatient setting. Indications for hospitalization include a diagnostic suspicion of a surgical emergency such as ovarian torsion or appendicitis, severe illness, pregnancy, tuboovarian abscess, or inability to tolerate or failure to respond to outpatient therapy. Adolescents with a diagnosis of PID, who are treated as outpatients, must be monitored with a repeat visit within 48 to 72 hours to ascertain adequate clinical improvement versus need for hospitalization. EPIDIDYMITIS Epididymitis is an unusual complication of sexually transmitted urethritis. Ascent of N. gonorrhoeae or C. trachomatis to the epididymis occurs in fewer than 1% of patients. Urethritis, often asymptomatic, usually accompanies sexually transmitted epididymitis. Epididymitis presents with an abrupt onset of unilateral testicular pain and edema (see Chapter 28). A hydrocele and palpable swelling of the testicle usually are present. Testicular torsion should be considered, and an expert should be consulted if the diagnosis is in question. Table 29-35 lists the evaluation for epididymitis. Table 29-36 lists CDC-recommended treatment regimens. Treatment must begin at the time of presentation. Hospitalization should be considered when severe pain suggests other diagnoses, such as testicular torsion, when patients are febrile, or if patients may not comply with treatment.
Table 29-34. Treatment Regimens for Pelvic
Inflammatory Disease Parenteral Regimens (One of the Following) Cefotetan, 2g IV q12h, or cefoxitin, 2 g IV q6h, plus doxycycline, 100 mg IV or PO q12h OR Clindamycin, 900 mg IV q8h, plus gentamicin, loading dose (2 mg/kg body weight) IV or IM, followed by a maintenance dose (1.5 mg/kg) q8h Parenteral therapy may be discontinued 24 hr after clinical improvement and continue Doxycycline, 100 mg PO b.i.d., or clindamycin, 450 mg orally q.i.d. continued for 14 days of total therapy For tuboovarian abscess, addition of either metronidazole, 500 mg PO b.i.d., or clindamycin, 450 mg PO q.i.d., to oral doxycycline provides better coverage against anaerobes Outpatient Regimens (One of the Following) Ofloxacin, 400 mg PO b.i.d., or levofloxacin, 500 mg PO q.d. for 14 days, with or without metronidazole, 500 mg PO b.i.d. for 14 days OR Ceftriaxone, 250 mg IM in a single dose, or cefoxitin, 2 g IM, with probenecid, 1 g PO in a single dose once, or other parenteral third-generation cephalosporin (e.g., ceftizoxime or cefotaxime) plus doxycycline, 100 mg PO b.i.d. for 14 days, with or without metronidazole, 500 mg PO b.i.d. for 14 days
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Table 29-35. Diagnostic Evaluation for Epididymitis
Gram-stained smear of urethral exudate or intraurethral swab specimen for diagnosis of urethritis and for presumptive diagnosis of gonococcal infection Diagnostic test for urethral Neisseria gonorrhoeae and Chlamydia trachomatis infection Examination of first-void urine for leukocytes if the urethral Gram stain is negative or not available; culture and Gramstained smear of uncentrifuged urine should be obtained Syphilis serologic profile and HIV counseling and testing Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80. HIV, human immunodeficiency virus.
Bed rest, scrotal elevation, and nonsteroidal antiinflammatory agents afford symptomatic relief. Patients treated as outpatients should be reevaluated in 3 days. If significant clinical improvement has not occurred, hospitalization and referral to a urologist may be indicated. Patients who have persistent tenderness and swelling after treatment should be evaluated for tuberculosis, fungal epididymitis, and neoplasm.
PREVENTION Although most pediatric health care providers are not specifically trained to deliver effective STD prevention, providers can deliver the following services that can affect individual risks and patient population prevalence rates. 1. Explain to all adolescent patients and their parents the concept of confidential preventive services. 2. Confidentially ask all adolescent patients whether they are sexually active. 3. Confidentially screen all sexually active adolescents for STDs. 4. For patients with positive results of tests for an STD, facilitate partner notification and treatment if possible. 5. Provide information on STD-preventive behaviors, such as abstinence and correct and consistent condom use. 6. Closely monitor sexually active adolescents with STD screening and risk reduction counseling (i.e., repeat visits every 4 to 6 months instead of annually).
Table 29-36. Treatment Regimens for Epididymitis
One of the following: For epididymitis most likely caused by gonoccocal or chlamydial infection: Ceftriaxone, 250 mg IM in a single dose, plus doxycycline, 100 mg orally twice daily for 10 days For epididymitis most likely caused by enteric organism, or for patients who are allergic to cephalosporins and/or tetracyclines: Ofloxacin, 300 mg orally twice daily for 10 days* Levofloxacin, 500 mg orally once daily for 10 days* Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
Adapted from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:1-80.
*Fluoroquinolones have not been recommended for persons younger than 18 years because they damage articular cartilage in juvenile animal models. Among children treated with fluoroquinolones, no joint damage attributable to therapy has been observed. Quinolones should not be used to treat possible gonorrhea infections acquired in Asia or the Pacific, including Hawaii, or California.
IM, intramuscularly; IV, intravenously; PO, per os (orally).
IM, intramuscularly.
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Table 29-37. Red Flags and Things Not to Miss
Diagnosis of More than One Sexually Transmitted Disease in the Same Patient If patient is diagnosed with syphilis, gonorrhea, or human immunodeficiency virus If patient reports engaging in unprotected sex with multiple partners If patient is immunocompromised If patient has a history of sexually transmitted diseases Abdominal Pain in an Adolescent Girl Pelvic inflammatory disease Tuboovarian abscess Ectopic pregnancy Appendicitis Ovarian cyst (rupture or torsion) Fever, Rash, Malaise, Arthalgia Disseminated goncoccemia Reactive arthritis Human immunodeficiency virus infection Rape Pregnancy Treatment of Partners Asymptotic Cervicitis or Urethritis
7. Remain informed on state and federal minor consent laws regarding STD care. In a busy pediatric clinical setting, effective HIV and STD prevention counseling presents a challenge. The CDC promotes delivering one or two brief (15- to 20-minute) “client-centered” HIV prevention counseling sessions. Providers help patients (1) identify the specific behaviors putting them at risk of acquiring or transmitting HIV and (2) commit to steps to reduce their HIV risk. The provider should focus on the adolescent’s personal risk or circumstances. A personalized risk assessment encourages the patient to identify, understand, and acknowledge his or her own behaviors and circumstances that put him or her at increased risk of acquiring STDs and HIV. The session should include an exploration of previous attempts to reduce risk and identification of successes and challenges in previous risk-reduction efforts. This in-depth risk assessment allows the provider to help the adolescent consider ways to reduce personal risk and commit to a single, explicit step to reduce risk. In the follow-up session, the provider asks the patient to describe the risk-reduction step attempted, acknowledges positive steps made, and helps the patient identify and commit to additional behaviors. The provider should also offer appropriate referrals, such as for substance abuse. By using this prevention model, providers can effectively help reduce their adolescent patients’ high-risk sexual behaviors and prevent infection with new STDs.
RED FLAGS Red flags are presented in Table 29-37. REFERENCES Introduction Centers for Disease Control and Prevention: Youth risk behavior surveillance— United States, 2001. MMWR Morb Mortal Wkly Rep 2002;51(SS-4): 13-15. Available at: http://www.cdc.gov/mmwr/PDF/SS/ SS5104.pdf (accessed November 14, 2003).
History, Physical Examination, and Laboratory Testing American Medical Association: AMA Guidelines for Adolescent Preventive Services (GAPS): Recommendations and Rationale. Baltimore, Williams & Wilkins, 1994. Centers for Disease Control and Prevention: Revised guidelines for HIV counseling, testing, and referral. MMWR Morb Mortal Wkly Rep 2001;50:1-57. Woods ER, Neinstein LS: Office visit, interview techniques, and recommendations to parents. In Neinstein LS (ed): Adolescent Health Care, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2002, pp 59-78. Genital Ulcer Disease and Herpes Simples Virus Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002; 51(No. RR-6):12-78. Corey L, Handsfield HH: Genital herpes and public health. JAMA 2000; 228:791-794. Corey L, Wald A: Genital herpes. In Holmes KK, Sparling PF, March PA, et al (eds): Sexually Transmitted Diseases, 3rd ed. New York, McGrawHill, 1999, pp 285-334. Fleming DT, McQuillan GM, Johnson RE, et al: Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111. Langenberg AGM, Corey L, Ashley RL, et al: A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med 1999;341:1432-1438. Wald A, Zeh J, Selke S, et al: Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995;333:770-775. Wald A, Zeh J, Selke S, et al: Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000;342:844-850. Genital Warts and Human Papillomavirus Cain JM, Howett MK: Preventing cervical cancer. Science 2000;288: 1753-1754. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51: 53-59. Ho GYF, Bierman R, Beardsley L, et al: Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338: 423-428. Koutsky LA, Kiviat NB: Genital human papillomavirus. In Holmes KK, Sparling PF, March PA, et al (eds): Sexually Transmitted Diseases, 3rd ed. New York, McGraw-Hill, 1999, pp 347-360. Moscicki AB, Ellenberg JH, Vermund SH, et al: Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls. Arch Pediatr Adolesc Med 2000;154:127-134. Moscicki AB, Hills N, Shiboski S, et al: Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA 2001;285:2995-3002. Saslaw D, Runowica CD, Solomom D, et al: American Cancer Society guidelines for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002:52:342-362. Sawaya GF, Brown AD, Washington AE, Garber AM: Current approaches to cervical-cancer screening. N Engl J Med 2001;344:1603-1607. Cervicitis, Uethritis, Vaginitis, and Upper Genital Tract Diseases Burstein GR, Romaplo AM: Chlamydia. In MB Goldman, MC Hatch (eds): Women and Health. San Diego, Calif, Academic Press, 1999, pp 273-284. Burstein GR, Zenilman JM: Non-gonococcal urethritis—A new paradigm. Clin Infect Dis 1999;(Suppl 1):S66-S73. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002;51:3053. Centers for Disease Control and Prevention: Take action on HEDIS. Available at: http://www.cdc.gov/nchstp/dstd/Reports_Publications/ HMOletter.pdf (accessed September 15, 2003) Chacko MR, Woods CR Jr: Gynecologic infections in childhood and adolescence. In Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases, vol 1, 4th ed. Philadelphia: WB Saunders, 1998, pp 509-548. Holmes KK, Stamm WE: Lower genital tract infections in women. In Holmes KK, Sparling PF, March PA, et al (eds): Sexually Transmitted Diseases, 3rd ed. New York, McGraw-Hill, 1999, pp 761-782.
Chapter 29 Sexually Transmitted Diseases Hook EW III, Handsfield HH: Gonococcal infections in the adult. In Holmes KK, Sparling PF, March PA, et al (eds): Sexually Transmitted Diseases, 3rd ed. New York, McGraw-Hill, 1999, pp 451-466. Kamb ML, Newman K, Peterman TA, et al: Most bacterial STDs are asymptomatic [abstract 022]. Oral presentation at Sexually Transmitted Infections at the Millennium Conference, Baltimore, May 2000. Scholes D, Stergachis A, Heidrich FE, et al: Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996;334:1362-1366. Westrom L, Eschenbach D: Pelvic inflammatory disease. In Holmes KK, Sparling PF, March PA, et al (eds): Sexually Transmitted Diseases, 3rd ed. New York, McGraw-Hill, 1999, pp 783-810. Sexual Assault American Academy of Pediatrics, Committee on Adolescence: Care of the adolescent sexual assault victim. Pediatrics 2001;107:1476-1479. American Academy of Pediatrics, Committee on Child Abuse and Neglect: Guidelines for the evaluation of sexual abuse of children: Subject review
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(RE9819). Pediatrics 1999;103:186-191. Corection published in Pediatrics 1999;103:1049. Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002; 51(RR-6):69-74. Hammerschlag MR: Use of nucleic acid amplification tests in investigating child sexual abuse. Sex Transm Infect 2001;77:153-154. Human Immunodeficiency Virus and Prevention American Academy of Pediatrics, Committee on Pediatric AIDS and Committee on Adolescence: Adolescents and human immunodeficiency virus infection: The role of the pediatrician in prevention and intervention. Pediatrics 2001;107:188-190. Centers for Disease Control and Prevention: Revised guidelines for HIV counseling, testing, and referral. MMWR Morb Mortal Wkly Rep 2001; 50(RR-19):1-57.
30
Menstrual Problems and Vaginal Bleeding
Marjorie Greenfield
withdrawal of hormonal support to the endometrial lining. If pregnancy were to occur, human chorionic gonadotropin (hCG) from the conceptus would stimulate the corpus luteum to continue producing progesterone.
Abnormal vaginal bleeding (Table 30-1) is a common problem reported by adolescents. The severity can range from a minor inconvenience to a medical emergency. Ninety-five percent of abnormal bleeding in adolescents is dysfunctional uterine bleeding (DUB). The term dysfunctional denotes abnormal bleeding without discernible pelvic disease; such bleeding is usually caused by a hormonal abnormality. The history, physical examination, and possibly a few blood tests should rule out most other causes of bleeding and allow appropriate management of DUB.
ENDOMETRIUM Histologic Changes through the Cycle The sequence of hormonal changes during the menstrual cycle leads to a synchronous response of the endometrium. Estrogen, in the first half of the cycle, causes the proliferative phase, characterized by endometrial growth and thickening. Progesterone, in the second half of the cycle, causes the secretory phase, creating glandular differentiation in the estrogenized endometrium, readying it for implantation of a conceptus.
THE OVULATORY MENSTRUAL CYCLE HYPOTHALAMUS Gonadotropin-releasing hormone (GnRH), a decapeptide secreted in pulses from the hypothalamus, is transported down a portal system to the pituitary gland. The pulsatile secretion of GnRH from the hypothalamus allows secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but has only a permissive effect and is not involved in regulation of their blood levels. Factors that interfere with hypothalamic function can reduce production of FSH and LH.
Normal Control of Menstrual Bleeding Menstruation occurs when a sequence of hormonally determined events in the endometrium leads to an organized sloughing of the endometrial surface. As estrogen and progesterone levels decline, the spiral arterioles undergo spasms in rhythmic waves, and the surface of the endometrium becomes ischemic. As the surface weakens, it loses its integrity, allowing menstrual blood to escape. Thrombin and platelet plugs limit blood loss (see Chapter 50). The superficial endometrium collapses and is shed. Menstrual flow stops as a result of synchronized vasoconstriction, tissue collapse, vascular stasis (clotting of blood in exposed vessels), and estrogen-induced “healing.” The self-limited character of menstrual bleeding depends on adequate clotting mechanisms and normal ovulatory hormonal events. This becomes important in the attempt to understand causes of abnormal menstrual bleeding.
PITUITARY Pituitary gland production of FSH and LH responds to negative feedback of circulating estrogen. There is also a positive feedback mechanism that increases LH production when estrogen levels rise sharply in the midcycle, producing the “LH surge” (Fig. 30-1). In adolescents, the positive feedback mechanism and LH surge are the last parts of the system to mature. OVARY Follicular Phase
UTERINE BLEEDING IN THE ADOLESCENT
The ovary controls the menstrual cycle. When estrogen and progesterone levels decline and a menstrual period begins, the pituitary gland, released from negative feedback inhibition, secretes FSH, stimulating the development of new ovarian follicles. As the dominant follicle emerges, it produces large amounts of estrogen. This rapid rise in estrogen leads to the LH surge; the LH surge triggers ovulation. Estrogen levels do not rise to the level that triggers positive feedback until the follicle is ready for ovulation; the follicle itself controls the timing of ovulation.
NORMAL ADOLESCENT CYCLES Normal adolescent menstrual cycles are not necessarily the same as normal ovulatory adult cycles (see Table 30-1). Among girls aged 13 to 16 who were evaluated by serial serum progesterone levels, only 33% of cycles were ovulatory in girls who had been menstruating for less than 11/2 years. Even 5 years after menarche, only 80% of the cycles were ovulatory. This anovulatory state is believed to result from immaturity of the hypothalamic-pituitary-ovarian (HPO) axis; the positive feedback mechanism for the LH surge is not consistently functional. Anovulatory cycles are, therefore, the norm for young adolescents. The normal cycle in a teenager is light to moderate bleeding lasting 2 to 8 days every 21 to 40 days. The best explanation for the cyclicity of bleeding in normal but anovulatory adolescents is that although the positive feedback mechanism of ovulation is not
Luteal Phase After ovulation, the follicle becomes a corpus luteum, a factory for progesterone synthesis. After 14 days, if conception has not occurred, the corpus luteum ceases its function, estrogen and progesterone levels decline, and menstruation begins as a result of 495
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ABNORMAL ADOLESCENT MENSTRUAL CYCLES: DYSFUNCTIONAL UTERINE BLEEDING
Table 30-1. Normal and Abnormal Menses
Normal cycle (adolescent): bleeding every 21-45 days for 2-8 days Normal cycle (adult, ovulatory): bleeding every 24-35 days for 3-7 days Menorrhagia: prolonged or excessive regular periods Menometrorrhagia: heavy, irregular periods Oligomenorrhea: infrequent periods Intermenstrual bleeding: bleeding between regular menstrual periods Dysfunctional uterine bleeding: abnormal uterine bleeding not caused by local uterine pathology; cause usually hormonal
Problems develop when the negative feedback does not occur and estrogen levels stay constant. Because hormone levels do not decline to allow a withdrawal bleed, a normal cyclic menstrual pattern is not seen. Constant levels of circulating estrogen stimulate the uterine lining to become abnormally thick and unstable. As dyssynchronous breakdown in the endometrial structure occurs, bleeding can be heavy and unpredictable, lasting days to months and leading to hemodynamic instability and anemia. This classic description of severe DUB may or may not be superimposed on a pattern of oligomenorrhea or amenorrhea. DEVELOPING A DIFFERENTIAL DIAGNOSIS
developed, there is negative feedback of estrogen on pituitary FSH. As estrogen levels rise, FSH decreases, causing the ovarian follicles to stop producing estrogen. The withdrawal of hormonal support causes the endometrium to slough, an “estrogen withdrawal bleed.” As the inhibition on the pituitary gland is released, FSH increases and the ovarian production of estrogen resumes. This allows for regular “menses” in the anovulatory adolescent. The bleeding is not quite as controlled and consistent as the cycles of estrogen-progesterone withdrawal bleeding in an ovulatory woman, but the decline in estrogen levels is effective at decreasing the thickness of the uterine lining enough so that bleeding is not excessive. This pattern, interspersed with occasional ovulatory cycles, appears to control bleeding adequately in most teenage girls.
HYPOTHALAMUS
COMMON CAUSES OF ABNORMAL UTERINE BLEEDING
Pulsatile GnRH
Anovulation
ANTERIOR PITUITARY
FSH
FSH, LH LH SURGE
FOLLICULAR PHASE
In contrast to the cyclical changes in estrogen levels seen with “normal” anovulatory cycles in teenagers, problematic bleeding is a result of chronic anovulation associated with a steady state of estrogen, FSH, and LH. Constant levels of estrogen provide constant stimulation of endometrial growth and can lead to hemorrhage, anemia, infertility, and endometrial cancer. As few as 50% of patients revert to regular cycles by 4 years after presentation.
LH LUTEAL PHASE
OVARY
Follicle
Dominant follicle
Coagulopathy
Corpus luteum
Ovulation
Estrogen ⫹ Progesterone
Estrogen Endometrium Spiral arterioles
Idealized 0 5 cycle day Menses
14 Proliferative phase
DUB, manifesting as heavy irregular menses, is the most common type of abnormal vaginal bleeding in teenagers. Other patterns of bleeding suggest other diagnoses (Table 30-2). Normal menses followed by intermenstrual bleeding may indicate a structural process, such as endometrial polyps or cervicitis, in which the hormonal environment does not control the bleeding. Normal menses with bleeding after intercourse can be from a vaginal or cervical lesion. Dark, possibly foul-smelling blood after the normal menstrual period suggests an obstructed uterine horn or hemivagina with slow leaking of sequestered blood through a fistulous tract. A detailed menstrual history can give clues to the diagnosis. In addition to the menstrual history, a sexual history, a medical history, a review of systems, a pelvic examination with a Papanicolaou (Pap) smear, and a urine pregnancy test are necessary to identify the site and cause of bleeding (Figs. 30-2 to 30-5). Additional testing is determined by the emerging differential diagnosis (Table 30-3).
28 Secretory phase
Figure 30-1. Hypothalamic-pituitary-ovarian endometrial axis: changes over time. FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. (Adapted from Nesse R: Managing abnormal vaginal bleeding. Postgrad Med 1991;89:207.)
Of nonpregnant adolescent girls admitted to the hospital for menorrhagia, as many as 19% have a coagulopathy. As the severity of the menorrhagia increases, coagulation problems are more likely to be present. Severe iron deficiency anemia, requirement for transfusion, and hemorrhage at first menses each confers an even greater chance of finding a coagulopathy. Idiopathic thrombocytopenia purpura, von Willebrand disease, and, less often, thrombocytopenia caused by systemic disease, such as leukemia or systemic lupus erythematosus, can manifest with menorrhagia (see Chapter 50). Screening for coagulopathy with a platelet count, prothrombin time, and activated partial thromboplastin time, plus von Willebrand disease screening with ristocetin cofactor/von Willebrand factor activity test, von Willebrand factor antigen test, and factor VIII clotting activity assay, is usually adequate. If coagulopathy is still strongly suspected, consultation with a hematologist may be necessary to rule out the rare coagulopathies that are not detectable with these initial tests.
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Table 30-2. Differential Diagnosis of Abnormal Vaginal Bleeding in Adolescents Bleeding Pattern MR
MMR
Source: Uterus Anovulation
+
+
Coagulopathy
+
Complication of pregnancy
IB
Suggestive Finding; Diagnostic Finding
Treatment
Common Causes No extrauterine source of bleeding seen on See Table 30-5 examination Responds appropriately to treatment More commonly found in cases of severe Treat coagulopathy; oral contraceptives bleeding especially if onset at menarche; may help with menorrhagia; complete family history, ROS suggestive of clotting menstrual suppression sometimes disorder; ecchymoses, petechiae may be required seen on examination Abnormal PT, PTT, platelet count, bleeding See also Chapter 50 time, or test for von Willebrand disease History of late period; pregnancy See Figure 30-6 symptoms (nausea, breast tenderness) Positive urine or blood pregnancy test
+
Source: Vagina Injury
Evaluation
Uncommon Causes Surgical or topical hemostasis; suture or allow to heal by secondary intention
+
History Visible laceration
Foreign body (e.g., retained tampon or contraceptive sponge)
+
History, foul discharge Visible foreign body
Removal
Cancer
+ +
Lesion seen, ± abnormal cytologic findings Biopsy
Referral to specialist; therapy chosen per type and stage of tumor
Source: Cervix Neoplasia Dysplasia/carcinoma
Less Common Causes + +
Bleeding point on cervix; abnormal cytology Colposcopy with directed biopsies Polyp seen
Hemangioma
+
Lesion seen
Infection (cervicitis) (see Chapter 29) Herpes
+
Cervical vesicles ± ulceration, ± pelvic pain, tenderness; Pap smear sometimes shows multinucleated giant cells Culture positive for herpes Flat or raised warts seen on cervix Pap smear + colposcopy necessary to differentiate from dysplasia; HPV typing may determine risk of cancer Friable inflamed cervix; yellow-green vaginal discharge, pH 7-8 Saline preparation: motile flagellates
Cervical polyp
Human papillomavirus (HPV)
+
Trichomonas
+
Source: Uterus Neoplasia Fibroid
Grasp with clamp or ring forceps and twirl off polyp in office; send specimen to pathologist Conservative versus excision or ablation
If primary infection, consider oral famcyclovir, 250 mg b.i.d. × 7-10 days Laser, LEEP, cryotherapy, trichloroacetic acid or 5-fluorouracil cream after Pap smear and colposcopy; treat for dysplasia or symptoms Metronidazole, 2 g orally once each for patient and sexual partners
Less Common Causes ±
±
Endometrial polyps Malignant uterine tumor
LEEP, laser, cryotherapy, or cone biopsy
+ ±
±
± Enlarged uterus on examination; NSAID sometimes helpful for palpable fibroids menorrhagia; myomectomy via Abnormal findings on ultrasound, and/or hysteroscope, laparoscope, or hysteroscopy laparotomy may be needed History of spotting superimposed on D&C or hysteroscopic excision normal menstrual cycle Hysteroscopy, saline sonogram, and/or D&C Abnormal Pap smear, enlarged uterus, Surgery determined by type of tissue at cervical os. tumor and stage Biopsy Continued
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Table 30-2. Differential Diagnosis of Abnormal Vaginal Bleeding in Adolescents—cont’d Bleeding Pattern MR
MMR
IB
Evaluation Suggestive Finding; Diagnostic Finding
Treatment
Source: Uterus Ovarian tumor producing estrogen (bleeding is uterine) Foreign body IUD
+
+
No other cause of bleeding (patient ovulatory, not pregnant, no PID) IUD in uterus; responds to therapy
NSAID sometimes useful for menorrhagia; removal if PID coexists or if necessary to control bleeding
Infection PID
+
+
Tender uterus and adnexae; purulent cervical discharge ± ↑ WBC count, ESR, or fever Clinical diagnosis, tests often positive for gonorrhea, chlamydia ± ↑ WBC count, ESR, fever Recent pregnancy; tender uterus
CDC guidelines (see Chapter 29)
Foul, dark blood after menses Abnormal pelvic examination and/or pelvic ultrasonography
Refer for surgical treatment
Postpartum or postabortal endometritis ± retained products of conception Congenital partially obstructed hemivagina or uterine horn
Less Common Causes Adnexal mass on examination or Surgery ultrasonography Surgical diagnosis and staging
+
+
+
D&C if retained tissue seen on sonogram; broad-spectrum antibiotics, methergine
CDC, Centers for Disease Control and Prevention; D&C, dilation and curettage; ESR, erythrocyte sedimentation rate; IB, intermenstrual bleeding, IUD, intrauterine device; LEEP, loop electroexcisional procedure; MMR, menometrorrhagia; MR, menorrhagia; NSAID, nonsteroidal anti-inflammatory drug; Pap, Papanicolaou; PID, pelvic inflammatory disease; PT, prothrombin time; PTT, partial thromboplastin time; ROS, review of systems; WBC, white blood cell.
Bleeding and Hormonal Contraceptives Abnormal bleeding during the first few months of low-dose oral contraceptive use is common and can be managed with reassurance
Figure 30-2. Sagittal section of the speculum examination. The Huffman (narrow Pederson) vaginal speculum is essential for examining adolescents. With blades 1.5 cm wide and 11 cm long, it is narrow enough to be tolerated by a virginal adolescent and also deep enough to reach the cervix. With one hand (usually the non-dominant hand), the examiner separates the patient’s labia minora and visualizes the introitus. The speculum is then inserted at an oblique angle. (From Swartz MH: Textbook of Physical Diagnosis: History and Examination, 2nd ed. Philadelphia, WB Saunders, 1994, p 380.)
if pregnancy is not suspected. Bleeding usually normalizes within three to four cycles. Prolonged use of combination estrogen-progesterone oral contraceptives, skin patches, vaginal rings, progestinonly oral contraceptives (mini-pill), and injectable or implantable progestin contraceptives may lead to deciduation and atrophy of the endometrium. This thin uterine lining may bleed unpredictably. Endometrial atrophy is best treated with supplemental estrogen, which thickens and stabilizes the uterine lining. For girls with normal pelvic examination findings and a negative pregnancy test, conjugated equine estrogens (e.g., Premarin), 1.25 mg, or estradiol, 2 mg taken daily with the oral contraceptive for 7 days, should regulate bleeding for many cycles afterward. This regimen may need to be repeated if the problem recurs. Doubling up on the birth control pill or giving the next dose of injectable contraceptive early does not diminish the bleeding, because this provides a progestin-dominant stimulus to an already atrophic endometrium. If estrogen supplementation is not successful, other causes of bleeding should be considered. Many girls have some breakthrough bleeding if they are late in taking a pill, especially in long-term pill users. Reminding the patient of the need to take pills consistently can help to prevent breakthrough bleeding. Illness and Medication Medications and illnesses that cause abnormal uterine bleeding do so by their effects on coagulation or on the hormonal milieu (Table 30-4). Chronic illnesses such as diabetes, cystic fibrosis, and sickle cell anemia can lead to anovulation. This chronic anovulation confers the short-term and long-term risks of unopposed estrogen exposure. If the patient’s medical condition cannot be improved, cyclic progestins or oral contraceptives should be considered if there are no contraindications (Table 30-5).
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MANAGEMENT OF ABNORMAL BLEEDING (see Table 30-5) ACUTE MANAGEMENT Treatment and evaluation of severe abnormal bleeding are usually begun simultaneously. The urine pregnancy test can be used to triage the patient; a negative blood hCG level effectively rules out pregnancy. Hemodynamic stability is assessed, and replacement of blood and fluids is used as needed. It is important to complete relevant blood work (complete blood cell count, prothrombin time, activated partial thromboplastin time, and, if possible, von Willebrand screening) before a blood transfusion is started. Most patients with bleeding severe enough to require hospitalization are anovulatory. Although both estrogens and progestins have been used to stop acute anovulatory bleeding, few studies are available to compare their effectiveness (Table 30-6). If the acute bleeding is caused by a coagulopathy, the underlying problem (see Chapter 50) should be addressed, although hormonal protocols for management of the vaginal bleeding can be employed simultaneously and are often successful.
A
LONG-TERM FOLLOW-UP AND PREVENTION OF RECURRENCE
B Figure 30-3. Sagittal-section illustrating the position of the speculum during inspection of the cervix. The examiner fully inserts the speculum before opening the blades. A, The angle of insertion is about 45 degrees to the examining table. As the blades are opened, the speculum is carefully maneuvered so that the cervix is fully seen. B, The thumb lever is then locked in place. (From Swartz MH: Textbook of Physical Diagnosis: History and Examination, 2nd ed. Philadelphia, WB Saunders, 1994, p 381.)
Pregnancy Complications Pregnancy can manifest with abnormal bleeding that may or may not be preceded by an episode of amenorrhea. Particularly abnormal pregnancies, such as ectopic pregnancies or those about to end in miscarriage, may manifest with abnormal bleeding without a “missed period.” The urinary hCG pregnancy tests in use today are positive in more than 98% of patients with ectopic pregnancies. Highly diluted urine may yield false-negative results. A negative serum hCG level essentially rules out the possibility that abnormal bleeding is caused by a complication of pregnancy (Fig. 30-6).
Once the initial bleeding is controlled, or if the patient with moderate/ severe bleeding is not actively bleeding at presentation, therapeutic goals include prophylaxis against recurrence, prevention of the longterm sequelae of unopposed estrogen stimulation to the endometrium, and treatment of anemia. Although the underlying cause of chronic anovulation may not be found, a basic workup should be performed (see section on amenorrhea). To prevent recurrence of bleeding, cyclic progestins or oral contraceptives should be used for 3 to 6 months. They decrease the thickness of the uterine lining and allow for orderly estrogen-progestin withdrawal bleeds. Because the uterine lining is usually quite thick at the onset of treatment, the first progestin withdrawal period may be quite severe but should not last longer than 1 week. This must be explained to the patient so that the heaviness of the next period is not viewed as failure of treatment. As the endometrial height diminishes with each succeeding menstrual period, bleeding should become lighter. For the teenager who does not need contraception, it is acceptable to discontinue treatment after 3 to 6 months and observe the patient for development of ovulatory cycles. Of girls who have severe DUB, 50% will have long-term problems with chronic anovulation and its associated risks of recurrent hemorrhage and uterine cancer. Therefore, a few months after treatment is stopped, the clinician should review the patient’s menstrual calendar and document ovulation. Prospective documentation of premenstrual symptoms (breast tenderness), a luteal phase serum progesterone level, or a basal body temperature chart is adequate for documenting ovulation (Table 30-7). If the patient remains anovulatory, cyclic progestin or oral contraceptive treatment should be reinstituted to prevent recurrent abnormal bleeding and to diminish the long-term risk of endometrial carcinoma. For the adolescent who needs contraception, it is best to continue oral contraceptives or equivalent treatment with skin patches or vaginal ring. There is no evidence that even long-term oral contraceptive use has any effect on the menstrual cycle within 1 year of discontinuance. Those who are anovulatory before using oral contraceptives, however, may continue to be anovulatory after the pills are stopped. Failure of anovulatory bleeding to respond to hormonal treatment is an indication to reevaluate the patient.
AMENORRHEA Amenorrhea or absence of menstrual periods is a symptom, not a diagnosis. Causes can be grouped into two categories: (1) end-organ
Figure 30-4. The bimanual examination. Palpation of the uterus is performed with one or two fingers of the examiner’s dominant hand inside the patient’s vagina and with the examiner’s other hand on the patient’s lower abdomen. As the uterus is trapped between the examining hands, pressure with the abdominal hand causes the cervix to move against the inside finger or fingers, giving the examiner an appreciation of the uterine size, shape, configuration, mobility, and tenderness. An empty bladder facilitates the examination. By pressing the vaginal examining finger or fingers into the lateral fornix anteriorly, superiorly, and laterally and pressing on the patient’s abdomen so that the vaginal and abdominal fingers try to appose, the examiner can palpate the adnexal structures as they move between the examining hands. This provides an appreciation of adnexal size, shape, mobility, and tenderness. A rectoabdominal examination may also be used to assess the uterus or adnexa if a vaginal examination is not tolerated. A, Sagittal section through the pelvic organs. B, Position of the uterus between the examining hands. (From Swartz MH: Textbook of Physical Diagnosis: History and Examination, 2nd ed. Philadelphia, WB Saunders, 1994, p 385.)
Figure 30-5. Obtaining smear for the Papanicolaou test. The endocervical brush and the longer end of the spatula are placed in the cervical os and rotated for cell collection. (From Swartz MH: Textbook of Physical Diagnosis: History and Examination, 2nd ed. Philadelphia, WB Saunders, 1994, p 383.)
or outflow tract anomalies and (2) inadequate hormonal stimulation to the endometrium. Primary amenorrhea is traditionally defined as no menstrual period by age 16 years or no menses in the absence of breast development by age 13 years. Age 14.5 years is the 95th percentile for menarche. Secondary amenorrhea denotes 3 to 6 months without menstrual bleeding in a previously menstruating girl or woman, although shortly after menarche, 12 to 18 months without periods may be normal. The evaluation of amenorrhea is driven by the patient’s needs and concerns, not necessarily by definitions. A 16year-old with 8 weeks of amenorrhea may need a pregnancy test. A 10-year-old with stigmata of Turner syndrome need not wait until age 13 for an evaluation of amenorrhea. Certain processes, such as imperforate hymen or müllerian agenesis (absence of the uterus and proximal vagina) can cause only primary amenorrhea. Other processes can cause amenorrhea at any time, depending on when the disease occurs. Anorexia nervosa, if it develops before menarche, can cause primary amenorrhea with or without pubertal delay. If anorexia develops later, it may cause secondary amenorrhea. Congenital anatomic conditions that cause only primary amenorrhea are suspected from the initial history and physical examination findings. Once these few specific diagnoses are ruled out, primary and secondary amenorrhea are evaluated similarly.
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Table 30-3. Diagnostic Approach to Abnormal Uterine Bleeding in Adolescence Evaluation Method
History Menstrual Medical Sexual Social Medications Family history Physical Examination General
Comments
When Needed
Last menstrual period, pattern of cycles, recent change, molimina (i.e., premenstrual symptoms), dysmenorrhea Pelvic pain, fever, vaginal discharge, coagulopathy, endocrine problems, major illness History of sexual intercourse (including most recent date), birth control used, history of abnormal Pap smear or sexually transmitted infection Stress, eating disorder, exercise, drugs, alcohol abuse, domestic violence Anticoagulants, hormones, drugs with endocrine or coagulation effects Clotting disorders, endocrinopathies
Always Always Always Always Always Always
Weight Body habitus, hirsutism, Tanner stage Stigmata of endocrine or coagulation disorders Signs of trauma To assess source of bleeding and possible cause Cervix and vaginal walls can usually be visualized even with a Huffman (narrow Pederson) speculum, even in a young virginal adolescent By rectoabdominal examination if bimanual examination not tolerated
Always
Always, if sexual contact is a possibility
Hemoglobin or hematocrit
If urine test results are negative and suspicion is high, check serum hCG With or without retic count, iron studies, ferritin
Clotting studies
Platelet count, PT, PTT, bleeding time, vWF testing
Blood type and screen
Treat Rh-negative teenagers who miscarry with RhoGAM Specimen can be obtained during examination; discarded if results rule out suspicion of infection
Pelvic External genitalia, vagina, cervix Uterus, adnexa
Always
Rectovaginal or rectoabdominal Tests Pregnancy test
Gonorrhea and chlamydial probes Pelvic ultrasonography Hysteroscopy/endometrial sampling
Heme in urine, heme in stool
If bleeding is heavy or objective quantification is desired* In menorrhagia at first period, severe bleeding, family history or personal history of coagulopathy and menorrhagia or failure to respond to treatment If pregnant or hemodynamically compromised If any chance of sexually transmitted infection If bimanual examination results are abnormal or if there is suspicion of congenital anomaly If bleeding is superimposed on normal ovulatory cycles and no extrauterine bleeding site is apparent; or if bleeding does not respond to hormonal therapy and coagulation studies and pregnancy test are negative If bleeding site is not apparent
*Patient’s assessment of menstrual blood loss is notoriously inaccurate. Even pad counts can vary tremendously among women with similar blood loss, although six to eight pads or tampons per day is considered the upper limit of normal. Hematologic parameters can be objective measures of severity of bleeding. hCG, human chorionic gonadotropin; Pap, Papanicolaou; PT, prothrombin time; PTT, partial thromboplastin time; vWF, von Willebrand factor.
OVERVIEW OF PROCESSES THAT LEAD TO AMENORRHEA Causes of amenorrhea may be divided into compartments: end-organ, outflow tract, and three other compartments that lead to inadequate
hormonal stimulation to the endometrium: the ovary, the pituitary, and the hypothalamus. The history, physical examination, and a few simple tests can usually identify which compartment has led to the problem. In teenagers, end-organ and outflow tract conditions are probably congenital, manifesting as primary amenorrhea with
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Table 30-4. Medications that Can Cause Abnormal
Uterine Bleeding Hormonal Effects Estrogens: oral estrogens, estrogen patch Progestins: oral progestins, progestin-only “mini-pill,” injectable or implantable progestin Estrogen/progestin: combination oral contraceptives, skin patches, vaginal rings Androgens: anabolic steroids, danazol Prolactin: many drugs raise prolactin levels, including estrogens, phenothiazines, tricyclic antidepressants, benzodiazepines, metaclopromide, and other drugs that deplete dopamine levels or block dopamine receptors Anticoagulant Effects Warfarin, heparin Aspirin, other nonsteroidal antiinflammatory drugs Chemotherapeutic agents that result in thrombocytopenia
normal secondary sexual development. Once these are ruled out, the general evaluation for amenorrhea can begin. CONGENITAL CAUSES OF PRIMARY AMENORRHEA IN ADOLESCENTS WITH NORMAL SECONDARY SEXUAL DEVELOPMENT (Table 30-8)
and abnormal anatomy are found. A mass (hematocolpos and/or hematometra) may be palpable. Inability of the Endometrium to Respond to Hormonal Stimulation Absence of the uterus or, in rare cases, absence or severe scarring of the endometrium can cause amenorrhea. The most common diagnosis in this category is müllerian agenesis (absence of the uterus and proximal vagina). A less common cause is androgen insensitivity syndrome (see Chapter 31). Asherman syndrome, or uterine scarring, is caused by prior dilation and curettage and/or severe uterine infection. The scarred endometrium does not respond to hormones, and menses are scanty or absent. This is extremely rare in teenagers. Müllerian Agenesis
Müllerian agenesis, also known as Mayer-Rokitansky-Kuster-Hauser syndrome, is associated with urinary tract and skeletal anomalies. Affected girls and women have normal gonadal function and completely normal secondary sexual development. Cyclic abdominal pain, if present, is mittelschmerz (ovulation pain). The vagina is usually a dimple or small in-pouching for which a procedure is needed later in life to allow sexual intercourse. Usually the uterus is absent, but there may be a small uterine remnant, usually without endometrium. These individuals cannot become pregnant, but with assisted reproductive technology, they can provide eggs to be fertilized with the male partner’s sperm and gestated in the uterus of a surrogate.
Obstruction to Menstrual Outflow
Androgen Insensitivity Syndrome
Congenital conditions, such as imperforate hymen, transverse vaginal septum, and (in rare cases) cervical anomalies, can obstruct menstrual outflow. The diagnosis is suspected when cyclic pain
Androgen insensitivity syndrome, formerly known as testicular feminization, occurs in persons who are phenotypically female but are chromosomally XY and lack androgen receptors. In complete androgen insensitivity syndrome, the external genitalia appear female, and the vagina is very shallow. The müllerian and wolffian duct systems are absent. At puberty, breasts develop as a result of gonadal estrogens. Axillary and pubic hair is absent. Malignant transformation of intraabdominal testes can occur, usually after age 25 years. In complete androgen insensitivity syndrome, gonadectomy is delayed until after puberty, to allow smooth secondary sexual development and prevent the majority of tumors.
Table 30-5. Management of Dysfunctional Uterine
Bleeding Mild (Hgb ≥ 11 mg/dL) Reassurance Instruction to keep a menstrual calendar Iron supplementation Periodic reevaluation: 2-3 months Moderate (Hgb 9-11 mg/dL) Actively bleeding: hormonal hemostasis—oral estrogen protocol,* then as for not actively bleeding Not actively bleeding: iron supplementation, regulate cycles with cyclic progestins† or oral contraceptives‡ for 3-6 months, then reevaluate Severe (Hgb ≤ 8 mg/dL or hemodynamically unstable) Not actively bleeding: transfusion if necessary, then as for moderate DUB Actively bleeding: transfusion/fluid replacement, hormonal hemostasis by IV or oral estrogen protocol, D&C if unable to stop bleeding with IV estrogen, then same as for moderate DUB *See Table 30-6. †
Medroxyprogesterone acetate (Provera), 10 mg/day or equivalent for 12 days each month.
‡
Any 30- to 35-μg estrogen ethinyl estrodiol pill.
D&C, dilation and curettage; DUB, dysfunctional uterine bleeding; Hgb, hemoglobin; IV, intravenous.
Explaining the Diagnosis The diagnosis of müllerian agenesis or androgen insensitivity can be psychologically traumatic. Just as she is forming her identity as a woman, the patient discovers she is “not normal” and cannot achieve the milestone of menarche. At the same time, she learns of impediments to reproduction and to sexual intercourse. Explanation to the patient that her vagina did not form completely and that she needs a procedure to help deepen it can give her words for her condition that she can use when she chooses to tell others about it. A multidisciplinary approach with counseling and, if possible, group support or contact with an older girl who has been through treatment can be helpful. CAUSES OF AMENORRHEA IN ADOLESCENTS WITH NORMAL ANATOMY Inadequate hormonal stimulation to the endometrium is the most common cause of secondary amenorrhea and of pubertal delay. There are three general situations that fall under this description: ● ● ●
chronic anovulation (which includes polycystic ovarian syndrome) hypogonadotropic hypogonadism (including the “athletic triad”) ovarian failure (hypergonadotropic hypoestrogenism)
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+ Urine or Blood hCG
Low suspicion for ectopic pregnancy
Suspect ectopic pregnancy?*
Pelvic exam
Pelvic exam Quantitative serum hCG and ultrasound
Ultrasound: pregnancy visible outside uterus
Ultrasound: visible intrauterine gestational sac Ectopic ruled out; follow pathway for "low suspicion for ectopic"
Cervix closed, no tissue passed (threatened abortion) Cervix open (inevitable abortion) or Tissue passed and still bleeding (incomplete abortion)
Ultrasound: no visible pregnancy
Treat for ectopic pregnancy
hCG > DZ
Passed sac, cervix closed, bleeding minimal (complete abortion)
hCG < DZ
Nonviable pregnancy Probable ectopic pregnancy
D&C
Serial hCG to document complete abortion (should fall to ≤ 5 mIU/mL by 6 wk)
Serial hCG at 48 hr and/or culdocentesis
Patient stable, reliable to follow-up; can go home with warnings to come in for serial serum hCG at 48 hr
hCG by 66% @ 48 hr = normal rise
Ultrasound and/or serial hCG to establish viability
hCG plateaued
Repeat ultrasound when hCG is expected to reach DZ
+ Chorionic villi = spontaneous abortion
Culdocentesis + for nonclotting blood
D&C
hCG falling (spontaneous abortion vs. tubal abortion) No villi; consider treatment for ectopic pregnancy or serial hCGs and observation
To surgery for ectopic pregnancy
Serial hCG until resolution
* Patient with pelvic/abdominal pain or risk factors (prior ectopic, prior tubal surgery, prior pelvic inflammatory disease, prior gonorrhea or chlamydia infection, chronic pelvic pain). If ruptured tubal pregnancy suspected (e.g., hemodynamic instability with pelvic pain), may take patient to surgery with only positive pregnancy test or positive culdocentesis.
DZ (discriminatory zone) is the hCG value at which a normal pregnancy would be expected to be visible on the ultrasound. Transvaginal scanning, which visualizes a pregnancy a few days earlier than the abdominal scan, has a lower DZ. Each institution should assess its own DZ based on ultrasound technology and the type of hCG test used. According to the 2nd International Reference Preparation, the DZ for transvaginal ultrasound is usually ≤ 1500 mIU/mL; DZ for abdominal sonogram is about 6000 mIU/mL. Can treat for presumed ectopic in OR or as for plateaued hCG below. Figure 30-6. Evaluation of abnormal bleeding in pregnancy. DZ, discriminatory zone; D&C, dilation and curettage; hCG, human chorionic gonadotropin.
Anovulation In chronic anovulation, the ovary makes estrogen, but ovulation does not occur. Because there is no ovulation, there is no cyclic elevation of progestins and no progestin withdrawal bleeding. Obesity, stress, hypothyroidism, and hyperprolactinemia can all lead to chronic anovulation. Nonetheless, a cause is usually not found. If hirsutism is present, it is evaluated with attention to ruling out the rare case of late-onset congenital adrenal hyperplasia, Cushing syndrome, and tumor of the ovary or adrenal gland (Fig. 30-7).
Polycystic ovarian syndrome (PCOS) can be a result of chronic anovulation. Patients with PCOS may have cystic ovaries, hirsutism, obesity, and amenorrhea or DUB. Insulin resistance and acanthosis nigricans are sometimes observed. PCOS is best considered an extreme at the end of the spectrum of manifestations of chronic anovulation. Patients with PCOS are usually treated as anovulatory (see later discussion), although insulin-sensitizing agents such as metformin are also effective.
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Table 30-6. Medications to Stop Acute Anovulatory Bleeding Medication
Dosage
Estrogens IV conjugated equine estrogens (Premarin)* Conjugated equine estrogens (Premarin)* Combination Estrogens/ Progestins High-dose oral contraceptive pills* Progestins Medroxyprogesterone acetate (Provera) Norethindrone acetate (Aygestin) Megesterol
25 mg IV q4h Maximum 4 doses 2.5 mg PO q6h × 5 days
50 μg ethinyl/estradiol pill q.i.d. × 5-7 days 10-40 mg per 24 hr PO × 12 days 5-10 mg per 24 hr PO × 12 days 40-120 mg/day × 12 days
Comments
Usually causes nausea One published study only; study showed effectiveness at stopping acute bleeding from many causes
May cause nausea, progestin side effects (see under “Progestins”) Outpatient method that provides estrogen and progestin No comparison studies of progestins versus estrogen or oral contraceptives; theoretically less effective if bleeding has been prolonged and endometrial basalis layer is exposed, because progestins only “organize” an already estrogenized proliferative endometrium; side effects of progestins are similar to normal premenstrual symptoms: breast tenderness, depression, bloating, water retention
*Must be immediately followed by 12-21 days of progestin-dominant therapy. Usually 30-50 μg estrogen daily oral contraceptives, although medroxyprogesterone acetate, 10 mg/day, can be used. IV, intravenously; PO, per os (orally); q.i.d., four times per day.
Hypogonadism Ovarian Failure
Table 30-7. Differentiating Ovulatory from Anovulatory
Menstrual Cycles Ovulatory
Menses
Dysmenorrhea
There is regularity of interval, flow, and duration, usually 28 ± 7 days lasting 3-7 days Possibly cramps with bleeding*
Molimina† Possibly breast (premenstrual tenderness,* symptoms) fluid retention, abdominal bloating, mood disturbance Mittelschmerz Possible midcycle unilateral pelvic pain Basal body Biphasic basal body temperature temperature, taken each day, usually before rising in A.M. Serum High serum progesterone progesterone 1–2 days before menses (5 ng/mL)
Anovulatory
Variable flow, duration, and interval No cramps or cramps only with passing clot None
In patients with hypergonadotropic hypogonadism, FSH and LH levels are in the menopausal range because the ovaries do not make estrogen, which would otherwise provide negative feedback. Ovarian failure may be caused by gonadal dysgenesis, or the ovaries may appear normal. Gonadal dysgenesis is associated with Turner syndrome and other X chromosome deletions and mosaic conditions (see Chapter 31). Some persons with Turner syndrome are chromosomally XY/XO mosaic and require gonadectomy at the time of diagnosis to prevent malignant transformation of the intraabdominal streak testis. Because of this risk, the karyotype must be obtained for all adolescents with unexplained ovarian failure, to evaluate for the presence of Y chromosomal material. Other less common causes of ovarian failure include autoimmune oophoritis, galactosemia, and exposure to cytotoxic chemotherapy or radiation therapy. Some ovarian failure is idiopathic. Hypothalamic Amenorrhea
None Monophasic basal body temperature Serum progesterone ≤1 ng/mL 1-12 days before bleeding
*Presence of these signs in a reliable historian strongly suggests ovulatory cycles. †Best documented prospectively and/or correlated with basal body temperature.
Hypogonadotropic hypogonadism is another low-estrogen condition. The pituitary gland, hypothalamus, or both are not appropriately cycling to stimulate the ovary to produce estrogen. FSH and LH levels in these cases are low or normal. This is found in the adolescent athletic triad of amenorrhea, disordered eating, and osteoporosis. Low body weight, chronic illness, anorexia nervosa, intense exercise, hypothyroidism, and hyperprolactinemia can all cause hypothalamic amenorrhea. Intracranial tumors, such as craniopharyngioma and prolactinoma, can also lead to this type of amenorrhea. Amenorrhea Related to Hormonal Contraceptives Amenorrhea that occurs while a person is using birth control pills, patches, rings, or long-acting implantable or injectable contraceptives is caused by the progestin-dominant hormonal environment provided
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Table 30-8. Congenital Anatomic Causes of Primary Amenorrhea with Normal Breast Development* Diagnosis
Patients with primary amenorrhea† Patients with primary amenorrhea and apparent obstruction or absence of vagina† Chromosomes‡ Gonads Serum testosterone‡ Vagina
Müllerian Agenesis
Cyclic pain Uterus Mass
Introitus bulges with Valsalva maneuver Associated anomalies Treatment
Fertility
Transverse Vaginal Septum
Imperforate Hymen
15%
1%
3%
1%
75%
5%
15%
5%
46,XX Ovaries Normal female level Absent or shallow
Axillary/pubic hair
Androgen Insensitivity (AI)
+ ± Absent or rudimentary –
46,XY Testes Normal male level (high) Absent or shallow
Absent unless AI is incomplete – Absent –
–
–
Urinary tract and skeletal Vaginal dilation or surgical neovagina
Inguinal hernias; gonadal malignancy in adulthood Gonadectomy after age 16-18 Vaginal dilation or surgical neovagina
Advanced reproductive technology required; in vitro fertilization surrogate with uterus to gestate pregnancy
Not fertile
46,XX Ovaries Normal female level Obstructed by septum which may be thick or thin, high or low +
46,XX Ovaries Normal female level Obstructed by thin membrane, which may look blue from hematocolpos +
+
+
Present
Present
+ Can present with acute urinary retention as hematocolpos mass obstructs urethra –
+ Can present with acute urinary retention
Major urinary tract abnormalities in 15% Surgical approach depends on extent and location of septum; may be extensive; should be done as soon as possible Variable, low septa have a better prognosis than do high septa
Possibly some increase in urinary tract abnormalities Excision of hymen as soon as possible; diagnostic needle aspiration contraindicated because of risk of infection
+
Usually fertile
*Cervix not visible on pelvic examination. Short vagina; may be absent or obstructed. †
Data from Reindollar RH, Byrd JR, McDonough PG: Delayed sexual development: A study of 252 patients. Am J Obstet Gynecol 1981;140:371.
‡
Sometimes useful in differentiating müllerian agenesis from androgen insensitivity.
+, present; −, absent; ±, may be present or absent.
to the endometrium and by suppression of ovulation. As long as pregnancy has been ruled out, further workup is generally not necessary. The endometrium in these cases is decidualized and atrophic. Shortterm additional estrogen taken with the combination birth control pills usually leads to resumption of menses. Conditions such as eating disorders and stress do not play a role in creating amenorrhea in a girl receiving hormone therapy because the hormonal environment provided to the endometrium is independent of her endogenous hormones. Menstrual cycles are expected to revert to normal by 6 months after discontinuance of oral contraceptive pills and by 12 months after the last depot-medroxyprogesterone acetate (Depo-Provera) injection. For amenorrhea that continues after that point, evaluation is indicated. EVALUATION OF THE AMENORRHEIC ADOLESCENT The evaluation for amenorrhea (Table 30-9) is rarely performed on an emergency basis. An organized history and physical examination with cautious use of ancillary tests can usually identify the general category in which the patient’s condition fits. Within that category, serious medical conditions can be ruled out before treatment is
initiated. Even when there is an obvious predisposing factor, such as intense competitive exercise, the protocol should be followed to allow precise identification of the current hormone state and to rule out serious coinciding conditions. History The history should cover the patient’s general health, including any immediate problems at the time of her birth, major illness, chronic illness, and exposure to chemotherapy or pelvic or central nervous system radiation therapy. Pubertal milestones are identified. Eating habits, emotional stress, exercise habits, sexual activity, birth control method, use of drugs and medications, and any change in weight must be addressed. Review of systems can identify sex hormonal abnormalities, including hirsutism, hot flashes, presence of cyclic abdominal pain, and/or premenstrual symptoms. Is there a breast discharge suggestive of a prolactinoma? Are there symptoms of any other hormonal syndrome, such as hypothyroidism? (See Chapter 49.) Are there any symptoms that might suggest an intracranial tumor, such as significant headaches or loss of peripheral vision?
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Patent Vagina Some Secondary Sexual Development History Physical exam, pregnancy test Serum prolactin, TSH (if abnormal, continue through flow diagram; also see Table 30-9) Serum FSH (if low estrogen state suspected) Progestin challenge + Progestin challenge (menstruationlike bleeding) Chronic anovulation (estrogen present)
Progestin challenge (minimal or no bleeding) Low estrogen (or inability of uterus to bleed)
Not pregnant; unsure of exam for outflow patency and presence of normal uterus; or risk factors for Asherman syndrome
Hirsutism + Serum T and 17-OH-P [T] > 200 mg/dL → w/u for ovarian or adrenal tumor (CT or ultrasound)
Repeat progestin withdrawal after priming endometrium with estrogen, 1.25 mg Premarin x 21 days; add Provera, 10 mg, last 5 days _ bleed
Figure 30-7. General workup for amenorrhea. CT, computed tomography; FSH, follicle-stimulating hormone; LH, luteinizing hormone; 17-OH-P, 17-hydroxyprogesterone; T, testosterone; TSH, thyroid-stimulating hormone.
+ bleed
[17-OH-P] > 300 mg/dL → w/u for late-onset congenital adrenal hyperplasia (cortrisyn challenge test) Hypoestrogenism All normal or mildly ↑ Serum LH, FSH* Hirsutism with mild elevation of T is consistent with Elevated diagnosis of chronic anovulation LH >40 IU/L FSH>20 IU/L Chronic anovulation
Gonadal failure
Consider Cushing syndrome 1 mg overnight dexamethasone suppression test * May be falsely suppressed by recent estrogen therapy; wait 2 weeks to check. Rarely a girl with high androgen levels will have an atrophic endometrium (despite estrogen presence) and will not bleed.
Physical Examination General appearance, pulse, and blood pressure should be noted. Vital signs may be depressed in anorexia nervosa and other starvation states. Weight and height should be plotted on a growth chart. Vision and fundi must be checked carefully. Secondary sexual characteristics may be undeveloped (delayed puberty), normal, or abnormal (hirsutism). Sexual maturation staging (see Chapter 59), observation
Endometrial or outflow tract abnormality (or noncompliance)
Low or normal
Image pituitary/ hypothalamus to rule out tumor and Kallman syndrome Normal Hypothalamic dysfunction
for evidence of hirsutism or virilization, nipple expression to check for galactorrhea, and palpation of the thyroid are performed. The abdomen should be examined to identify a pelvic mass, which may indicate hematocolpos or pregnancy. On pelvic examination, external genitalia should be observed for estrogen effect. Are the tissues pink, moist, and full, or red, thin, and atrophic? Is the vagina patent? Is the cervix visible or at least palpable?
Chapter 30 Menstrual Problems and Vaginal Bleeding Table 30-9. General Workup for Amenorrhea in Girls
with Normal Anatomy and Some Secondary Sexual Development Visit 1 From History and Physical Examination 1. Some secondary sexual development (for pubertal delay, see Chapter 59) 2. Patent vagina 3. Cervix seen or palpated 4. Uterus palpated or visualized by ultrasonography Suspect Inadequate Hormonal Stimulation to Endometrium 1. Assess estrogen status, prolactin, and thyroid function a. Serum PRL, thyroid-stimulating hormone (TSH) b. Serum follicle-stimulating hormone (FSH) if hypoestrogenic state is suspected c. For assessment of estrogen status, perform progestin challenge Schedule Next Visit in 3-4 Weeks Visit 2 Review Results of PRL and TSH 1. ↑ PRL (or any galactorrhea) requires evaluation for pituitary adenoma; CT with contrast or MRI is needed to check for pituitary tumor; many medications can lead to elevation of PRL (see table 30-4); any elevation of PRL can lead to ovulatory dysfunction 2. ↑ TSH necessitates assessment of free T4; if hypothyroid, thyroid hormone replacement may completely resolve ovulatory dysfunction 3. Even if PRL or TSH levels are abnormal, continue workup to identify where the patient’s condition falls in the spectrum of ovulatory dysfunction (see Fig. 30-7) Review of Response to Progestin Challenge 1. Was there menstruation-like bleeding? 2. Follow flowsheet to identify hormonal state of the patient (see Fig. 30-7) 3. Remainder of care plan depends on the hormonal state (normal versus low estrogen) and on the compartment that has caused the problem
507
Evaluation of the Hypothalamic-Pituitary-Ovarian Axis Laboratory Studies and the Progestin Challenge (see Fig. 30-7)
After obtaining the history and physical examination results, the examiner should assess for hypothyroidism and prolactinoma with serum levels of thyroid-stimulating hormone (TSH) and prolactin. At the same time, an assessment of the estrogen status of the patient is performed. Because single blood estrogen levels are unreliable, physiologic testing is done by progestin challenge. Progestins cause bleeding only if the endometrium is in a proliferative state, primed by prior estrogen exposure. The progestin challenge test is positive if menstruation-like bleeding occurs within 2 weeks after treatment with 5 days of 5 to10 mg of oral medroxyprogesterone acetate or any equivalent dose of a progestin. Progestin Challenge Results
Bleeding that occurs after the progestin challenge proves that there is a functional uterus and outflow tract. The amount of bleeding is approximately proportional to the amount and duration of prior estrogen exposure. If bleeding is similar to a menstrual period, the patient’s condition belongs to the category of chronic anovulation with an estrogenized endometrium. Failure of the progestin challenge to lead to menstruation-like bleeding indicates a low-estrogen state or the inability of the uterus to demonstrate bleeding. If the patient may have been pregnant for a few days at the time of the progestin challenge, the pregnancy test should be repeated 2 weeks later. If the pelvic findings are entirely normal and the patient has no historical risk factors for Asherman syndrome, her condition belongs to the category of hypogonadism (hypoestrogenic amenorrhea). If there is any question of the ability of the uterus to bleed, progestin withdrawal should be repeated after priming the endometrium with estrogen. Although the general rule is that failure to bleed after progestin withdrawal indicates a low estrogen state, there is one rare exception. A few girls with very high androgen levels, as may be seen in polycystic ovarian syndrome or late-onset congenital adrenal hyperplasia, may have an atrophic endometrium (and failure to have a withdrawal bleed after progestins) despite the presence of estrogen. Severe hirsutism is not usually seen with true low-estrogen states.
CT, computed tomography; MRI, magnetic resonance imaging; PRL, prolactin.
THINGS NOT TO MISS
On bimanual examination (see Fig. 30-4), if the uterus is palpable, is it normal in size or prepubertal? Are the ovaries palpable? If the digital examination and speculum examination are not tolerated, the vagina can be probed with a saline-moistened swab to determine its length. On rectovaginal or rectoabdominal examination, are there any masses consistent with hematometria or hematocolpos? If there is evidence of an obstructed or absent vagina, a rectoabdominal examination can be performed to check for a mass and to identify the uterus if present. Ultrasonography is helpful in corroborating the physical examination findings. In girls without pubertal development, estrogen levels are always low. Visualization of the cervix in these cases is not as important as it is in the pubertal adolescent with delayed menarche, because abnormal anatomy is rarely found. The cause of the delay is almost always hypothalamic, pituitary, or ovarian. In the postpubertal girl, if the physical examination demonstrates normal female external genitalia and a patent vagina with visualization or palpation of the cervix, the workup can then progress to the general evaluation for amenorrhea. The cause is usually in the HPO axis.
The examiner must never forget that the most common cause of amenorrhea in the general population is pregnancy. The examiner needs to obtain a private history, earn the patient’s confidence, and provide confidentiality if it is requested. When the diagnosis is in doubt, a pregnancy test should be conducted even if the patient does not admit to sexual activity. Commercially available urine pregnancy tests turn positive by the first missed period. In rare cases, women with abnormal pregnancies (ectopic and those about to miscarry) have hCG levels too low to detect in the urine. A blood hCG level is diagnostic. TREATMENT OF AMENORRHEA End-Organ and Outflow Tract Anomalies In all cases of outflow obstruction, it is important to allow menstrual blood to escape, because failure to do so can lead to severe endometriosis and scarring of the reproductive organs. The procedure may be as simple as hymenotomy, or it may involve complicated vaginal and cervical reconstruction. All efforts should be made to preserve reproductive function.
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If the uterus is absent, as in müllerian agenesis and androgen insensitivity syndrome, treatment is aimed at creating adequate vaginal depth for satisfactory sexual intercourse once that is desired. These procedures are best held off until the patient is mature and motivated, because they entail the patient’s taking responsibility for ongoing dilation of her vagina. The presence of a Y chromosome, as in androgen insensitivity syndrome, necessitates surgical gonadectomy to prevent malignancy. Estrogen replacement therapy is then necessary. Hormonal Causes of Amenorrhea If the underlying cause is identified, such as hypothyroidism, obesity, or an eating disorder, treatment should be aimed at the specific problem. Often, however, a specific cause is not found or is not easily treated. Regardless of cause, hormonal replacement is indicated in order to improve self-image and to prevent the sequelae of untreated sex hormone abnormalities (Table 30-10). In general, hypoestrogenic states necessitate estrogen-progestin hormone replacement therapy or oral contraceptives to complete pubertal development, to prevent vaginal atrophy, and to possibly help avert osteoporosis. Patients with chronic anovulation require cycling with 12 days of progestins at least every 2 or 3 months to bring about withdrawal bleeding. This helps prevent excessive bleeding, endometrial hyperplasia, and cancer. An alternative treatment is oral contraceptives, or equivalent treatment with the contraceptive patch or vaginal ring, which have the added benefit of suppressing ovarian androgens (thus ameliorating hirsutism) and providing contraception. The length of time to
continue therapy depends on whether spontaneous cycles can be expected to resume. In the obese girl with PCOS, a modest weight loss of 20 to 30 pounds often leads to resumption of ovulatory cycles.
DYSMENORRHEA Dysmenorrhea is defined as crampy lower abdominal or low back pain temporally associated with menstruation. It is a common problem that causes much suffering and interferes in some cases with school attendance. In one study, 60% of 12- to 17-year-old girls reported some dysmenorrhea; 14% frequently missed school. Dysmenorrhea is categorized as either the very common primary dysmenorrhea, associated with no clinically detectable pelvic pathologic process, or the much less common secondary dysmenorrhea, caused by an underlying pelvic abnormality. Primary dysmenorrhea usually begins with the onset of menstrual flow and lasts from hours to a few days. The cramping may be accompanied by nausea, vomiting, diarrhea, and/or headache. Primary dysmenorrhea begins when the cycles become ovulatory, usually by the third postmenstrual year. MECHANISM OF PRIMARY DYSMENORRHEA Primary dysmenorrhea by definition is not associated with clinically discernible pelvic pathology. The pain results from uterine contractions caused by high levels of prostaglandins originating in the premenstrual secretory endometrium. Women with dysmenorrhea
Table 30-10. Hormone Replacement Options for Amenorrheic Conditions* Hormone Replacement
Chronic anovulation (estrogen present)
Hypogonadism (low-estrogen state)†
Benefits of Therapy
Progestin therapy with medroxyprogesterone acetate, 5-10 mg/day PO or 5 mg norethindrone acetate 12 days/ month every 1-3 months
Diminishes risk of sudden menorrhagia and of endometrial hyperplasia/ cancer later in life; creates predictable normal menses
Low-dose oral contraceptive pills (20-35 μg of estrogen) or contraceptive patch
Same as for progestin therapy; provides contraception; improves hirsutism by suppressing ovarian androgens
Oral medroxyprogesterone acetate 5-10 mg/day or 2.5-5 mg norethindrone acetate on days 1-12 of the month (by calendar) plus oral conjugated estrogens, 0.625 mg/day
Prevents osteoporosis,‡ heart disease, and atrophic vaginal changes; eliminates hot flashes if present
Low-dose oral contraceptive pills (20-35 μg of estrogen)
Same as HRT; provides contraception in case of spontaneous ovulation (if that is a possibility); many adolescents prefer taking oral contraceptives to taking “medications”
*These options may need modification according to the individual’s response. †
See Chapter 59 for treatment of pubertal delay.
‡
Estrogen therapy may not prevent bone loss in girls with amenorrhea and low body weight.
HRT, hormone replacement therapy.
Risks of Therapy
Some premenstrual symptoms may occur while the patient is taking progestin; does not provide contraception or address cause of amenorrhea; does not suppress androgens to treat hirsutism Does not address cause of amenorrhea; some parents object to their daughters’ taking oral contraceptives; side effects can include nausea, headache, and breakthrough bleeding Does not address cause of amenorrhea; does not provide contraception (if ovulation is possible, given the diagnosis); premenstrual symptoms may occur while the patient is taking progestins; some adolescents prefer oral contraceptives to “medications” Same as risks of oral contraceptives for chronic anovulation
Chapter 30 Menstrual Problems and Vaginal Bleeding have greater resting uterine tone during menses and more severe contractions than do asymptomatic controls. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) diminishes these objective findings as well as the sensation of cramps. Systemic release of prostaglandins probably accounts for the other symptoms, such as nausea and diarrhea, often seen with primary dysmenorrhea. Because progesterone from the postovulatory corpus luteum induces the change from a proliferative to a secretory endometrium, primary dysmenorrhea occurs only in ovulatory cycles. Anovulatory bleeding may cause cramping as a clot passes through the cervix, but as a rule it is not associated with pain. SECONDARY DYSMENORRHEA A small percentage of adolescents with menstrual pain have underlying pathologic processes. Table 30-11 presents the differential diagnosis of menstrual pain.
509
EVALUATION OF DYSMENORRHEA History Routine inquiry enables girls who are suffering from dysmenorrhea to get treatment. It is important to assess the timing of pain, the degree of disruption of daily routines, the associated symptoms, the response to over-the-counter medications, and the sexual history. The history helps to differentiate primary from secondary dysmenorrhea. Dysmenorrhea associated with one specific menstrual period in a sexually active adolescent suggests a pregnancy complication or pelvic inflammatory disease (PID). Menstrual pain beginning at menarche or at any other time during which the cycles are believed to be anovulatory suggests outflow tract obstruction, because anovulatory bleeding does not cause primary dysmenorrhea. Endometriosis may be difficult to diagnose because its manifestation may be similar to that of primary dysmenorrhea. However, endometriosis that is diagnosed in the adolescent is often associated with intermittent,
Table 30-11. Differential Diagnosis of Dysmenorrhea
Description of Pain
Primary
Secondary Congenital partial outflow obstruction (e.g., rudimentary uterine horn, obstructed hemivagina) Endometriosis
Atypical secondary dysmenorrhea Pelvic inflammatory disease Pregnancy complication
Occurrence of Dysmenorrhea in Anovulatory Cycles
Diagnosis
Treatment
Crampy lower abdominal/ low back pain ± radiation to upper thighs ± nausea, vomiting, diarrhea, headache; begins at time of menstrual flow; lasts 1-3 days
No
Normal abdominal and pelvic examination; internal pelvic examination can be reserved for sexually active girls and older teenagers; rectoabdominal examination assesses pelvic pathology
NSAIDs and/or oral contraceptives; see Table 30-12
Pain begins at or shortly after menarche and occurs with bleeding
Yes
Pelvic examination ± ultrasonography ± laparoscopy; found in 8% of adolescents who underwent laparoscopy for pain
Surgical relief of obstruction
Increasingly severe dysmenorrhea ± chronic pelvic pain exacerbated during menses
No
Found in 16% to 70% of adolescents who underwent laparoscopy for pelvic pain; pelvic examination finding may be normal or there may be tenderness of the uterosacral ligaments/cul-de-sac and/or ovarian masses; although congenital obstruction of menstrual outflow increases chance of endometriosis, most teenagers with endometriosis have normal anatomy; diagnosis is by laparoscopy
Surgical and/or hormonal therapy; post-treatment prophylaxis with oral contraceptives
Pain during or immediately after menses
Yes
Follow CDC recommendations (see Chapter 29)
Pain and bleeding may coincide and may be interpreted by the patient as a painful menstrual period
N/A
Pelvic examination: tender uterus and adnexa, ± cervicitis, ± ↑ WBC count, ± ↑ ESR, ± fever UCG, or serum hCG
See Figure 30-6
CDC, Centers for Disease Control and Prevention; ESR, erythrocyte sedimentation rate; hCG, human chorionic gonadotropin, N/A, not applicable; NASIDs, nonsteriodal anti-inflammatory drugs; UCG, urinary chorionic gonadotropin; WBC, white blood cell.
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non–menstrually related pelvic pain that worsens before and during menses. Examination and Testing In the evaluation of dysmenorrhea, an internal pelvic examination can be reserved for girls who are sexually active, for older adolescents, for girls who do not respond to standard treatment with NSAIDs or oral contraceptives, and for those with atypical manifestations. If necessary, a rectoabdominal examination or ultrasound study can diagnose a pelvic mass and may be better tolerated than vaginal examination in young virginal adolescents. If the pain is associated with one particular period, pregnancy and PID should be ruled out. PID is a clinical diagnosis based on history, vital signs, abdominal and pelvic examination, and white blood cell count (see Chapter 29). The goals of treatment of endometriosis in an adolescent with dysmenorrhea include alleviation of pain and, if possible, prevention of progression of the disease. If endometriosis is suspected on the basis of tenderness on pelvic examination or failure to respond to NSAIDs and oral contraceptives, the benefits of laparoscopy to make the diagnosis should be weighed against the risks. For adult patients in whom the history strongly suggests endometriosis, some experts recommend empirical treatment with GnRH analogues, rather than starting with laparoscopy. This may also be an efficacious and costeffective approach for adolescents. TREATMENT OF DYSMENORRHEA (Table 30-12) NSAIDs work by decreasing production of prostaglandins in the endometrium. About 80% of women with primary dysmenorrhea obtain relief of pain and the associated gastrointestinal symptoms with most NSAIDs. Oral contraceptives are successful in diminishing primary dysmenorrhea by inducing atrophy of the endometrium; the result is decreased production of prostaglandins. Because this effect may take 3 or 4 months to develop, NSAIDs should be offered concurrently for the first few treatment cycles. Low-dose oral contraceptives, if not contraindicated, are the treatment of choice for dysmenorrhea in sexually active adolescents requiring contraception. Acupuncture, transcutaneous electrical nerve stimulation, supplemental ω-3 fatty acids, and calcium antagonists have also shown some promise in treating primary dysmenorrhea.
examiner also should not mistake acute pelvic pain with vaginal bleeding for dysmenorrhea but should consider pregnancy complications and PID in the differential diagnosis of sudden onset of “menstrual” pain. The practitioner should consider endometriosis and/or congenital anomaly with partial menstrual outflow obstruction in cases of severe dysmenorrhea with abnormal pelvic findings, poor response to the usual therapies, or generalization of pelvic pain beyond the time of the menstrual flow.
VAGINAL BLEEDING IN THE PREPUBERTAL CHILD Vaginal bleeding is abnormal in white girls younger than 8 and in girls of African descent younger than 7. It is always abnormal in the absence of secondary sexual characteristics. Although childhood vaginal bleeding is uncommon, it can be caused by serious problems such as intracranial tumors, vaginal malignancy, and sexual abuse. The source of bleeding in a young girl can be the lower genital tract or the uterus.
ETIOLOGY In a child without signs of puberty, a vulvovaginal source of bleeding is most likely. Common causes within this category include vaginal foreign body, infectious vulvovaginitis, urethral prolapse, vulvar injury, and lichen sclerosus. There are also some common vulvovaginal conditions that only rarely manifest with bleeding. In condyloma acuminatum, mild vulvar trauma or secondary infection can lead to bleeding. During a pinworm infestation, scratching can result in bleeding excoriations. Uncommon lower genital tract conditions, including vaginal or cervical malignancy, vaginal polyps, and hemangiomas of the vagina, vulva, or cervix, can manifest with vaginal bleeding. Although malignancy is rare, it was found in 12% to 21% of the patients in published series of cases of early childhood vaginal bleeding and must not be missed. Except for a small amount of endometrial bleeding as the newborn withdraws from relatively high fetal levels of estrogen, uterine bleeding is always pathologic in childhood. Possible causes include ●
SUMMARY AND THINGS NOT TO BE MISSED
● ●
The examiner should not miss the opportunity to treat the adolescent with primary dysmenorrhea who is suffering in silence. The
●
precocious puberty isolated premature menarche autonomous estrogen secretion from either an ovarian or adrenal tumor exposure to exogenous estrogen
Table 30-12. Treatment of Primary Dysmenorrhea Medication
NSAID
Oral contraceptives or contraceptive patch
Regimen
Ibuprofen, 200 mg Naproxen sodium, 275 mg Naproxen sodium, 550 mg Mefenamic acid, 250 mg
2 tablets PO q4-6h 2 tablets to start, then 1 PO q6h 1 tablet PO q12h 2 tablets to start, then 1 PO q6h
Any low-dose pill (≤35 μg of estrogen) or ortho Evra
Cyclic
Comments
Over-the-counter 12-hr regimen is appealing to patients Suggested in some studies as most effective drug Particularly useful if birth control method is needed; a few cycles may be needed to reach maximum effectiveness
*Aspirin has not been shown to be better than placebo in the treatment of primary dysmenorrhea. NSAID treatment is effective if started at the onset of cramping and bleeding. NSAID, nonsteroidal antiinflammatory drug; PO, per os (orally).
Chapter 30 Menstrual Problems and Vaginal Bleeding Vulvovaginal Sources of Bleeding (Table 30-13 and Fig. 30-8) Vaginal Foreign Body
Vaginal bleeding is more predictive of vaginal foreign body than is vaginal discharge. The chief complaint of vaginal bleeding without discharge results in the finding of vaginal foreign body in 50% of cases. In contrast, if the bleeding is associated with vaginal discharge, there may be less than a one-in-five chance of finding a foreign body. Usually the foreign body consists of a small wad of what appears to be toilet paper or other fibrous material. This is neither palpable on rectoabdominal examination nor visible on a sonogram or radiograph. Other items, such as small toys, pen tops, and safety pins have been reported. The child usually does not recall or admit to placing the foreign object in the vagina. How did the foreign material get into the vagina? The prepubertal hymen is acutely and uncomfortably sensitive to touch, and normal masturbation in girls is thought to involve clitoral and labial manipulation, with less than 1% of girls engaging in vaginal or anal penetration. Among girls referred from a general outpatient pediatric practice to a child gynecology clinic who were subsequently found to have vaginal foreign bodies, most met criteria for confirmed sexual abuse. The approach to evaluation of the girl with a vaginal foreign body needs to include an assessment for the possibility of sexual molestation (see Chapter 36). A screening interview of the child alone with a trained professional and cultures for sexually transmitted infections are indicated. Infectious Vulvovaginitis
Vulvovaginitis most commonly manifests with discharge or irritation, but vaginal bleeding is sometimes reported. Although most vulvovaginitis is caused by irritants or mixed bacteria, vaginal bleeding is most commonly seen in single-organism infections with group A streptococci, Shigella species, and, on occasion, gonococci. Diagnosis is made from visualization of vaginal discharge and from culture yielding a specific pathogen. The treatment for bacterial vulvovaginitis includes either culture-driven or broad-spectrum systemic antibiotic therapy and local hygiene measures, such as sitz baths, wiping from front to back after defecation, and appropriate hand washing. Urethral Prolapse
Urethral prolapse is an eversion of the urethral mucous membrane through the meatus. Careful examination reveals red, friable, and sometimes necrotic tissue at the urethra, which is occasionally mistaken for cervical prolapse or a vaginal tumor. Many approaches to treatment have been reported. Local care with sitz baths is often all that is needed. Topical estrogen cream or antibiotics have been used. Surgical resection of the mucosa can be reserved for cases in which initial treatment fails or when bleeding or necrosis is severe. Trauma
Vulvovaginal trauma in girls is usually caused by straddle injury. Other reported mechanisms of injury include vaginal penetration and tearing resulting from sudden forced stretching of the perineum from leg abduction. Evaluation of the child with vulvovaginal trauma requires a detailed history of how the injury occurred, with attention to the consistency and plausibility of the story. The hymen is lacerated only if the injury involved penetration into the vagina. A suspicion of sexual abuse requires a report to the proper authorities and evaluation of the ongoing safety of the child (see Chapter 36). A vulvar laceration that is bleeding but that can be completely visualized is treated with ice packs, pressure, and suturing if necessary. Vulvar hematomas are common and usually self-limited
511
as tissue pressure controls continued expansion. Hematomas with overlying lacerations often develop bacterial cellulitis. A surgical approach with evacuation of the hematoma and ligation of bleeding vessels can be reserved for situations in which the hematoma is very large or continues to expand. If the bleeding points cannot be isolated, the hematoma cavity can be packed for 24 hours. If the apex of the laceration cannot be seen, examination with the patient under sedation or general anesthesia is necessary to assess for trauma to the hymen or vagina. Hymenal laceration implies that the injury has penetrated the vagina. Because the vaginal wall is very thin, penetrating vaginal injuries often extend into adjacent structures. If the laceration extends to the vaginal apex, exploratory surgery is necessary to exclude extension into the peritoneal cavity. If hematuria is found, cystourethrography is recommended to evaluate the bladder and urethra. Urethral obstruction from a hematoma may necessitate suprapubic catheter placement. Home care after initial treatment of vulvar injury includes ice packs for 6 hours, followed by warm sitz baths two to three times a day to promote comfort and help prevent secondary infection. Malignancy
Vaginal or cervical botryoid sarcoma (embryonal rhabdomyosarcoma) can manifest as a grapelike mass that is visible at the introitus. Endodermal sinus tumor has a similar appearance. The diagnosis of these malignancies is made from biopsy. Because these tumors grow below the epithelium of the vagina, superficial biopsy may not be diagnostic. Vaginal clear cell adenocarcinoma is rare and should become even more so as the cohort of women exposed to diethylstilbestrol (DES) in utero continues to age. DES was taken off the market in 1972, and the youngest people exposed in utero are now in their 30s. Vaginal adenocarcinoma is occasionally seen in girls who were not DES-exposed. Lichen Sclerosus
Lichen sclerosus is a hypotrophic dermatologic condition often found in the vulvar area. It appears as a thinning of the skin to a parchmentlike appearance. The classic appearance is of an hourglass surrounding the introitus and anus. As a result of the thinness of the epidermis, minor trauma can lead to significant bleeding and subepithelial bruising. Lichen sclerosus has been misdiagnosed as fungal infection, hemangioma, sexual abuse, and severe vulvar trauma. The diagnosis is usually clinical, based on the characteristic appearance, but biopsy can confirm the diagnosis if necessary. Uterine Sources of Vaginal Bleeding If the external examination and vaginoscopy do not demonstrate a vulvovaginal source of bleeding, uterine bleeding should be suspected. Other indications that the source may be uterine include growth spurt, secondary sexual development, ovarian cyst, abdominal tumor, or risk factors for precocious puberty, such as previous cranial irradiation or stigmata of McCune-Albright syndrome. Except for the occasional neonatal estrogen withdrawal bleeding, all uterine bleeding in children is pathologic, usually indicating estrogen effect on the endometrium. Serious underlying conditions, including brain tumor and malignant ovarian tumor, may yield no signs or symptoms other than vaginal bleeding at presentation. Causes of uterine bleeding in children are categorized in the following sections (Fig. 30-9) (see Chapter 59). Precocious Menarche
Cyclic menses with no other secondary sexual characteristics has been termed precocious menarche. The cause is not known, but it is
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Section Four Genitourinary Disorders
Table 30-13. Causes of Lower Genital Tract Bleeding in Girls Diagnostic Features Common Causes Vaginal foreign body
Infectious vulvovaginitis
Urethral prolapse
Lichen sclerosus
Trauma
Malignancy Sarcoma botryoides (embryonal rhabdomyosarcoma of vagina or cervix) or endodermal sinus tumor of vagina Adenocarcinoma of vagina or cervix
Uncommon Causes Human papillomavirus
Pinworms (Enterobius vermicularis) Hemangiomas of lower genital tract
Vaginal bleeding with or without discharge; usually a wad of toilet paper or other fibers; case reports of small toys, pen tops, safety pins; may be seen on unaided visual examination especially when patient is in the knee-chest position; vaginoscopy* is “gold standard” to make diagnosis and to rule out additional masses in vagina Vaginal discharge usually reported; may follow URI (group A streptococci) or diarrheal episode (Shigella); vulva may look reddened from primary infection or from irritating secretions; wet preparation shows white blood cells; vaginal culture may grow specific organism Careful examination demonstrates red edematous or necrotic mass encircling urethral meatus; vagina can be identified posterior to mass; sometimes occurs after hard Valsalva maneuver; age range: 5-9 yr Vulvar ecchymoses and abrasions may be seen with minimal trauma; characteristic white parchment-like thin skin, often in hourglass symmetric pattern around introitus/anus; biopsy is diagnostic but unnecessary when lesion is characteristic; some cases improve at puberty Evaluate for possibility of neglect or abuse to determine whether it is safe for patient to be discharged home Straddle injury: evaluate extent of lacerations/ stability of hematoma Penetrating injury: evaluate extent of injuries and perform EUA; perform laparotomy or laparoscopy if wound extends to vaginal apex; evaluate bladder and rectum if laceration extends into vagina or if urine or stool test is positive for blood
Management
Removal of foreign body usually resolves bleeding/ discharge; persistent or recurrent bleeding is suggestive of additional foreign material; possibility of sexual abuse should be considered
If no response to local hygiene measures and specific antibiotics, consider EUA or vaginoscopy to look for another cause (e.g., foreign body) Sitz baths with or without estrogen cream or oral or topical antibiotics; usually effective within 2 weeks; urethral catheterization if patient cannot void; resection or cautery of mass with anesthesia if local care fails or if patient is symptomatic or tissue is necrotic Recommend good hygiene, prevention of trauma (e.g., loose clothes, padded bicycle seat); no treatment needed in asymptomatic patients; topical corticosteroids can diminish irritation EUA needed when injuries are more than minor; small vulvar hematoma; pressure, ice pack, rest, and evaluation of size stability; large or expanding hematoma: incision or evacuation of clots and ligation of visible vessels or pack; repair lacerations; careful evaluation for abuse or neglect necessary
Grapelike mass protruding from vagina; peak age, 2 yr (90% < 5 yr); biopsy is diagnostic, but tumor is below epithelium (can be missed); full staging required
Initial treatment is chemotherapy followed by surgery or radiation; exenteration is no longer standard first-line care
Vaginoscopy with biopsy; staging required; expect incidence in children to diminish because most adenocarcinomas of the vagina occurred in girls exposed to DES in utero and DES has been off the market for more than 30 years
Radical surgery
Lesions can be single or multiple, 1 mm to large cauliflower-like masses, flesh-toned or pink or white; abrasion or secondary infection with ulceration can lead to vulvar bleeding
Evaluate for sexual abuse especially if diagnosed after age 2 years; for small vulvar condylomata, office podophyllin or TCA Large or resistant to treatment: laser ablation under general anesthesia; recurrence rate: 25% Cervical/vaginal lesions: laser in operating room with patient under general anesthesia; colposcopy with biopsy if indicated Mebendazole; evaluate family members, classmates, and playmates; clean and trim patient’s fingernails Treatment can be withheld if no symptoms; many spontaneous regressions; successful reported treatments include surgical excision, laser ablation, topical estrogen, and systemic corticosteroids
Transparent tape (Scotch tape) test shows eggs; flashlight examination at night can show worms at vagina or anus Urethral, vulvar, vaginal, and cervical hemangiomas have been reported; appear purple or dark-red and soft; blanching occurs with pressure; overlying epithelium is usually intact, but bleeding occurs when trauma leads to ulceration; biopsy, if done, should be in hospital with blood replacement available
*Vaginoscopy: With the availability of fiberoptics, visualization of the full length of the vagina can be performed with only a 3- to 5-mm-diameter instrument. A hysteroscope or cystoscope with saline as the distending medium is ideal. In a cooperative child, fiberoptic vaginoscopy can be accomplished in the office. A nasal speculum can be substituted, if necessary, during examination of prepubertal girls under anesthesia. DES, diethylstilbestrol; EUA, examination under anesthesia; TCA, trichloroacetic acid; URI, upper respiratory infection.
Chapter 30 Menstrual Problems and Vaginal Bleeding
513
Child < 8 Years with Vaginal Bleeding
History: Pattern of bleeding (how long? how often? how much?) Estrogen exposure Pubertal symptoms Sexual abuse or injury Vulvovaginal symptoms Family history (including age at menarche) Office physical exam: Height/weight growth charting Sexual maturation rating (Tanner stage) Abdominal exam—mass External genitalia—lesion, estrogenization Distal vagina—discharge, foreign body (including knee-chest position) ± Rectal exam—mass, palpable foreign body
No signs of puberty
Some sign of estrogen effects or puberty
Obvious vulvovaginal diagnosis
Diagnosis not obvious
See Table 30-13
Bone age or cytologic maturation index of vaginal cells
Identify any source of exogenous estrogen
Figure 30-8. Evaluation of vaginal bleeding in girls younger than 8 years or without signs of puberty. CT, computed tomography.
Work-up for precocious puberty (see Fig. 30-9)
Culture of any vaginal discharge Vaginoscopy for foreign body or visible bleeding site Rectoabdominal exam Examination under anesthesia
Diagnosis made or Lesion seen and biopsy performed
See Table 30-13
Estrogen effects found on bone age or vaginal cells
Pelvic mass, no estrogen effects
See Fig. 30-9
Radiologic imaging with ultrasound or CT
Exam results entirely normal
Consider pelvic ultrasound, work-up for precocious menarche vs. early precocious puberty: serial height and bone age
If uterine mass present, surgical referral needed
considered a rare form of incomplete precocious puberty. In these children, there is a small increase in serum estrogen levels that does not lead to short stature. Gonadotropin levels are prepubertal. After other sources of vaginal bleeding are ruled out by examination with anesthesia and vaginoscopy, growth rate and/or bone age can be monitored over months to ensure that menstruation was not an early sign of precocious puberty. In precocious menarche, normal adult height and fertility are achieved.
Complete Precocious Puberty
In complete precocious puberty, more than one manifestation of puberty has occurred. Growth acceleration and breast development may precede uterine bleeding, but the sequence of pubertal events may be disordered, with uterine bleeding as the initial finding. Adrenarche may or may not coexist. The menstrual bleeding may be
Section Four Genitourinary Disorders
514 No history of iatrogenic estrogen exposure
Serum gonadotropins (FSH, LH, hCG)
GnRH stimulation test if results unclear
b. estrogen-secreting tumors of the ovary or adrenal gland c. apparent autonomous function of the ovary (McCune-Albright syndrome, follicular cysts of the ovary) 3. gonadotropin and gonadotropin-like molecules (e.g., hCG) not derived from maturation of the HPO axis 4. mixed peripheral and central precocious puberty
Bone age
Other Causes of Uterine Bleeding in Children
(Serum estradiol probably unnecessary, since physical findings are bioassay and blood levels may fluctuate)
Retarded Pubertal level bone age/ gonadotropins hypothyroidism or response to GnRH stimulation test Serum TSH to confirm diagnosis
Gonadotropindependent precocious puberty* (see Chapter 59)
Work-up for intracranial lesion: neurology, ophthalmology, EEG, CT, or MRI
Normal exam findings or untreatable lesion
Abnormal exam findings or test results
Treat lesion Consider GnRH if possible analog to retard pubertal changes and improve adult Solid or height (see mixed Chapter 59) ovarian tumor
Surgery
Low gonadotropins
hCG present; not pregnant
Repeat history to look for exogenous source of estrogen
Work-up for ovarian tumor
Physical exam for stigmata of McCuneAlbright* (bony abnormalities, café-au-lait skin macules)
Uterine malignancy is extremely rare in children. Findings include no secondary sexual characteristics and irregular bleeding whose source is in the uterus. A preliminary diagnosis is made from abdominal or rectal examination, hysteroscopic examination with the patient under general anesthesia, or ultrasonography. Full staging and treatment are carried out according to oncology protocol. EVALUATION (see Figs. 30-8 and 30-9) History The history is used to differentiate vulvovaginal from uterine causes of bleeding. The pattern of bleeding (how long, how often, how much), previous vulvovaginal symptoms or trauma, and any possibility of sexual abuse must be addressed. Evidence of estrogen effects, including growth spurt, known estrogen exposure, and family history of precocious puberty, should be sought.
Consider skeletal survey or bone scan
Physical Examination
Abdominal or rectoabdominal exam for mass (ovarian or adrenal) Consider abdominal imaging with ultrasound or CT Pelvic or abdominal mass
Ovarian cyst: may be transient
Adrenal tumor
Consider close follow-up: cystectomy if surgery needed
Surgery
*Follicular cysts are often found with true precocious puberty and with McCuneAlbright syndrome. Surgical treatment is not effective at ameliorating pubertal development in these syndromes.
Figure 30-9. Evaluation of uterine bleeding in a child with estrogen effects or other pubertal findings. CT, computed tomography; EEG, electroencephalography; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging; TSH, thyroidstimulating hormone.
anovulatory or ovulatory. Causes of complete precocious puberty (see Chapter 59) are as follows: 1. central or gonadotropin-dependent precocious puberty 2. peripheral or gonadotropin-independent pseudoprecocious puberty a. exogenous estrogen
The general physical examination includes height, weight, sexual maturation rating (formerly known as Tanner staging) with particular attention to breast budding, and abdominal examination. External genitalia should be visualized in the frog-leg position, which can be done with the patient semisitting on an examination table, in stirrups, or in the parent’s lap. Vulvar lesions are noted. Is there evidence of estrogen effect? Is there vaginal discharge of fluid, pus, or blood? The knee-chest position may allow better visualization of the vaginal walls. Specimens for culture, if indicated by signs of vaginitis, can be obtained by small calcium alginate swab (Calgiswab), by nonbacteriostatic saline lavage with an eyedropper, or by the catheter-within-a-catheter technique of Pokorny. Cotton swabs are abrasive as they pass through the hymen and should be avoided. The rectoabdominal examination can assess for a pelvic mass. Further examination and testing are determined by findings. The genital examination can be frightening for children. Time spent developing rapport, engendering the child’s trust, and assuring the child (truthfully) that she can stop the examination at any time pays off when the examination is completed. The examiner should give as much control as possible, such as letting the child choose who will be in the room and decide whether she wants to climb up to the table or be lifted by her parent. Sometimes an adequate result can be obtained with the girl herself separating the labia and keeping the examiner’s hands off. Physicians need to reinforce for her that when it comes to her private parts, “no means no,” even in the doctor’s office. That said, distraction often works well. If the child is not able to allow an office examination, she can be examined under sedation or anesthesia, if necessary. Summary and Things Not to Miss In the list of causes of vulvovaginal bleeding, the most concerning possibilities include malignancy and sexual abuse. Both diagnoses require a high index of suspicion and may mandate persistence on the part of the evaluator. When bleeding is uterine, the cause of the endometrial hormonal stimulation is most important. If the source of hormones cannot be eliminated, attention must be turned to ameliorating peripheral effects of early sex steroid exposure.
Chapter 30 Menstrual Problems and Vaginal Bleeding REFERENCES Normal and Abnormal Menstrual Bleeding in the Adolescent Gordon CM: Adolescent gynecology, part I—Common disorders: Menstrual disorders in adolescents: Excess androgens and polycystic ovary syndrome. Pediatr Clin North Am. 1999;46:519. Kadir RA, Economides DL, Sabin CA, et al: Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders. Haemophilia. 1999;5:40. Mitan LAP, Slap GB: Adolescent medicine: Adolescent menstrual disorders. Med Clinics North Am 2000;84:851. Speroff L, Glass RH, Kase NG: Dysfunctional uterine bleeding. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 575. Speroff L, Glass RH, Kase NG: Oral contraception. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 867. Speroff L, Glass RH, Kase NG: Regulation of the menstrual cycle. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 201. Amenorrhea Aiman J, Smentek C: Premature ovarian failure. Obstet Gynecol 1985;66:9. Byrne J, Fears TR, Gail MH, et al: Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788. Coney PJ: Effect of vaginal agenesis on the adolescent: Prognosis for normal sexual and psychological adjustment. Adolesc Pediatr Gynecol 1992;5:8. Glueck CJ, Wang P, Fontaine R, et al: Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS). J Adolesc Health 2001;29:160. Neinstein LS, Castle G: Congenital absence of the vagina. Am J Dis Child 1983;137:669. Reindollar RH, Byrd JR, McDonough PG: Delayed sexual development: A study of 252 patients. Am J Obstet Gynecol 1981;140:371. Russell JB, Mitchell D, Musey PI, et al: The relationship of exercise to anovulatory cycles in female athletes: Hormonal and physical characteristics. Obstet Gynecol 1984;63:452. Sabatini S: The female athlete triad. Am J Med Sci 2001;322:193. Speroff L, Glass RH, Kase NG: Amenorrhea. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 421. Speroff L, Glass RH, Kase NG: Anovulation and the polycystic ovary. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 487. Dysmenorrhea Bevan JA, Maloney KW, Hillery CA, et al: Bleeding disorders: A common cause of menorrhagia in adolescents. J Pediatr 2001;138:856. Davis AR, Westhoff CL: Primary dysmenorrhea in adolescent girls and treatment with oral contraceptives. J Pediatr Adolesc Gynecol 2001;14:3.
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Klein JR, Litt IF: Epidemiology of adolescent dysmenorrhea. Pediatrics 1981;68:661. Laufer MR, Groitein L, Bush M, et al: Prevalence of endometriosis in adolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol. 1997;10:199. Ling FW: Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93:51. Proctor ML, Roberts H, Farquhar CM: Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea. Cochrane Database Syst Rev 2001;(4):CD002120. Schroeder B, Sanfilippo, JS: Adolescent gynecology, part I—Common disorders: Dysmenorrhea and pelvic pain in adolescents. Pediatr Clin North Am 1999;46:555. Smith RP: Pressure-velocity analysis of uterine muscle during spontaneous dysmenorrheic contractions in vivo. Am J Obstet Gynecol 1989;160:1400. Speroff L, Glass RH, Kase NG: Menstrual disorders. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 557. Speroff L, Glass RH, Kase NG: Oral contraception. In: Clinical Gynecologic Endocrinology and Infertility, 6th ed. Baltimore, Lippincott Williams & Wilkins, 1999, p 867. Zhang WY, Li Wan Po A: Efficacy of minor analgesics in primary dysmenorrhoea: A systematic review. Br J Obstet Gynaecol 1998;105;780. Vaginal Bleeding in the Prepubertal Child Eberlein WR, Bongiovanni AM, Jones IT, et al: Ovarian tumors and cysts associated with sexual precocity. Pediatrics 1960;57:484. Friedrich WN, Grambsch P, Broughton D, et al: Normative sexual behavior in children. Pediatrics 1991;88:456. Herman-Giddens ME: Vaginal foreign bodies and child sexual abuse. Arch Pediatr Adolesc Med 1994;148:195. Hill NCW, Oppenheimer LW, Morton KE: The aetiology of vaginal bleeding in children: A 20-year review. Br J Obstet Gynaecol 1989;96:467. Imai A, Horibe S, Tamaya T: Genital bleeding in premenarcheal children. Int J Gynaecol Obstet 1995;49:41. Kellogg ND, Parra JM, Menard S: Children with anogenital symptoms and signs referred for sexual abuse evaluations. Arch Pediatr Adolesc Med 1998;152:634. Lyon AJ, DeBruyn R, Grant DB: Transient sexual precocity and ovarian cysts. Arch Dis Child 1985;60:819. Merritt DF: Evaluation of vaginal bleeding in the preadolescent child. Semin Pediatr Surg 1998;7:35. Paradise JE, Willis ED: Probability of vaginal foreign body in girls with genital complaints. Am J Dis Child 1985;139:472. Perlman SE: Management quandary. Premenarchal vaginal bleeding. J Pediatr Adolesc Gynecol 2001;14:135. Pokorny SF: Prepubertal vulvovaginopathies. Obstet Gynecol Clin North Am 1992;19:39. Richardson DA, Hajj SN, Herbst AL: Medical treatment of urethral prolapse in children. Obstet Gynecol 1982;59:69. Root AW: Precocious puberty. Pediatr Rev 2000;21:10.
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Ambiguous Genitalia
Jack S. Elder
the upper third of the vagina (see Fig. 31-1). In the absence of testosterone, the vestigial wolffian duct structures remain as the Gartner duct and the epoophoron and paroophoron. The external genitalia start developing via a common pathway from the cloacal folds in the third week of gestation, modifying into the urogenital sinus, the genital tubercle, the urethral folds, and the genital (labioscrotal) swellings (see Fig. 31-2). Dihydrotestosterone (DHT) is the active hormone that stimulates the development of the male external genitalia. Testosterone is converted into DHT by the 5α-reductase enzyme, which is present in cells in the urogenital sinus. Intracellular DHT binds to the androgen receptor, causing the genital tubercle and the urethral plate to elongate into the phallus. By the third month of gestation, the urethral folds fuse in the midline to form the urethra, and the genital swellings fuse to form the scrotum. Female external genitalia differentiate in the absence of DHT. The genital tubercle forms the clitoris, the genital swellings become the labia majora, and the urethral folds become the labia minora (see Fig. 31-2). The vagina is formed from the urogenital sinus. By the 15th week of gestation, differentiation of the external genitalia is complete. The male genitalia continue to enlarge throughout the second and third trimesters.
The infant with ambiguous genitalia presents a challenge in diagnosis and management for the physician and parent. Questions of diagnosis and management have profound and lifelong implications for the patient and family. Advances in genetics, endocrinology, and surgical techniques have enabled earlier diagnosis as well as improved treatment.
EMBRYOLOGY All embryos possess indifferent internal and external genital structures that will feminize unless they are acted on by a masculine influence. Sexual characteristics emerge from common bipotential precursors, and errors are possible at each stage of development. Normal sexual differentiation is the result of a series of wellregulated steps (Figs. 31-1 to 31-3). Initially, the indifferent gonad forms on the genital ridges at 3 to 5 weeks’ gestation. Chromosomal information dictates whether a gonad will differentiate into a testis or an ovary. The sex-determining Y (SRY) gene, which codes for the testisdetermining factor, is located on the short arm of the Y chromosome (see Fig. 31-3). The testis-determining factor causes the primordial germ cells to become organized into testicular cords starting in the sixth week of gestation. The SRY gene sequentially affects autosomal genes to induce Sertoli cell development in the bipotential primordial gonad. By the ninth week, Leydig cells are formed and testosterone production begins. An ovary forms in the presence of two X chromosomes. Both X chromosomes appear to be active in the germ cell and oocyte from the onset of meiosis to ovulation. In the formation of an ovary, the primitive cords break up into cell clusters that give rise to the ovarian medulla, and in the seventh week of gestation, the surface epithelium gives rise to cortical cords, which eventually develop into follicular cells in the fourth month of gestation. In XX embryos, the medullary cords regress. The fetal gonads dictate the development of the genital ducts (see Fig. 31-1). At the seventh week of gestation, the fetus has indifferent mesonephric (wolffian) and paramesonephric (müllerian) ducts. These structures complete their development during the third fetal month. In the male embryo, testosterone secreted by the Leydig cells of the fetal testes diffuses into the target cells and binds to a cytoplasmic receptor. Under the influence of local testosterone, the wolffian duct becomes the epididymis, the vas deferens, the seminal vesicle, and the ejaculatory duct (see Fig. 31-1). The testosterone diffuses into the target cells and binds to a cytoplasmic receptor. This receptor-testosterone complex stimulates the differentiation of the wolffian duct structures. The Sertoli cells in the fetal testes secrete müllerian-inhibiting substance (MIS), also termed antimüllerian hormone. The remnants of the müllerian duct in the male fetus are the appendix testis (a short stalklike structure on the upper pole of the testis) and the prostatic utricle (a tiny diverticulum in the prostatic urethra). In the female embryo, the absence of MIS production allows the müllerian ducts to develop into the fallopian tubes, the uterus, and
CLASSIFICATION OF INTERSEX DISORDERS Sexual differentiation is a well-regulated sequence of events. Developmentally, chromosomal sex determines gonadal sex, which then determines phenotypic sex. A straightforward organizational scheme for intersex disorders is based on the histologic features of the gonads (Table 31-1). The five possible classifications are female pseudohermaphroditism, male pseudohermaphroditism, mixed gonadal dysgenesis, true hermaphroditism, and gonadal dysgenesis (Table 31-2). A patient with an intersex disorder may have ambiguous genitalia, normal-appearing external genitalia (female or male), or a minor abnormality such as hypospadias and an undescended testis.
EVALUATION The child with ambiguous genitalia should be evaluated by a team consisting of a geneticist (dysmorphologist), pediatric endocrinologist, pediatric urologist, and ethicist (Fig. 31-4). Decisions regarding the evaluation, gender assignment, and long-term management need to be made jointly on the basis of the diagnosis and the future potential for successful sexual function. HISTORY AND PHYSICAL EXAMINATION A thorough history taking and physical examination must be performed, with full attention given to the history of the pregnancy, the family history, and the pedigree. Identically afflicted relatives should be identified, but more subtle signs must not be missed. 517
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Figure 31-1. Development of the internal genitalia from the indifferent stage. (From Rubenstein SC, Mandell J: The diagnostic approach to the newborn with ambiguous genitalia. Contemp Urol 1994;6:13. Reprinted with permission from Natalie Johnson.)
Sudden infant death, infertility, amenorrhea, hirsutism, and variant forms of sexual development in any relative should be investigated. The mother should be questioned about any medication, especially hormones, taken during pregnancy. On physical examination, the genitalia should be meticulously examined and documented; one important finding is a gonad located in the scrotum or the labioscrotal fold. Any phenotypically male infant with bilateral nonpalpable testes or subcoronal hypospadias and cryptorchidism should undergo full evaluation. Rectal examination may disclose a cervix. Other potential findings include hyperpigmentation of the areola and labioscrotal folds (congenital adrenal hyperplasia [CAH]), palpation of the uterus as a thickened structure, hypertension, signs of dehydration and failure to thrive, and associated congenital anomalies.
it should be filled by means of a small feeding tube to allow visualization of the pelvic structures. Inability to discern the cervix or vagina by radiography does not exclude their existence. Endoscopy, cystourethroscopy, and vaginoscopy allow more complete examination of the genitalia, and if these tests are performed with contrast material under fluoroscopic control, the anatomy may be defined more accurately. Exploratory laparotomy (or laparoscopy) and gonadal biopsy are used in selected cases to confirm the gonadal histologic and morphologic features of the wolffian and müllerian duct structures to aid in the assignment of sex. At the time of exploration, gonadal tissue at high risk for malignant degeneration may be removed if necessary. Laparotomy and biopsy are indicated if the results will affect the sex of rearing or if there is a risk of gonadal malignancy in the future.
DIAGNOSTIC STUDIES
FEMALE PSEUDOHERMAPHRODITISM
Laboratory analysis provides an important tool for the evaluation and treatment of these conditions. An initial study is a karyotype determination. Testing of multiple tissues (blood lymphocytes, skin fibroblasts) may be necessary if chromosomal mosaicism is suspected. The finding of Barr bodies in a buccal smear may be inaccurate in the newborn, and this evaluation is generally not obtained. If the gonads are nonpalpable, the serum 17-hydroxyprogesterone level should be measured (Fig. 31-5). Serial serum electrolyte levels should also be determined because the most common cause of intersex disorder, CAH (from 21-hydroxylase deficiency), may result in life-threatening salt wasting (hyponatremia, hyperkalemia, acidosis). Steroid profiles, such as testosterone, androstenedione, adrenocorticotropic hormone (ACTH), plasma renin, and 11-deoxycortisol determinations, are necessary on occasion. Voiding cystourethrography and retrograde genitography determine whether the uterus, cervix, and vagina are present. Abdominopelvic ultrasonography should be performed to study the pelvic organs for the presence of a uterus and the inguinal area for the presence of gonads (testes or ovotestes) and for the size and presence of the kidneys and adrenal glands. If the bladder is empty during the study,
Female pseudohermaphroditism is the condition of a person with a 46,XX karyotype who is partially virilized; it is the most common intersex disorder. The ovaries and müllerian derivatives are normally developed, and sexual ambiguity is limited to the external genitalia. Because patients with this disorder have normal internal structures, they are potentially fertile. The timing of intrauterine exposure to androgen determines the severity of the masculinization. If the differentiating external genitalia are exposed to androgens, there may be complete labioscrotal fusion and possibly a phallic urethra. In contrast, androgen exposure primarily during the second and third trimesters causes only clitoral hypertrophy. The most common cause of genital ambiguity in the newborn is one form of CAH, the frequency of which is estimated to be 1 in 14,000 births of white infants (Table 31-3). CAH results from a deficiency in the activity of one of the enzymes required for cortisol biosynthesis (Table 31-4; see also Fig. 31-5). Cholesterol is the building block for adrenal hormone synthesis. Through a series of enzymatic reactions, cholesterol is converted to cortisol, aldosterone, and sex hormones (see Fig. 31-5). CAH is caused
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Genital tubercle Urethral folds Urogenital slit Labioscrotal swelling Anal pit Tail 16.8 mm Glans Genital tubercle Urogenital slit Urethral folds Labioscrotal swelling
Figure 31-2. Differentiation of male and female external genitalia from indifferent primordia. (From Grumbach MM, Conte FA: Disorders of sex determination. In Wilson JD, Foster DW [eds]: Williams Textbook of Endocrinology. Philadelphia, WB Saunders 1998.)
Anus 49.0 mm
45.0 mm Glans penis Clitoris Urethral meatus
Labia minora
Scrotum
Vaginal orifice Labia majora
Raphe
Anus
by a deficiency of an enzyme in this pathway, resulting in decreased synthesis of the desired hormone and an elevated ACTH level, secondary to reduced cortisol feedback on the fetal hypothalamicpituitary-adrenal axis. The elevated ACTH level causes an overproduction of the precursors of cortisol proximal to the enzyme deficiency, which are then transformed to various androgens, including dehydroepiandrosterone, androstenedione, and androstenediol. CAH is an autosomal recessive disorder. Girls and boys are affected in equal frequencies. However, genital ambiguity occurs primarily in girls. The condition in boys is not discovered at birth unless the boys experience a salt-losing crisis, are identified by universal state-wide postnatal screening tests, are identified through prenatal screening performed because of the birth of an affected sibling, or have one of the less common enzyme defects. Precocious puberty develops in untreated boys with CAH. CAH is the only intersex disorder that can be life-threatening if untreated. More than 90% of the cases are a result of a deficiency of the enzyme 21-hydroxylase, whereas deficiency of the 11β-hydroxylase enzyme accounts for another 5% of cases. Less common are deficiencies of the enzymes 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and desmolase (see Table 31-3). A 21-hydroxylase deficiency may be mild or severe. The severe or “salt-wasting” type of 21-hydroxylase deficiency is a life-threatening disease and manifests with impaired secretion of cortisol and aldosterone, resulting in anorexia, vomiting, hyponatremia, hyperkalemia,
acidosis, dehydration, and circulatory collapse. This usually occurs after the fifth day of life. The more severe the enzymatic defect, the more masculine the phenotype is (Figs. 31-6 and 31-7). There is also a “simple virilizing” type of CAH with normal aldosterone biosynthesis and a mild “nonclassic” form in which the infant is asymptomatic, but androgen excess develops during childhood or at puberty. Other causes of adrenal insufficiency with or without intersex signs in infancy and childhood are noted in Table 31-5; manifestations are noted in Table 31-6. The second most common cause of CAH, 11β-hydroxylase deficiency, results in decreased production of cortisol and corticosterone and increased production of desoxycorticosterone, a steroid with a salt-retaining effect. There is marked heterogeneity in the clinical and hormonal manifestations of this autosomal recessive disorder. Typically, affected girls present with ambiguous genitalia at birth and may become hypertensive either in infancy or later in childhood. Affected boys appear normal at birth, but hypertension and precocious puberty develop. There is no salt-wasting component to the classic form of this syndrome, but in rare cases, gene mutations result in a salt-wasting form of the condition. Other enzyme deficiencies that lead to CAH include deficiencies of 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and desmolase. These conditions do not cause female pseudohermaphroditism; girls with these conditions are not virilized.
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Table 31-1. Classification of Intersex Disorders
XY
Disorder TDF
Testes
Seminiferous tubules (Sertoli cells)
Leydig cells
hCG (LH)
Female pseudohermaphroditism Male pseudohermaphroditism True hermaphroditism
Testosterone
Mixed gonadal dysgenesis
Antimüllerian hormone
Pure gonadal dysgenesis
Dihydrotestosterone Retrogression of Müllerian ducts
DHT: androgen receptor
Androgensensitive cell
Transcription and translation
Masculinization of urogenital sinus and external genitalia Figure 31-3. A diagrammatic scheme of male sex determination and differentiation. DHT, dihydrotestosterone; hCG, human chorionic gonadotropin; LH, luteinizing hormone; TDF, testis determining factor. (From Wilson JD, Foster DW [eds]: Williams Textbook of Endocrinology. 8th ed. Philadelphia, WB Saunders, 1992, p 918.)
Another cause of female pseudohermaphroditism is excessive androgen production by the mother, which occurs with adrenal or ovarian tumors or human chorionic gonadotropin (hCG)–dependent luteoma of pregnancy. EVALUATION Patients with CAH and ambiguous genitalia are genetically female with normal ovaries (Table 31-7). The karyotype is 46,XX. Because there is no production of testosterone or MIS by the male gonads, the wolffian structures are absent, and the development of the fallopian tubes, the uterus, and the upper vagina is normal. Only the development of the external genitalia is affected in such patients. Examination of girls with the 21-hydroxylase or 11-hydroxylase enzyme deficiency reveals variable degrees of virilization. With the mildest forms, there is simply clitoral hypertrophy and a normally positioned vagina; in the most severe forms, there is complete labioscrotal fusion, a long phallus with a urethral opening at its tip, and a high insertion of the vagina on the urethra (see Figs. 31-6 and 31-7). The gonads are nonpalpable because the ovaries do not descend into the inguinal canal or labia unless an inguinal hernia is present. The severity of the virilization effect is directly proportional to the
Gonads
Karyotype
Ovaries only
46,XX
Testicles only
46,XY
Ovarian and 46,XX; 46,XY; testicular tissue and mosaic Ovary and testis Ovotestis and testis Ovotestis and ovary Two ovotestes Testis and streak 45,XO/46,XY gonad with mosaicism Streak gonads only 46,XX or 46,XY or 45,XO
severity of the enzyme deficit. Any phenotypically male neonate with nonpalpable testes should be evaluated for CAH. In full-term newborns with a 21-hydroxylase deficiency, serum levels of 17-hydroxyprogesterone are typically elevated, ranging from 3000 to 40,000 ng/dL (normal, 100 to 200 ng/dL); in those with mild forms, the level is at the upper limit of normal. In premature infants, 17-hydroxyprogesterone levels may be normally elevated (false positive). Measurement of urinary 17-ketosteroid and pregnanetriol level is not usually performed. Salt-losing patients often have hyponatremia and hyperkalemia on a regular or lowsalt diet. In newborns with the 11-hydroxylase deficiency, plasma 11-deoxycortisol and 11-deoxycorticosterone levels are elevated. Radiologic evaluation includes a pelvic ultrasound study to try to identify a uterus and ovaries, an inguinal ultrasound study to try to identify gonads (testes, if present, indicate that the patient does not have CAH), and an adrenal ultrasound study, because 50% of neonates with CAH have adrenal glands that are enlarged or at the upper limit of normal in size. TREATMENT Initial management is directed at correcting or preventing hypoglycemia, hyponatremia, hyperkalemia, hypovolemia, and shock. In addition to saline infusion and correction of electrolyte abnormalities, hydrocortisone therapy is started. When the child is stabilized and receiving appropriate doses of glucocorticoids and mineralocorticoids, surgical management is considered. The procedure, termed feminizing genitoplasty, involves (1) clitoroplasty, in which the erectile tissue of the clitoris is removed, preserving normal clitoral sensation, and (2) vaginoplasty, in which the lower vagina is exteriorized (see Fig. 31-7). PRENATAL SCREENING The 21-hydroxylase deficiency is an autosomal recessive condition; consequently, there is a 25% risk that a sibling of an affected child will have CAH. The gene for CAH is linked with the human leukocyte antigen class I and class II genes. DNA probes for these genes can be used to define the sequences associated with CAH. If genetic material can be obtained from the embryo or fetus (by chorionic villus biopsy at 10 weeks’ gestation) with an affected sibling before the external genitalia have completely developed, treatment may be
Chapter 31 Ambiguous Genitalia Table 31-2. Etiologic Classification of Hermaphroditism
Female Pseudohermaphroditism Androgen exposure Fetal source 21-Hydroxylase (P450 c21) deficiency 11β-Hydroxylase (P450 c11) deficiency 3β-Hydroxysteroid dehydrogenase II (3β-HSD II) deficiency Aromatase (P450arom) deficiency Maternal source Virilizing ovarian tumor Virilizing adrenal tumor Androgenic drugs Undetermined origin Associated with genitourinary and gastrointestinal tract defects Male Pseudohermaphroditism Defects in testicular differentiation Denys-Drash syndrome (mutation in WT1 gene) WAGR syndrome (Wilms tumor, aniridia, genitourinary malformation, retardation) Deletion of 11p13 Camptomelic syndrome (autosomal gene at 17q24.3-q25.1) and SOX 9 mutation XY pure gonadal dysgenesis (Swyer syndrome) Mutation in SRY gene Unknown cause XY gonadal agenesis Deficiency of testicular hormones Leydig cell aplasia Mutation in LH receptor Lipoid adrenal hyperplasia (P450 scc) deficiency; mutation in steroidogenic acute regulatory protein 3β-HSDII deficiency 17-Hydroxylase/17,20-lyase (p450 c17) deficiency Persistent müllerian duct syndrome Gene mutation, müllerian-inhibiting substance (MIS) Receptor defects for MIS Defect in androgen action 5α-Reductase II mutations Androgen receptor defects Complete androgen insensitivity syndrome Partial androgen insensitivity syndrome (Reinfenstein and other syndromes) Smith-Lemli-Opitz syndrome Defect in conversion of 7-dehydrocholesterol to cholesterol True Hermaphroditism XX XY XX/XY chimeras From Rapaport R: Hermaphroditism (Intersexuality). In Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics, 16th ed. Philadelphia, WB Saunders, 2000, p 1760.
given to prevent virilization of the genitalia. If dexamethasone is administered to the mother at 10 weeks’ gestation, it will cross the placenta and suppress the overproduction of cortisol precursors. Amniotic fluid can also be assayed for 17-hydroxyprogesterone as a complementary study. The earlier the initiation of dexamethasone therapy, the less likely it is that significant virilization will occur in the fetus with CAH. Postnatal screening is available in many states and measures 17-hydroxyprogesterone on routine heel stick samples examined
521
for phenylketonuria and other metabolic disorders. This is used primarily to detect salt-losing conditions before affected persons develop an adrenal crisis.
MALE PSEUDOHERMAPHRODITISM Male pseudohermaphroditism is the condition of a person who is chromosomally male (46,XY) and has normal testes who undergoes incomplete virilization (Table 31-8; see also Table 31-2). The abnormality includes a spectrum of conditions, including failure of target tissue response to testosterone or dihydrosterone, failure of conversion of testosterone to dihydrosterone, a defect in testicular differentiation, a disorder in testosterone synthesis, and a defect in production of MIS. Some of these conditions do not result in obviously ambiguous genitalia; however, in all cases, sexual differentiation is abnormal.
ANDROGEN RESISTANCE (INSENSITIVITY) Testicular feminization (complete androgen resistance or insensitivity syndrome) is an X-linked disorder of patients with a 46,XY karyotype who have an abnormality of the androgen receptor, either qualitatively abnormal or at undetectable low levels. During embryonic development, differentiation of the wolffian ducts and virilization of the external genitalia are inhibited, and secretion of MIS causes regression of the müllerian ducts. Consequently, affected individuals have bilateral testes; normal female external genitalia with a short, blind-ending vagina; and wolffian-derived internal duct structures. At puberty, breasts develop, but the patients do not menstruate or develop any pubic or axillary hair. Diagnosis usually occurs at puberty after evaluation for amenorrhea (see Chapter 30). Androgen resistance results in increased luteinizing hormone secretion, which causes elevated levels of both testosterone and estradiol. The elevated level of estradiol is responsible for breast development. Markedly elevated serum luteinizing hormone and testosterone levels and a 46,XY karyotype establish the diagnosis. The assignment of female sexual identity should be reinforced. The diagnosis of testicular feminization may be made before puberty when a phenotypic girl undergoing hernia repair is found to have an inguinal or labial testis. Treatment includes bilateral orchiectomy because there is a significant risk of gonadal cancer with age. Estrogen replacement then becomes necessary. If complete androgen resistance is diagnosed in a prepubertal girl, the decision of whether to perform bilateral gonadectomy at the time of diagnosis or delay the procedure until pubertal development has occurred is controversial. Because of the underdeveloped müllerian structures, patients are candidates for vaginoplasty, which is usually performed with a segment of large or small bowel. There is spectrum of X-linked incomplete androgen resistance syndromes. Müllerian development does not occur, and wolffian duct derivatives usually are hypoplastic. In these syndromes (Reifenstein, Lubs, Gilbert-Dreyfus), development of the external genitalia is variable and ranges from genital ambiguity to severe hypospadias with chordee (ventral penile curvature). The testes are small and are often undescended. Biopsy of the testes reveals azoospermia. At puberty, there is usually poor virilization, absent or sparse axillary and pubic hair, and gynecomastia. Serum luteinizing hormone, testosterone, and estradiol levels are elevated. Gender assignment of these patients depends on their phenotype and gender identity. Some who have a phenotype of a mild virilized female with clitoromegaly choose not to have any reconstructive surgery. Phenotypic boys and men with severe hypospadias and chordee can undergo satisfactory urethral reconstruction and resemble normal boys and men.
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Ambiguous Genitalia
Gonad(s) palpable
Ultrasound
Gonad(s) impalpable
Müllerian structures absent
Müllerian structures present
Müllerian structures present
17-Hydroxyprogesterone
Karyotype
Gonads
XY
XY
Testis
Ovary
Male pseudohermaphroditism
Normal
Elevated
XO/XY mosaic
XX; XY; XX/XY mosaic
XX
XX
XY
Testis and streak
Ovary and testis and/or ovotestis
Ovary
Ovary
⫾Testes
Mixed gonadal dysgenesis Sex reversal syndrome
Müllerian structures absent
Nonadrenal female pseudohermaphroditism True hermaphroditism
Male pseudohermaphroditism
Congenital adrenal hyperplasia
Figure 31-4. Algorithm portraying evaluation of an infant with ambiguous genitalia.
5α-REDUCTASE DEFICIENCY External genital development in boys is stimulated by the 5α-reduced product of testosterone, DHT (see Fig. 31-3). Boys and men with a 5α-reductase deficiency have a small phallus or ambiguous genitalia with perineoscrotal hypospadias, a bifid scrotum, and inguinal or scrotal/labial testes. Because the testes produce MIS, there is a blind vaginal pouch that opens into the urogenital sinus or urethra. However, the wolffian duct derivatives are present. In untreated patients, at puberty the female phenotype transforms into a masculine phenotype with penile/phallic enlargement, scrotal rugation and pigmentation, enlargement and descent of the testes into the labioscrotal folds, and deepening of the voice. In addition, at puberty gender identity often changes from female to male in untreated individuals. The diagnosis is suggested by a high testosterone-to-DHT ratio, either under basal conditions or after gonadal stimulation with hCG. Genitography shows wolffian duct structures. Early diagnosis of 5α-reductase deficiency is important for allowing appropriate gender identification. In many cases, DHT therapy results in significant phallic enlargement, and hypospadias repair can then be performed, which results in a satisfactory male appearance. If the genitalia are clearly
female, however, bilateral orchiectomy and estrogen replacement are indicated. ABNORMAL TESTICULAR DIFFERENTIATION If testicular differentiation is abnormal, genital development is also often abnormal. In the vanishing testis syndrome, the testes form but involute during gestation. If testicular regression occurs before 8 weeks’ gestation, the embryo has no testosterone or MIS, and female external genitalia and müllerian development result. Testicular regression also may occur late in gestation, usually from testicular torsion. In this instance, the individual has a normal phallus but bilateral impalpable testes, and müllerian derivatives are absent. In these patients, the karyotype is 46,XY. Usually, the baseline gonadotropin levels are high, and the testosterone level is low. After a series of hCG injections, the serum testosterone level should rise dramatically in normal boys and men with functioning testes but is unchanged in those with the vanishing testis syndrome. Although the diagnosis of anorchia can be made by endocrine methods, confirmation with laparoscopy is recommended. Management includes treatment with exogenous testosterone at puberty. Patients with this disorder are sterile.
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Cholesterol 20,22-Desmolase 17,20-Desmolase Pregnenolone
17-OH
17-OH Pregnenolone
3B-HSD Progesterone
3B-HSD 17-OH
3B-HSD
17,20-Desmolase 17-OH Progesterone Androstenedione
21-OH Desoxycorticosterone
Dehydroepiandrosterone
21-OH
17B Red
11 Deoxycortisol
11-OH
11-OH
Corticosterone
Cortisol
Estrone
Testosterone
17B Red
*
Estradiol
5A Red Dihydrotestosterone
18-OH 18-Hydroxycorticosterone Aldosterone MINERALOCORTICOIDS
GLUCOCORTICOIDS
ANDROGENS
ESTROGENS
* Conversion of testosterone to estradiol is by p450 aromatase enzyme activity Figure 31-5. Scheme of adrenal steroid biosynthesis. 11-OH, 11β-hydroxylase; 17-OH, 17α-hydroxylase; 18OH, 18-hydroxylase; 21-OH, 21-hydroxylase; 3B-HSD, 3β-hydroxysteroid dehydrogenase; 17B Red, 17β-reductase; 5A Red, 5α-reductase.
DISORDER OF TESTOSTERONE SYNTHESIS Five enzymes are involved in the biosynthesis of testosterone: 20,22-desmolase, 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, 17,20-desmolase, and 17-ketosteroid reductase. The first three enzymes also are involved in the production of corticosteroids; thus, a deficiency of one of these enzymes also causes CAH (see Fig. 31-5). A defect in desmolase activity causes severe adrenal and gonadal insufficiency. Because testosterone is not produced, most affected boys and men have female external genitalia with a blind vaginal pouch, undeveloped wolffian duct derivatives, and no müllerian structures. Sonography demonstrates large, lipid-laden adrenal glands, and the disorder has been termed congenital lipoid adrenal hyperplasia. Death from adrenal insufficiency often occurs in infancy. The diagnosis is made by demonstration of low levels of all steroids in urine and plasma and an absent adrenal response to ACTH. A defect in 3β-hydroxysteroid dehydrogenase results in reduced testosterone production but increased dehydroepiandrosterone production, allowing some virilization of affected boys and men; the typical appearance is severe hypospadias with chordee. In its complete form, deficiencies of aldosterone, cortisol, estradiol, and testosterone occur. The usual presentation is adrenal crisis with severe salt loss, although milder forms have been described. The diagnosis is made by detection of the precursors of aldosterone and cortisol, pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone. Treatment is similar to that of patients with 21-hydroxylase deficiency, except for the need for gonadal steroids at puberty.
A defect in the 17α-hydroxylase enzyme results in impaired synthesis of 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, which in turn results in impaired synthesis of cortisol and sex steroid. Affected individuals may experience hypertension, hypokalemia, and alkalosis. Because of impaired testosterone synthesis, the external genitalia in affected boys and men show minimal or no virilization. The diagnosis is suspected in 46,XY persons with ambiguous or female genitalia, hypokalemic alkalosis, and hypertension. The diagnosis of 17α-hydroxylase deficiency is confirmed by demonstration of high levels of corticosterone, deoxycorticosterone, progesterone, and pregnenolone, as well as low levels of aldosterone and renin. A defect in 17,20-desmolase activity or 17β-hydroxysteroid dehydrogenase activity causes reduced testosterone secretion and thus ambiguous genitalia in persons with the 46,XY karyotype. They have virilization of the wolffian duct derivatives, and müllerian structures are absent. Inguinal or intraabdominal testes are common. An unusual feature of 17β-hydroxysteroid dehydrogenase deficiency in boys and men is that at puberty significant virilization can occur, often in association with gynecomastia. Affected patients have elevated levels of androstenedione and estrone and low levels of testosterone and estradiol. In most patients with the 46,XY karyotype and a disorder in testosterone synthesis, the genitalia are female or ambiguous in appearance. If the sex of rearing is decided to be male, early hypospadias repair and orchiopexy are recommended. If a female gender is assigned, however, gonadectomy and clitoroplasty should be performed, and vaginoplasty may be necessary at puberty.
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Table 31-3. Diagnosis and Treatment of Congenital Adrenal Hyperplasia Disorder
Signs and Symptoms
Laboratory
Lipoid congenital adrenal hyperplasia
Salt-wasting crisis Male pseudohermaphroditism
Low levels of all steroid hormones, with decreased or absent response to ACTH Decreased or absent response to hCG in male pseudohermaphroditism ↑ ACTH ↑ PRA
3β-HSD deficiency
Classic form: Salt-wasting crisis Male and female pseudohermaphroditism Precocious puberty Disordered puberty
3β-HSD deficiency
Nonclassic form: Precocious puberty, disordered puberty, menstrual irregularity, hirsutism, acne, infertility
21-OH deficiency
Classic form: Salt-wasting crisis Female pseudohermaphroditism Postnatal virilization
21-OH deficiency
Nonclassic form: Precocious puberty, disordered puberty, menstrual irregularity, hirsutism, acne, infertility
11β-Hydroxylase deficiency
Classic form: Female pseudohermaphroditism Postnatal virilization in boys and girls Hypertension
11β-Hydroxylase deficiency
Nonclassic form: Precocious puberty, disordered puberty, menstrual irregularity, hirsutism, acne, infertility
17α-OH/17,20lyase deficiency
Male pseudohermaphroditism Sexual infantilism Hypertension
↑ ↑ Baseline and ACTH-stimulated Δ5 steroids (pregnenolone, 17-OH pregnenolone, DHEA, and their urinary metabolites) ↑ ACTH ↑ PRA Suppression of elevated adrenal steroids after glucocorticoid administration ↑ Baseline and ACTH-stimulated Δ5 steroids (pregnenolone, 17-OH pregnenolone, DHEA, and their urinary metabolites) ↑ Δ5/Δ4 serum and urinary steroids Suppression of elevated adrenal steroids after glucocorticoid administration ↑ ↑ Baseline and ACTH-stimulated 17-OH progesterone and pregnanetriol ↑ ↑ Serum androgens and urinary metabolites ↑ ACTH ↑ PRA Suppression of elevated adrenal steroids after glucocorticoid administration ↑ Baseline and ACTH-stimulated 17-OH progesterone and pregnanetriol ↑ Serum androgens and urinary metabolites Suppression of elevated adrenal steroids after glucocorticoid administration ↑ ↑ Baseline and ACTH-stimulated compound S and DOC and their urinary metabolites ↑ ↑ Serum androgens and their urinary metabolites ↑ ACTH ↓ PRA Hypokalemia Suppression of elevated steroids after glucocorticoid administration ↑ Baseline and ACTH-stimulated compound S and DOC and their urinary metabolites ↑ Serum androgens and their urinary metabolites Suppression of elevated steroids after glucocorticoid administration ↑ ↑ DOC, 18-OH DOC, corticosterone, 18-hydroxycorticosterone Low 17-α-hydroxylated steroids and poor response to ACTH Poor response to hCG in male pseudohermaphroditism ↓ PRA ↑ ACTH Hypokalemia Suppression of elevated adrenal steroids after glucocorticoid administration
Therapeutic Measures
Glucocorticoid and mineralocorticoid administration Sodium chloride supplementation Gonadectomy of male pseudohermaphrodite Sex hormone replacement consonant with sex of rearing Glucocorticoid and mineralocorticoid administration Sodium chloride supplementation Surgical correction of genitals and sex hormone replacement as necessary consonant with sex of rearing Glucocorticoid administration
Glucocorticoid and mineralocorticoid replacement Sodium chloride supplementation Vaginoplasty and clitoral recession in female pseudohermaphroditism
Glucorticoid administration
Glucocorticoid administration Vaginoplasty and clitoral recession in female pseudohermaphroditism
Glucocorticoid administration
Glucocorticoid administration Surgical correction of genitals and sex hormone replacement in male pseudohermaphroditism consonant with sex of rearing Sex hormone replacement in female pseudohermaphroditism
Adapted from Miller WL, Levine LS: Molecular and clinical advances in congenital adrenal hyperplasia. J Pediatr 1987;111:1. From Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics, 16th ed. Philadelphia, WB Saunders, 2000, p 1731. ACTH, adrenocorticotropic hormone (corticotropin); DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; hCG, human chorionic gonadotropin; HSD, hydroxysteroid dehydrogenase; PRA, plasma renin activity. ↑, increased; ↑↑, greatly increased; ↓, decreased.
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Table 31-4. Causes of Virilization in Girls Condition
P-450 C21 deficiency (21-hydroxylase) 3β-Hydroxysteroid dehydrogenase deficiency P-450 C11 deficiency (11β-hydroxylase) Androgenic drug exposure (e.g., progestins) Mixed gonadal dysgenesis* True hermaphrodite Maternal virilizing adrenal or ovarian tumor Idiopathic
Additional Features
Salt loss in some Salt loss Salt retention/hypertension Exposure by 12th wk of gestation Karyotype: 45,X/46,XY Testicular and ovarian tissue present Rare; positive history Unknown cause
Adapted from Styne DM: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics. 2nd ed. Philadelphia, WB Saunders, 1994, p 636. *Or mosaic Turner syndrome.
PERSISTENT MÜLLERIAN DUCT SYNDROME Also termed hernia uteri inguinale, persistent müllerian duct syndrome is an X-linked condition that results from a defect in the production of MIS, an abnormality in the secretion of MIS, or a lack of response by the müllerian duct to MIS. This form of male pseudohermaphroditism does not cause ambiguous genitalia. The typical presentation is an infant or child with an inguinal hernia and cryptorchidism in whom routine exploration discloses müllerian structures (fallopian tube and uterus) as well as an epididymis and vas. In many cases, transverse testicular ectopia is present. Treatment includes removal of the müllerian structures; care must be taken not to injure the wolffian duct derivatives.
MIXED GONADAL DYSGENESIS Mixed gonadal dysgenesis is the second most common cause of ambiguous genitalia in newborns. Most affected patients have chromosomal mosaicism with a 45,XO/46,XY karyotype. Nearly all have incomplete virilization (Fig. 31-8). Patients with a more feminine phenotype typically have genital ambiguity with phallic enlargement, a urogenital sinus, and varying degrees of labioscrotal fusion. Internal genitalia include a unilateral streak gonad; persistent müllerian duct structures (fallopian tube, uterus, and vagina) ipsilateral to the streak; a contralateral testis, which may or may not be undescended; and frequently a fallopian tube on the side of the testis. Individuals with a more feminine phenotype usually have an intraabdominal testis, whereas in those with a more masculine phenotype, the testis is usually inguinal or scrotal. Approximately 33% of patients have somatic stigmata of Turner syndrome: a shield-shaped chest, webbed neck, cubitus valgus, multiple pigmented nevi, and short stature. Approximately 60% are reared as girls because of the diminutive phallus, which is usually hypospadiac. Histologically, the streak gonad is composed of fibrous connective tissue resembling ovarian stroma. The testis lacks germinal elements but at puberty has abundant Leydig and Sertoli cells. Thus, at puberty most patients with a retained testis undergo virilization, and the serum testosterone level is in the normal adult range. It is thought that the incomplete virilization at birth represents delayed development of the testis in utero. Management depends on several factors. First, the testis lacks germinal elements. Second, most patients have significant hypospadias,
Figure 31-6. Spectrum of external virilization in congenital adrenal hyperplasia. A, Clitoromegaly. B and C, Progressive labioscrotal fusion. D, Complete virilization with penile urethra. (From Griffin JE, Wilson JD: Disorders of sexual differentiation. In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr [eds]. Campbell’s Urology, 6th ed. Philadelphia: WB Saunders, 1992:1509.)
with a uterus and a vagina. Individuals with a male gender assignment must undergo reconstructive surgery, but usually the appearance of the penis can be relatively normal if the corporal bodies of the penis are sufficiently long. Third, gonadal tumors develop in 25% of patients and include seminoma, gonadoblastoma, dysgerminoma, and embryonal cell carcinoma. Tumors may develop in either the testis or the streak gonad. If a tumor develops in an intraabdominal testis, ipsilateral müllerian structures are always present. Tumors may develop in a scrotal streak gonad but not in a scrotal testis if it descended before birth. If a tumor is present in a streak gonad, it is also present in the contralateral intraabdominal testis. Approximately 50% of affected patients are less than 148 cm in height. For these reasons, most infants with mixed gonadal dysgenesis are reared as girls. If gender assignment is female, early exploratory laparotomy and prophylactic gonadectomy are advisable.
TRUE HERMAPHRODITISM True hermaphroditism is the least common of the intersex disorders. In an individual with this condition, the gonads contain both ovarian and testicular tissue. Patients may have an ovotestis on one side and an ovary or testis on the other (unilateral), bilateral ovotestes (bilateral), or a testis on one side and an ovary on the other (lateral). The most common finding is an ovary on the left side and a testis on the right. Nearly all patients have a urogenital sinus, and most have a uterus. The ductal system usually follows from the ipsilateral gonad: a fallopian tube on the side of the ovary and an epididymis on the side of the testicle. If an ovotestis is present, the adjacent ducts
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Figure 31-7. Spectrum of virilization of external genitalia in girls with congenital adrenal hyperplasia (CAH). A, Clitoromegaly without labioscrotal fusion. B, Mild clitoromegaly with labioscrotal fusion. C, Severe virilization in a girl with CAH. D, Same patient as in part C after feminizing genitoplasty.
may be wolffian, müllerian, or both. If an ovotestis is present, it may be anywhere along the course of normal testicular descent, and often it is associated with an inguinal hernia. The appearance of the external genitalia is variable. Nearly all affected persons have incomplete virilization; that is, they have hypospadias. At puberty, 80% of affected patients develop gynecomastia, and 50% menstruate. Individuals reared as boys may show cyclic hematuria. Ovulation is more common than spermatogenesis, but both are uncommon. Sixty percent of affected patients have a 46,XX karyotype, but the SRY gene has been detected in many. Twenty percent have a 46,XY karyotype; the remainder demonstrate mosaicism or chimerism. Gonadal neoplasms have been reported in patients with an XY cell
line. Because most have a masculine phenotype, approximately 70% have been reared as boys. The primary consideration in these patients is gender assignment. If the phallus is diminutive, the infant probably should be reared as a girl, irrespective of the internal genitalia, because the potential for phallic growth is minimal. If there are both a phallus and a vagina, the sex of rearing should be based on the findings at exploratory laparotomy. If a testis that can be placed in the scrotum is identified, the infant should be raised as a boy. If there are normal müllerian structures on one side that are associated with an ovary, strong consideration should be given to rearing the infant as a girl. After gender assignment, the contradictory gonadal tissue and internal ducts should be excised.
Chapter 31 Ambiguous Genitalia
527
Table 31-5. Causes of Adrenal Insufficiency in Infancy
Table 31-6. Clinical Manifestations of Adrenal
and Childhood
Insufficiency
Congenital Adrenal Hypoplasia Secondary to ACTH deficiency Autosomal recessive X-linked
Cortisol Deficiency Hypoglycemia Inability to withstand stress Vasomotor collapse Hyperpigmentation (primary adrenal insufficiency with ACTH excess) Apneic spells Hypoglycemic seizure Muscle weakness, fatigue
Adrenal Hemorrhage Congenital Adrenal Hyperplasia P-450scc (cholesterol side chain cleavage) deficiency 3β-Hydroxysteroid dehydrogenase deficiency P-450 C21 (21-hydroxylase) steroid dehydrogenase deficiency P-450 C11 (11β-hydroxylase) deficiency P-450 C17 (17-hydroxylase) deficiency Isolated Deficiency of Aldosterone Synthesis P-450c11 (18-hydroxylase) deficiency P-450c11 (18-hydroxysteroid dehydrogenase) deficiency Pseudohypoaldosteronism: End-Organ Unresponsiveness to Aldosterone Congenital Adrenal Unresponsiveness to ACTH Addison Disease Autoimmune Infections of the adrenal gland Tuberculosis Histoplasmosis Meningococcosis Infiltration of the adrenal gland Sarcoidosis Hemochromatosis Amyloidosis Metastatic cancer Adrenoleukodystrophy Drugs (Suppress Adrenal Steroidogenesis) Withdrawal of steroid therapy given for more than 7-10 days Metyrapone Ketoconazole From Styne DM: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 639. ACTH, adrenocorticotropic hormone.
GONADAL DYSGENESIS TURNER SYNDROME Although patients with gonadal dysgenesis do not have ambiguous genitalia, the condition represents an important disorder of sexual differentiation. The karyotype is 45,XO, and this abnormality is found in 1 in 10,000 newborn girls. Typical features include short stature, sexual infantilism at puberty, and distinctive somatic abnormalities. At birth, loose skin folds on the neck are apparent, as is lymphedema of the extremities. Later, characteristic facial features become apparent, including prominent low-set ears, epicanthal folds, ptosis, low posterior hairline, and micrognathia. Affected patients have a shield-shaped chest and often a webbed neck. Associated anomalies may include renal abnormalities, coarctation of the aorta, cubitus valgus, puffy hands and feet, and short fourth metacarpals. Treatment includes estrogen replacement at puberty. All affected patients are sterile.
Aldosterone Deficiency Vomiting Hyponatremia Urinary sodium wasting Salt craving Hyperkalemia Acidosis Failure to thrive Volume depletion Hypotension Dehydration Shock Diarrhea Muscle weakness Androgen Excess or Deficiency (Caused by Enzyme Defect) Ambiguous genitalia From Styne DM: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 639. ACTH, adrenocorticotropic hormone.
Table 31-7. Diagnostic Tests for Suspected Congenital
Adrenal Hyperplasia Test
Finding
Blood Karyotype 17-Hydroxyprogesterone Testosterone 11-Deoxycortisol Androstenedione Serial electrolytes
46,XX Elevated Elevated Elevated (with 11β-hydroxylase deficiency) Elevated ↓ Na, ↑ K
Radiology Ultrasonography (pelvis, inguinal canal, adrenal glands) Genitogram K, potassium; Na, sodium. ↓, decreased; ↑ increased.
PURE GONADAL DYSGENESIS Individuals with pure gonadal dysgenesis have normal female external genitalia, but the internal structures are similar to those in patients with Turner syndrome (bilateral streak gonads, müllerian
Section Four Genitourinary Disorders
528
Table 31-8. Causes of Inadequate Masculinization
in Boys Condition
Additional Features
Testicular feminization syndrome (complete)* Testicular feminization syndrome (partial)* Partial androgen insensitivity syndromes 5α-Reductase deficiency Vanishing testis syndrome P-450scc deficiency 3β-Hydroxysteroid dehydrogenase deficiency P-450c17 deficiency 17,20-Desmolase deficiency 17β-hydroxysteroid oxidoreductase deficiency Dysgenetic testes Leydig cell hypoplasia
Female external genitalia, absence of müllerian structures Same as for complete syndrome, with ambiguous external genitalia Family history frequently positive Autosomal recessive, virilization at puberty Unknown or vascular event; may occur at >12 weeks’ gestation Salt loss Salt loss Salt retention/hypertension Adrenal function normal Adrenal function normal Possible abnormal karyotype Rare
Adapted from Styne DM: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 636. *Or androgen insensitivity.
duct development, and sexual infantilism). The patients are normal or tall in height, have few congenital anomalies, and have either a 46,XX or 46,XY karyotype. Those with the 46,XY form often have clitoromegaly. Gonadal tumors may arise in patients with a 46,XY karyotype, and prophylactic gonadectomy is recommended for these individuals. Patients may present with amenorrhea. Virilization indicates the presence of a tumor of one of the streak gonads. Gonadal dysgenesis is characterized by abnormal testicular development, and in the 46,XY form, there is a variety of phenotypic differences, ranging from normal male to genital ambiguity, depending on the extent of testicular development. The condition may be sporadic or familial. Swyer syndrome consists of the female phenotype with female internal genitalia, normal or tall stature, and sexual infantilism with primary amenorrhea. These patients have streak gonads that do not secrete testosterone or antimüllerian substance, and therefore müllerian derivatives develop. All of these patients are at risk for dysgerminoma, seminoma, and gonadoblastoma. Consequently, at laparotomy, gonadectomy (removal of the streak gonads) is recommended. Pubertal development should be initiated by estrogen replacement therapy in patients reared as girls.
AMBIGUOUS GENITALIA ASSOCIATED WITH DEGENERATIVE RENAL DISEASE DENYS-DRASH SYNDROME Denys-Drash syndrome is the clinical triad of genital abnormalities, nephropathy, and Wilms tumor. Most persons with this condition have a female phenotype or ambiguous genitalia and dysgenetic gonads. Although 46,XY is the most common karyotype, some patients with 46,XXY and 46,XX karyotypes and with hypoplastic
gonads or streak gonads have been reported. The nephropathy is progressive into end-stage renal disease and is caused by focal or diffuse mesangial sclerosis. In this syndrome, Wilms tumor typically develops before the age of 2 years and is frequently bilateral. Denys-Drash syndrome is an autosomal dominant disorder. WAGR SYNDROME “WAGR” syndrome refers to the association of Wilms tumor, aniridia, genitourinary anomalies, including hemihypertrophy, and mental retardation. Some of these patients have ambiguous genitalia, and some develop bilateral gonadoblastoma. The syndrome is secondary to a deletion at chromosome 11p13.
GENDER ASSIGNMENT AND MANAGEMENT When a baby is born, the parents, the family, and their friends immediately want to know the baby’s weight and its gender. If the neonate has ambiguous genitalia, the possible confusion among the medical team regarding gender assignment can have a profound effect on how the baby is viewed and treated by his or her family. Gender assignment in these patients is an emergency. It is noteworthy that the issue of gender assignment or reassignment has become extremely controversial. Recommendations should be made by a multidisciplinary team. Important issues include (1) the presence of other congenital anomalies; (2) the size of the phallus; (3) the potential for providing a cosmetically and functional male or female genital appearance after reconstructive surgery; (4) the potential for gonadal malignancy; (5) the potential for fertility, including the use of artificial reproductive technology; (6) the potential for sex steroid production; (7) the neurologic status of the patient; and (8) parental preferences. The initial discussion with the parents should include the fact that the genitalia of the child are incompletely formed and that more extensive testing must be performed before gender assignment. Until a definite sex has been assigned, the newborn should be referred to as “the baby,” rather than “he,” “she,” or “it.” The infant should never be alluded to as “half-boy and half-girl.” For inquisitive family and friends, the parents may simply state that the baby is quite ill and will need to be hospitalized for several days; most of the time, no further questions regarding the baby’s gender will follow. It sometimes takes several days to identify the cause of the ambiguous genitalia; only after the cause is determined can the gender assignment be made. In the unlikely event that an intersex condition is found for the first time in an older child, the assigned gender should not be changed except in very unusual circumstances. When a neonate with ambiguous genitalia is assigned a male gender, current surgical techniques allow a remarkably normal genital appearance as long as the phallus is satisfactory in size. If the penis is diminutive, it may be necessary to give two or three monthly injections of testosterone enanthate to determine whether there is significant phallic growth potential. Nearly all of these infants have hypospadias, often with chordee. If there is significant chordee, the stretched penile length may be difficult to assess accurately and tends to be underestimated. In the absence of chordee, the stretched penile length is determined with a ruler pressed into the suprapubic fat pad above the symphysis pubis. The measurement includes the tip of the glans to the base (excluding redundant foreskin). The width is measured at midshaft during stretching. A micropenis has a stretched length or width below 2.5 standard deviations of the mean for age. At 40 weeks’ gestation, this measurement (micropenis) is approximately 27 to 30 mm for length and 9 to 10 mm for diameter. Clitoral enlargement is present if the clitoris exceeds 6 mm in a full-term neonate. Gonadal (testis) size is considered small if the longest diameter is less than 0.8 cm. If a male gender assignment is made,
Chapter 31 Ambiguous Genitalia
529
Figure 31-8. Patient with mixed gonadal dysgenesis. A and B, External genitalia shows normal-sized phallus and hypospadiac urethra. C, Laparotomy shows streak gonad (arrow).
the reconstructive procedure can be performed at 6 to 12 months of age, usually with one procedure. If the patient is assigned a female gender, reconstructive surgery, termed feminizing genitoplasty, should be performed as soon as is feasible from a medical standpoint. This procedure involves both a clitoroplasty and a vaginoplasty. If only clitoromegaly is present, only a reduction clitoroplasty is necessary. Reconstructive surgical techniques have allowed this procedure to be performed in a way that allows an excellent cosmetic appearance and satisfactory sexual function. In this procedure, the corporal bodies of the clitoris are removed, and the glans (tip of the phallus) and the neurovascular bundle, which provides sensation, are preserved. In patients with mixed gonadal dysgenesis or true hermaphroditism, reduction clitoroplasty may be performed shortly after laparotomy and gonadal biopsy. In infants with CAH, genitoplasty needs to be deferred until the baby is stable from a medical standpoint. If the vagina opens onto
a urogenital sinus, a vaginoplasty must be performed in conjunction with reduction clitoroplasty. In patients born without a vagina, bowel vaginoplasty is usually deferred until puberty. For infant girls with CAH, the sex of rearing nearly always should be female. With feminizing clitoroplasty, the cosmetic and functional anatomic result should be quite satisfactory. With proper hormonal regulation, these individuals can bear children, and the likelihood of tumor formation is no different from that in other women. If there is full masculine development with labioscrotal fusion (scrotum) and a phallus with a urethra at its tip, whether to assign a male or female gender is controversial, because some authorities think that the individual’s brain may have already undergone sex steroid imprinting as male. In a patient with male pseudohermaphroditism secondary to complete androgen resistance, a female gender assignment is most appropriate. The testes have a 6% to 30% risk of undergoing malignant
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Section Four Genitourinary Disorders
degeneration in adulthood and therefore should be removed. Timing of gonadectomy is controversial, however: Some investigators recommend the procedure during childhood, whereas others advocate waiting until after puberty to allow feminization because of augmented estradiol secretion. If the testes are to be removed after puberty, the caregiver must be careful in explaining to the patient the reason for the procedure and should not refer to the gonads as testicles. After gonadectomy, estrogen support must be initiated. Individuals with an incomplete form of androgen resistance have a variable phenotypic appearance. The müllerian structures are absent, and the wolffian structures are generally hypoplastic. In some cases, significant virilization occurs at puberty. In general, a male gender assignment should be made only if there is an excellent response with significant phallic growth after parenteral administration of testosterone. In boys with a 5α-reductase deficiency, pseudovaginal perineoscrotal hypospadias is apparent. These boys have normal testes and wolffian duct derivatives, but external virilization is absent. Although some of these boys may be assigned a female gender, marked virilization occurs at puberty with penile enlargement, testicular descent, scrotal rugation, and deepening of the voice. Consequently, these patients are good candidates for a male gender assignment if they have an adequate response to parenteral androgens. In children with a 46,XY karyotype and a disorder in testosterone synthesis, the genital appearance is variable, from female to hypospadiac male. However, the tissue response to testosterone stimulation should be normal. Some of these patients, such as those with a 17α-dehydrogenase defect, eventually restore their capacity for testosterone synthesis and show significant virilization at puberty. All have bilateral testes, which may be intraabdominal, inguinal, or labioscrotal. In these patients, the enzyme defect should be identified and androgen stimulation initiated to determine whether there is sufficient penile growth response to allow a male gender assignment. Children with persistent müllerian duct syndrome have a normal penis and wolffian duct derivatives but internally have a fallopian tube or tubes and a uterus. The likelihood of gonadal malignancy is low. These patients are reared as boys, but the likelihood of fertility is reduced. Complete excision of the müllerian duct derivatives often results in injury to the vas deferens and is often unnecessary. In neonates with mixed gonadal dysgenesis, the phenotypic appearance is variable, from predominantly masculine to predominantly feminine. After puberty, the testis contains no spermatogonia. Consequently, the patient is sterile, irrespective of gender assignment. Furthermore, in 25% of cases, a gonadal tumor develops, either in the streak or in the testis. If the patient has a female phenotype, a female gender assignment should be made. However, those with a normal-sized phallus and a scrotal testis can be reared as male. In such patients, the streak gonad should be promptly removed. If a child with mixed gonadal dysgenesis is reared as a boy, the short stature may be treated with growth hormone. Patients with pure gonadal dysgenesis have bilateral streak gonads and a female phenotype without ambiguous genitalia. Because the risk of tumor development in the streak is 30%, prophylactic gonadectomy is necessary. Patients with true hermaphroditism have variable karyotypes and phenotypes. Gender assignment in these patients can be a difficult decision. In general, ovarian tissue functions better than testicular tissue. For example, the ovary produces estrogen in a cyclic pattern that allows breast development and, in some cases, menses and ovulation. In fact, pregnancy in true hermaphrodites has been reported. In contrast, spermatogenesis in testicular tissue is uncommon, and testosterone production is often inadequate. Furthermore, testes have a 2% to 3% likelihood of undergoing malignant degeneration. Nevertheless, approximately 70% of affected patients are assigned a male gender. The most important criterion is the phallic size. If the penis is small, one way to test it is to measure the serum testosterone level and reassess stretched penile length after hCG stimulation,
because a poor response to hCG is predictive of poor penile growth and masculinization at puberty. After a decision regarding assignment of gender, all discordant gonadal tissue must be removed. In addition, if a female gender assignment is made, feminizing genitoplasty should be performed before hospital discharge.
RED FLAGS Danger signs include manifestations of adrenal insufficiency, in addition to a male phenotype without a palpable testis in the scrotum, hyperpigmentation (increased ACTH production), and hypertension. Although normal at birth, male patients with CAH experience an adrenal crisis once circulating placental-maternal steroid hormones are catabolized and excreted. This phenomenon often occurs between the 3rd and 10th days of life. The initial diagnosis in the boy with salt-losing CAH may be sepsis, pyloric stenosis, meningitis, or other more common neonatal conditions.
REFERENCES Ahmed SF, Cheng A, Dovey L, et al: Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab 2000;85:658. American Academy of Pediatrics Section on Endocrinology and Committee on Genetics: Technical report: Congenital adrenal hyperplasia. Pediatrics 2000;106:1511. Barthold JS, Kumasi-Rivers K, Uphadhyay J, et al: Testicular position in the androgen insensitivity syndrome: Implications for the role of androgens in testicular descent. J Urol 2000;164:497. Baskin LS: Fetal genital anatomy reconstructive implications. J Urol 1999;162:527. Berenbaum SA: Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm Behav 1999;35:102. Birnbacher R, Marberger M, Weissenbacher G, et al: Gender identity reversal in an adolescent with mixed gonadal dysgenesis. J Pediatr Endocrinol Metab 1999;12:687. Borer JG, Nitti VW, Glassberg KI: Mixed gonadal dysgenesis and dysgenetic male pseudohermaphroditism. J Urol 1995;153:1267. Cheikhelard A, Luton D, Philippe-Chomette P, et al: How accurate is prenatal diagnosis of abnormal genitalia? J Urol 2000;164:984. Damiani D, Fellous M, McElreavey K, et al: True hermaphroditism: Clinical aspects and molecular studies in 16 cases. Eur J Endocrinol 1997; 136:201. DeSautel MG, Stock J, Hanna MK: Müllerian duct remnants: Surgical management and fertility issues. J Urol 1999;162:1008. Diamond M: Pediatric management of ambiguous and traumatized genitalia. J Urol 1999;162:1021. Diamond M, Sigmundson HK: Sex reassignment at birth: Long term review and clinical implications. Arch Pediatr Adolesc Med 1997;151:298. Farkas A, Chertin B, Hadas-Halpren I: 1-Stage feminizing genitoplasty: 8 years of experience with 49 cases. J Urol 2001;165:2341. Forest MG: Prenatal diagnosis, treatment, and outcome in infants with congenital adrenal hyperplasia. Curr Opin Endocrinol Diabet 1997;4:209. Forest MG: Diagnosis and treatment of disorders of sexual development. In DeGroot LJ, Jameson JL (eds): Endocrinology, 4th ed. Philadelphia, WB Saunders, 2001, p 1974. Ganesan A, Smith GHH, Broome K, et al: Congenital adrenal hyperplasia: Preliminary observations of the urethra in 9 cases. J Urol 2002;167:275. Grumbach MM, Conte FA: Disorders of sex differentiation. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds): Williams Textbook of Endocrinology, 9th ed. Philadelphia, WB Saunders, 1998, p 1303. Hovatta O: Pregnancies in women with Turner’s syndrome. Ann Med 1999;31:106. Kaefer M, Diamond D, Hendren WH, et al: Incidence of intersexuality in children with cryptorchidism and hypospadias: Stratification based on gonadal palpability and meatal position. J Urol 1999;162:1003. Kuhnle U, Bullinger M, Schwarz HP: The quality of life in adult female patients with congenital adrenal hyperplasia: A comprehensive study of the impact of genital malformations and chronic disease on female patients’ life. Eur J Pediatr 1995;154:708.
Chapter 31 Ambiguous Genitalia Meyer-Bahlburg HFL: Variants of gender differentiation. In Steinhausen H-C, Verhulst FC (eds): Risks and Outcomes in Developmental Psychopathology. New York, Oxford University Press, 1999, p 298. Meyer-Bahlburg HFL, Gruen RS, New MI, et al: Gender change from female to male in classical congenital adrenal hyperplasia. Horm Behav 1996; 30:319. Miller WL: Dexamethasone treatment of congenital adrenal hyperplasia in utero: Experimental therapy of unproved safety. J Urol 1999;162:537. Mueller RF: The Denys-Drash syndrome. J Med Genet 1994;31:471. Reiner WG, Gearhart JP, Jeffs R: Psychosexual dysfunction in males with genital anomalies: Late adolescence, Tanner stages IV to VI. J Am Acad Child Adolesc Psychiatr 1999;38:865. Schober JM: Long-term outcomes and changing attitudes to intersexuality. BJU Int 1999;83(Suppl 3):39. Schober JM: Sexual behaviors, sexual orientation and gender identity in adult intersexuals: A pilot study. J Urol 2001;165:2350.
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Shapiro E: Sonographic appearance of normal and abnormal fetal genitalia. J Urol 1999;162:530. Slijper FME, Drip SLS, Molenaar JC, et al: Long-term psychological evaluation of intersex children. Arch Sex Behav 1998;27:125. Sheldon CA, Gilbert AA, Lewis AG: Vaginal reconstruction: Critical technical principles. J Urol 1994;152:190. Snyder HM, Retik AB, Bauer SB, et al: Feminizing genitoplasty: A synthesis. J Urol 1983;129:1024. Speiser PW: Prenatal treatment of congenital adrenal hyperplasia. J Urol 1999;162:534. Stratakis CA, Rennert OM: Congenital adrenal hyperplasia: Molecular genetics and alternative approaches to treatment. Crit Rev Clin Lab Sci 1999;36:329. Zucker KJ, Bradley SJ, Oliver G, et al: Psychosexual development of women with congenital adrenal hyperplasia. Horm Behav 1996;30:300.
32
Mental Retardation and Developmental Disability
Gregory S. Liptak
mildly affected group. Genetic methods help identify the cause in adolescents with severe retardation and may determine a diagnosis in about 80% of cases in which the cause was previously undiagnosed. These diagnoses include fragile X syndrome, Rett syndrome, CATCH-22 (cardiac defects, abnormal face, thymic hypoplasia, cleft palate, hypocalcemia—defects on chromosome 22), subtelomeric deletion syndromes, and Angelman syndrome.
DEFINITIONS Mental retardation is defined as limitations in intelligence and adaptive skills that begin in childhood. The formal definition of mental retardation has been based on the intelligence quotient (IQ) derived from formal testing. Unfortunately, although the IQ score is an average of many abilities, it has been viewed as a single entity. In 1992, the American Association on Mental Retardation defined mental retardation as an IQ less than 70 or 75, with onset of limitations before age 18 years and with limitations in two or more adaptive skills (Table 32-1). Further characterization is noted in Table 32-2. The association recommends that once a child has received a diagnosis of mental retardation, the strengths and weaknesses in four domains should be described. These domains are intellectual functioning and adaptive skills, psychological and emotional considerations, physical health and etiologic considerations, and environmental considerations. This process can then be used to identify the social supports that the child would require to maximize his or her potential. For example, a child could be described as “a 4-year-old child who is mentally retarded with good social skills but who needs supports in self-direction and safety.” The term developmental disability is used to describe a broader array of conditions, including mental retardation. Developmental disabilities may be isolated, as in the child with impaired vision, or may be multiple, as in the child with delays in fine motor, gross motor, and social functioning. There may be considerable overlap in specific disorders in terms of the affected functions (Fig. 32-1).
DIAGNOSIS Pursuing a single cause for delayed development in a child is important for providing insight into prognosis, recurrence risk, therapies, counseling, and linkage with a supportive group. From a community perspective, having specific diagnoses helps in the development of prevention strategies. However, it is not sufficient. Identification of the child’s functional abilities, strengths and weaknesses, overall physical health, and environmental factors is critical for optimizing the child’s health, development, and functioning. In addition, the origin of developmental disability is not apparent in many children, or there may be multiple possible causal factors or multiple disabilities. For example, as many as 23% of children with developmental disabilities may have two disabilities; 6% may have three or more. Even if a specific diagnosis cannot be made, early identification of developmental delay can lead to a program of early intervention or remediation that will improve the child’s ultimate functioning. IDENTIFICATION
EPIDEMIOLOGY
Identifying a child who is at increased risk for developmental delay requires a process of selection (screening). The screening process may be minimal, as with the child who has obvious multiple congenital anomalies or when the parents express concern about their child’s development; or the screening may require a more formal test, as in the general screening of children who have no apparent risk factors. Once a child is identified as being at increased risk, a comprehensive evaluation needs to be performed. The greater the number of biologic risk factors, the greater is the likelihood that the child will develop abnormally. For prenatal and perinatal risk factors, a combination of three or more factors was predictive of later developmental delay; in one study, 11% of mothers had three or more risk factors but accounted for 43% of the children with disabilities.
Developmental disabilities are common; about 5.5% of patients in a general practice may have cognitive and language disorders, and 4.0% may have motor abnormalities. These disabilities and their prevalence rates per 1000 children include (1) mental retardation (10.3), (2) cerebral palsy (CP) (2.0), (3) hearing impairment (1.0), and (4) visual impairment. Overall, chromosomal disorders (24%), syndromes (12%), perinatal-postnatal hypoxic-ischemia or infectious or traumatic injury (2.6%), intrauterine infection (7%), inborn errors of metabolism (5%), and undetermined factors (18%) account for most instances of severe mental retardation (Table 32-3). Delayed development is more frequent in certain populations, such as those of low socioeconomic status, including the homeless. The prevalence of specific conditions that cause developmental delay varies with gender, age (especially inasmuch as many conditions, such as chromosomal anomalies, are associated with high mortality rates and are less frequent after infancy), and location. The distribution of etiologic factors in children with mental retardation also differs with the degree of delay. Chromosomal disorders, such as trisomy 21 (Down syndrome), are more common in moderately and severely retarded individuals, whereas environmental deprivation is more common in those with mild retardation. The percentage of children having retardation with an unknown cause is also greater in the
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Biologic risks include intracranial hemorrhage; intrauterine growth retardation; very low birth weight (usually 5 years), or the Titmus tester (>4 years) should be performed. Loss of Hearing Early detection of hearing loss is critical for optimizing the language development of these children. Previous hearing screening strategies were based on identifying children at high risk for hearing loss. These strategies, however, missed a significant number of children. This has led to the implementation of universal hearing screening for newborns in some states. In areas where this has not been implemented, screening for hearing loss should begin in the neonatal period for newborns at high risk by using otoacoustic emissions or brainstem auditory evoked potentials. Criteria for classifying a child at high
Table 32-2. Severity of Mental Retardation and Adult Age Functioning Level
Mental Age as Adult*
Mild
9-11 yr
Moderate
6-8 yr
Severe
3-5 yr
Profound
Figure 34-2. Interaction of stresses acting on mother and crying infant. (Adapted from Hewson P, Oberklaid F, Menahem S: Infant colic, distress, and crying. Clin Pediatr 1987;26:74.)
Infant INFANT DISTRESS Temperament
Pain
Head Ears Eyes Abdomen Joint/bone
Feeding problems
Underfeeding Overfeeding Inappropriate feeding
Discomfort
Wet Cold Hot Insufficient contact Excessive contact
Other (colic)
Cow's milk allergy Excessive gas Prenatal influences
Chapter 34 The Irritable Infant seizures, poor feeding, hiccups, diarrhea, sleeplessness, hyperactivity, and tremors. Treatment of neonatal drug withdrawal includes replacing the opiate with paregoric or methadone or suppressing symptoms with phenobarbital. In the evaluation of the irritable neonate, a careful infant and maternal drug history are important to obtain along with urine drug toxicology profile if indicated. IMMUNIZATION REACTIONS Some infants may become irritable after administration of childhood immunizations. Irritability after administration of the diphtheriatetanus-pertussis vaccine was common, with fretfulness in 70% of infants and irritability for more than 3 hours after 1% of doses. Fortunately, it appears that the current practice of using an acellular pertussis component results in irritability much less commonly, although quantitative data are not available. The irritability associated with immunizations may be attenuated by acetaminophen.
SUMMARY AND RED FLAGS Although at times a simple diagnosis is easily established, the infant with excessive irritability often presents a significant challenge. Establishment of the likely diagnosis, combined with exclusion of significant pathophysiologic processes (see Table 34-3), is a prerequisite to the formulation of an appropriate management plan. Through a logical and stepwise approach, the clinician can usually establish the cause and develop a treatment plan (see Table 34-1). When the clinician cannot determine the underlying cause, close follow-up monitoring should result in optimal patient care. Red flags include inconsolability; abnormal level of consciousness or abnormal vital signs; evidence of trauma or anemia (blood loss, sickle cell, leukemia); vomiting; diarrhea; hematochezia and abdominal tenderness or distention; signs of tourniquet syndrome; eye tearing, photophobia, or conjunctival irritation (corneal abrasion); abnormalities of growth, including head circumference; and signs of cardiorespiratory compromise. REFERENCES The Irritable Infant Harkness M: Corneal abrasion in infancy as a cause of inconsolable crying. Pediatr Emerg Care 1989;5:242-244. Ludwig S: Shaken baby syndrome: A review of 20 cases. Ann Emerg Med 1984;13:104-107. Poole S: The infant with acute, unexplained, excessive crying. Pediatrics 1991;88:450-455. Reijneveld SA, Brugman E, Hirasing RA: Excessive infant crying: The impact of varying definitions. Pediatrics 2001;108:893-897. Trocinski D, Pearigen P: The crying infant. Emerg Med Clin North Am 1998;16:895-910.
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Hardoin R, Henslee J, Christenson C: Colic medication and apparent lifethreatening events. Clin Pediatr 1991;30:281-285. Hill DJ, Heine RG, Cameron DJS, et al: Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr 2000;136:641-647. Hill D, Menahem S, Hudson I, et al: Charting infant distress: An aid to defining colic. J Pediatr 1992;121:755-758. Hunziker U, Barr R: Increased carrying reduces infant crying: A randomized controlled trial. Pediatrics 1986;77:641-648. Lothe L, Lindberg T: Cow’s milk whey protein elicits symptoms of infantile colic in colicky formula-fed infants: A double-blind crossover study. Pediatrics 1989;83:262-266. Lothe L, Lindberg T, Jakobsson I: Cow’s milk formula as a cause of infantile colic: A double-blind study. Pediatrics 1982;70:7-10. Lucassen PLBJ, Assendelft WJJ, Gubbels JW, et al: Effectiveness of treatments for infantile colic. BMJ 1998;316:1563-1569. Miller A, Barr R: Infantile colic: Is it a gut issue? Pediatr Clin North Am 1991;38:1407-1423. Parkin P, Schwartz C, Manuel B: Randomized controlled trial of three interventions in the management of persistent crying of infancy. Pediatrics 1993;92:197-201. Singer J: A fatal case of colic. Pediatr Emerg Care 1992;8:171-172. St James-Roberts I: Persistent infant crying. Arch Dis Child 1991;66: 653-655. St James-Roberts I: Managing infants who cry persistently. BMJ 1992;304:997-998. Taubman B: Parental counseling compared with elimination of cow’s milk or soy milk protein for the treatment of infant colic syndrome: A randomized trial. Pediatrics 1988;81:756-761. Tourniquet Syndromes Alpert J, Filler R, Glaser H: Strangulation of an appendage by hair wrapping. N Engl J Med 1965;273:866-867. Curran J: Digital strangulation by hair wrapping. J Pediatr 1966;69:137-138. Haddad F: Penile strangulation by human hair. Urol Int 1982;37:375-388. McClure W, Gradinger G: Hair strangulation of the glans penis. Plast Reconstr Surg 1985;76:120-123. McNeal R, Cruickshank J: Strangulation of the uvula by hair wrapping. Clin Pediatr 1987;26:599-600. Teething Macknin M, Piedmonte M, Jacobs J, et al: Symptoms associated with infant teething: A prospective study. Pediatrics 2000;105:747-752. Seward M: Local disturbances attributed to eruption of the human primary dentition. Br Dent J 1971;130:72-77. Seward M: General disturbances attributed to eruption of the human primary dentition. J Dent Child 1972;39:178-183. Drug Reactions Chasnoff I, Lewis D, Squires L: Cocaine intoxication in a breast-fed infant. Pediatrics 1987;80:836-838. Mortimer E: Drug toxicity from breast milk? [letter]. Pediatrics 1977;60: 780-781. Rogers W: Fussy baby: A new cause [letter]. Pediatrics 1979;63:347-348. Zuckerman B, Bresnahan K: Developmental and behavioral consequences of prenatal drug and alcohol exposure. Pediatr Clin North Am 1991; 38:1387-1406.
Infantile Colic Barr R, Kramer M, Pless I, et al: Feeding and temperament as determinants of early infant crying/fussing behavior. Pediatrics 1989;84:514-521. Barr R, McMullan S, Spiess H, et al: Carrying as colic “therapy”: A randomized controlled trial. Pediatrics 1991;87:623-630. Carey W: The effectiveness of parent counseling in managing colic. Pediatrics 1994;94:37. Danielsson B, Hwang C: Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr Scand 1985;74:446-450. Garrison M, Christakis D: A systematic review of treatments for infant colic. Pediatrics 2000;106:184-190.
Vaccine Reactions Ipp M, Gold R, Greenberg S, et al: Acetaminophen prophylaxis of adverse reactions following vaccination of infants with diphtheria-pertussistetanus toxoids-polio vaccine. Pediatr Infect Dis J 1987;6:721-725. Long S, Deforest A, Smith D, et al: Longitudinal study of adverse reactions following diphtheria-tetanus-pertussis vaccine in infancy. Pediatrics 1990;85:294-302. Pickering L (ed): American Academy of Pediatrics 2000 Red Book: Report of the Committee on Infectious Diseases, 25th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2000.
35
Unusual Behaviors
William J. Swift
Hugh F. Johnston*
9% have thought of suicide, 2% have seriously considered suicide, and 1% have attempted suicide. Among college students, there is a fivefold increase in suicide ideation, with 43% thinking of suicide at some point, 15% seriously considering suicide, and 5% attempting suicide. Because of this high prevalence of suicide ideation, the assessment for the risk of suicide is the first part of the evaluation of any child who presents with unusual behaviors. The approach in evaluating suicide ideation is based on whether the child is just thinking of suicide or is making suicide threats or attempts (Fig. 35-1).
Unusual behaviors in children are common and consist of psychiatric conditions that range from variations in normal behavior to lifethreatening suicide attempts. Almost 20% of children have a diagnosable psychiatric illness that can result in a high degree of stress in the family. These unusual behaviors may be grouped into the following chief complaints: suicidal thoughts and attempts, disruptive behaviors, hallucinations, unexplained physical complaints, and delayed development.
HISTORY
SUICIDAL THOUGHTS When suicidal ideation is present, most parents report that the child has previously thought of committing suicide. However, the office interview may be the first time that the child verbalizes this thought. The clinician needs to determine the seriousness of these thoughts. To assess risk, the interviewer should focus on the risk factors for completed suicides. These risk factors are male sex, adolescence, conscious plan, available means (medications or firearms), depression, hopelessness, impulsiveness, low frustration tolerance, use of intoxicants, sexual identity conflicts, recent death of family member or friend, and previous suicide attempts. Although depression is an important risk factor for suicide, only half of adolescents who attempt suicide have clinically diagnosable depression. In the nondepressed group, the crucial characteristics for suicide are impulsivity and low frustration tolerance. Other than for the most frivolous thoughts of suicide, any adolescent who is thinking of suicide should be persuaded to discuss this issue with a responsible adult and should be encouraged to seek counseling. If significant risk factors exist for suicide, the patient should be referred to a child psychiatrist or other mental health provider on an emergency basis.
The history is the most important tool for identifying the psychiatric disorder (Table 35-1). The first step in conducting the history is to ensure the child’s safety with regard to injury to the child either by the child (suicide attempt) or by someone else (physical or sexual abuse). After the child’s safety is ensured, the history should focus on the stressors that may be precipitating the behavior and on the symptoms that may distinguish which disorder or disorders are causing the behavior. Besides psychiatric illnesses, the clinician should also focus on possible medical causes of these behaviors, including medication side effects, substance abuse, and medical illnesses ranging from encephalopathies to endocrinopathies (e.g., hypothyroidism). Because comorbidity is common in children with psychiatric illnesses, the clinician should consider combinations of illnesses that may cause these symptoms. The clinician should obtain the information from multiple sources, interviewing the parents and the child separately, or interviewing other adults who have spent a significant amount of time with the child (e.g., a teacher). Interviewing the child separately provides a better chance of uncovering destructive behaviors (e.g., substance abuse or sexual activity) and of obtaining the child’s perspective. Because of the strong genetic predisposition in some of these disorders, a detailed psychiatric family history should be obtained. Often these disorders are undiagnosed; hence, the family history should include both the presence of symptoms and diagnoses in family members. Because many of these disorders have symptoms that occur in clusters, a diagnostic manual that classifies these symptom clusters into individual diagnoses has been developed. This manual, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), contains descriptive diagnostic criteria that are based on the presence or absence of various symptoms.
SUICIDE THREATS AND ATTEMPTS Once the patient’s thoughts of suicide have escalated to suicide threats or attempts, the patient’s life is in great danger. This is a medical emergency; the patient should be immediately referred to an experienced mental health professional. Because the child’s problemsolving abilities and judgment are impaired, someone else must ensure the child’s safety. This usually necessitates a psychiatric hospitalization. Only after suicide risk is accurately assessed can outpatient management be considered. After a suicide gesture or attempt, the accuracy of this assessment depends on the patient’s cooperating and having a clear consciousness. If the patient is uncooperative, stuporous, or confused, the evaluation results are unreliable, and the patient is assumed to be potentially suicidal. Once the patient is alert, he or she must be able to communicate a plausible theory that led to the suicidal behavior. Without such a theory, the patient has no insight into his or her actions, and hence the clinician cannot predict whether the suicide attempt will be repeated. Even with a plausible theory, the crucial factors that led to the act must be changed before the clinician can
SUICIDAL THOUGHTS AND ATTEMPTS Suicide is the third leading cause of death in adolescents. The thought of killing oneself as a solution to a problem is common among adolescents and young adults. Of children younger than 15 years, *This chapter is an updated and edited version of the chapter by Theodore Reeves Warm and Robert L. Findling that appeared in the first edition.
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into those treated by a primary health care provider and those that should be treated by a mental health specialist.
Table 35-1. Essential Elements of the Patient’s History
Assess suicide potential (ensure safety) Interview child alone Interview multiple sources Obtain family history for symptoms and disorders Rule out medical causes, including substance use Consider comorbidities Inquire about past mental health referrals
CHRONIC DISRUPTIVE BEHAVIOR
consider discharging the patient from the hospital. A highly agitated mental state may also suggest high suicide risk. Finally, the patient must be sincerely glad to be alive. People who have attempted suicide frequently promise that they will not do it again. Because of the high incidence of repeat attempts, these promises are unreliable. The combination of not being remorseful, no plausible theory, and being unable to resolve or change the initiating factors warrants inpatient care and is a red flag. Because of the inherent difficulties in predicting suicidal acts, it is best for the clinician to err on the side of safety when in doubt.
DISRUPTIVE BEHAVIORS Disruptive behaviors are the most common chief complaint of unusual behavior in a patient presenting to a health care provider’s office. These behaviors may be associated with a wide variety of diagnoses, ranging from attention-deficit/hyperactivity disorder (ADHD) to schizophrenia. These conditions may be divided into those that are chronic (Fig. 35-2) and those that are episodic and recent in onset (Figs. 35-3 and 35-4). Disruptive behaviors may be further subdivided
Chronic disruptive behaviors are usually brought to the attention of the health care provider because of an acute crisis (e.g., school failure, destruction of property). The precipitating event that leads to consultation may be an escalation in the severity of the behavior or a change in the family or school that makes such behaviors less tolerable. The DSM-IV lists three main diagnoses within the category of disruptive behavioral disorders: ADHD, oppositional defiant disorder (ODD), and conduct disorder. It is common for a child to present with combinations of these disorders. Treatment by Primary Care Physician Attention-Deficit/Hyperactivity Disorder
The cardinal features of this condition are hyperactivity (being fidgety, on the move), distractibility (short attention span), and impulsiveness (acting without forethought) (Table 35-2). The prevalence of this condition is four to nine times higher in boys than in girls. Difficulty in appropriately diagnosing this disorder is in differentiating age-appropriate hyperactivity/inattentiveness from pathologic behavior. The DSM-IV has divided this condition into three subtypes: ADHD—combined type; ADHD—predominantly inattentive type; and ADHD—predominantly hyperactive-impulsive type. To diagnose these conditions, the examiner must note at least six of nine symptoms for inattention or six of nine symptoms for hyperactivity/impulsivity. Symptoms must be present for at least 6 months, be maladaptive, and be inconsistent with the child’s developmental age.
Thinking of Suicide
Suicide Threats/Attempts
Assessment by primary care provider
Assessment by mental health professional
Suicide risk factors
Suicide risk factors plus: Alert? Plausible theory? Factors changed? Glad to be alive?
Risk for suicide threat/attempt
Risk for repeated attempt
Negligible risk
Low to high risk
Negligible risk
Low to high risk
Alert parents, encourage referral to mental health professional
Alert parents, emergent referral to mental health professional
Outpatient management
lnpatient management
Figure 35-1. Assessment of suicide ideation.
Chapter 35 Unusual Behaviors Treatment by Clinician
Referral to Psychiatrist
Symptoms
Symptoms
Overactive Impulsive Inattention
Rebellious
Oppositional Defiant Disorder
ADHD
Antisocial
ADHD- Inattentive Conduct disorder ADHD- HyperactiveImpulsive
Tics (motor/vocal)
Belligerence Mood liability Cognitive impairment Cage questionnare
Transient tic disorder Substance use disorders Chronic motor or vocal tic disorder
Substance dependence
Tourette disorder
Substance abuse Substance-induced disorders Intoxication Withdrawal
Figure 35-2. Evaluation of chronic disruptive behaviors. ADHD, attentiondeficit/hyperactivity disorder.
The nine symptoms of inattention are (1) careless schoolwork, (2) difficulty in sustaining attention, (3) inattentiveness (child does not listen), (4) failure to finish work, (5) disorganization, (6) avoidance of tasks that require sustained attention, (7) loss of objects necessary for tasks, (8) easy distractibility, and (9) forgetfulness. The nine symptoms of hyperactivity/impulsivity are (1) fidgeting or squirming in one’s seat, (2) inappropriately getting out of one’s seat, (3) inappropriately running or climbing on objects, (4) inability to play quietly, (5) often being on the go, (6) talking excessively, (7) stating answers before questions are completed, (8) difficulty in waiting one’s turn, and (9) interrupting others. For the diagnosis, some of these symptoms must be present before the child is 7 years of age, they must occur in at least two separate settings (home, school), and they must significantly impair the child’s social or academic function. The chronic hyperactivity of this syndrome may be subtle. Although children with ADHD tend to move around more than other children, the hyperactivity may be of concern only in certain situations. These circumstances are those in which the child is expected to be quiet (school, places of worship). Some children with ADHD can sit and be attentive in quiet and relaxed situations, whereas a noisy and active setting (unstructured classroom) precipitates inappropriate behavior. As these children become older, they also become less overtly hyperactive; an adolescent may only feel restless. This restlessness may also significantly contribute to academic underachievement. Despite intentions for diligent studying, the restlessness may cause the affected teenager to feel the need to walk around, which distracts him or her from studies.
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Impulsivity significantly contributes to the child’s morbidity. Just as impulsive children’s activities change rapidly, so do their emotions. An impulsive child whose emotions quickly escalate is at risk for physically aggressive behaviors such as hitting or biting. In older children, the impulsive aggression is manifested as explosive behavior. Because of their explosive behavior, inability to wait their turn in a game, and then talking back to teachers, these children have great difficulty with both peer and teacher relations. Impulsivity can also be potentially life-threatening because the child may act before considering the consequences. This may manifest as risk-taking behaviors (sexual activity, substance use) or as actions such as running into the street after a ball without checking for oncoming traffic. Hyperactivity and impulsivity in children are readily apparent to adults; however, the manifestations of inattention and distractibility are not as overtly visible. In young children, inattentive behavior consists of shifting from one activity to another and having difficulty finishing tasks. The parents may incorrectly consider these actions to represent a lack of motivation. In adolescents, inattentive behavior may result in poor school performance. These children may forget to do homework or may need excessively long periods to complete assignments because of their inability to focus on their work. Because the assumptions about an inattentive child’s character are often inaccurate (lazy, behavior problem), the clinician should consider the diagnosis of attention-deficit disorder (with or without hyperactivity) in any child who is academically underachieving. Potential problems in the diagnosis of ADHD are the duration of symptoms, the definition of abnormal age-specific symptoms, and the absence of symptoms in certain settings. Because ADHD is a chronic disorder, the diagnosis necessitates that symptoms be present for at least 6 months. Acute changes in a child’s behavior are usually the result of a recent psychological stressor and should not be considered a part of ADHD. The second problem is defining when a behavior is abnormal. Children normally become less active and impulsive as they get older. The classroom teacher represents an excellent resource who can determine whether the patient’s level of activity and degree of impulsivity are abnormal. Standardized behavioral checklists (filled out by the parents and teachers) report the degree of patient’s abnormal behaviors with regard to an age-specific reference population. The final problem is the common misconception that hyperactive children demonstrate their inattentive, impulsive, and hyperactive behaviors in the examination room. Most children with ADHD are attentive and still during a brief outpatient visit. The clinician should not rely on observations performed in the office but should instead obtain information from multiple sources, including parents, teachers, day care workers, and even a direct classroom observation by a trained health care professional. Before settling on a diagnosis of ADHD, the clinician must rule out the other psychiatric and medical causes for these symptoms. Some of the psychiatric conditions that may resemble this condition or occur with it are learning disorders, oppositional behavior, and other psychiatric illnesses that may better account for the symptoms (pervasive developmental disorders, mood disorders, anxiety disorders, substance abuse). Because of the high association of learning disorders with ADHD, each evaluation should include an assessment for learning problems. This assessment consists of individual testing by a psychometrician to assess the child’s abilities and deficiencies. Because of the genetic predisposition to ADHD, a psychiatric family history should also be obtained. In this family history, the parents may report feelings of restlessness or difficulties in completing tasks. In the medical evaluation for ADHD, further diagnostic testing should be directed by the results of a complete history and thorough physical examination. The preschool-aged child should be screened for lead poisoning and iron deficiency, whereas the older child should undergo further diagnostic tests, as directed by the results of history and physical examination, to rule out such conditions as hyperthyroidism, absence seizures, hearing loss, and substance abuse.
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588 TREATMENT BY CLINICIAN
REFERRAL TO PSYCHIATRIST
MENTAL STATUS CHANGES
STUPOR DISORIENTATION
DELUSIONS AND/OR HALLUCINATIONS Schizophrenia
Delirium
Schizophreniform Bipolar Disorders Bipolar I (Mania) Bipolar II (Hypomania) Mixed Disorder Cyclothymic
Figure 35-3. Evaluation of episodic disruptive behaviors.
LABILE EMOTIONS
REACTION TO STRESSOR
UNSTABLE RELATIONSHIPS IMPULSIVITY IDENTITY PROBLEM
Adjustment Disorder Borderline Personality Disorder
REFERRAL TO PSYCHIATRIST PERVASIVE EMOTIONS
DEPRESSED MOOD LOSS OF INTEREST
ADHD, a chronic illness, may cause problems throughout the patient’s lifetime. Psychotropic medications usually reduce some of the outward symptoms of this condition (e.g., hyperactivity); however, the patient can have significant morbidity unless the patient learns how to deal with the learning and behavior problems associated with this condition. Therefore, successful treatment requires a multidisciplinary approach consisting of family education, psychological counseling, academic remediation, behavior modification, and psychotropic medications.
Major Depressive Disorder EPISODES OF FEAR WORRY AVOIDANCE Anxiety Disorders Panic Disorder Generalized Anxiety Disorder Separation Anxiety Disorder Obsessive-Compulsive Disorder Post-Traumatic Stress Disorder Specific or Social Phobia ECCENTRICITY SOLITARINESS
Schizotypal Personality Disorder Figure 35-4. Evaluation of episodic disruptive behaviors with pervasive emotions.
Table 35-2. Challenges in Diagnosis and Treating
Attention-Deficit/Hyperactivity Disorder (ADHD) Problems in Diagnosing ADHD No hyperactivity report may be present in teenagers; instead, the patient may have only restlessness Differentiating inattention from lack of motivation is difficult Differentiating age-appropriate from pathologic behavior (behavioral checklists, teacher’s report) is difficult Hyperactive children have normal behavior in quiet, structured settings Sudden onset of hyperactivity is secondary to a stressor and not to ADHD Comorbidities (learning disabilities, conduct disorder, oppositional defiant disorder) should be ruled out Problems in Treating ADHD Treatment must be multifactorial and not consist just of stimulants Behavioral modification must have realistic goals, with consistent and frequent rewards
Chapter 35 Unusual Behaviors The first step in treating ADHD is to educate the family with regard to the causes, potential problems, chronicity, and treatment of this condition. Additional important resources are books from the lay press as well as support groups for parents who have children with ADHD. The second step in treating ADHD is to initiate coping skills that can be used to enhance socially appropriate behavior (e.g., task completion, turn taking in games) at home and in school. These coping skills include establishing a predictable schedule for family activities (bedtime, mealtime routines), distracting the child to another activity when the child’s excitement level accelerates, and instituting individually tailored, reward-based behavior modification techniques. For behavior modification to be successful, the following elements are essential: 1. 2. 3. 4. 5.
identification of specific behaviors to work on selection of tasks small enough to ensure the child some success an attractive chart for recording success reliable rewards with small items or privileges (preferably daily) small punishments for failure to comply (loss of television or telephone for the evening) 6. consistent reward and punishment for the corresponding behavior Some of the problems in successfully implementing behavioral techniques are unrealistic expectations, inconsistency, and delays in rewarding success. In the classroom, the child should be placed in the front to make classroom distractions less apparent to the child. Many children with ADHD have significant trouble with their self-esteem because of poor school performance, difficulty in peer relations, and intrafamilial discord. To address the child’s emotional issues and problems with self-image, the clinician may recommend psychotherapy. Behavior modification programs, psychosocial interventions, psychological therapies, and parent education are all useful interventions in the management of ADHD. However, for most children, the efficacy of such interventions is relatively small in comparison to the typical response produced by stimulant medication. Furthermore, many failed behavior modification programs become successful after the child has been appropriately treated with medications. Methylphenidate preparations (Ritalin, Concerta, and others) and amphetamine preparations (Dexedrine, Adderall, and others) are the mainstay of stimulant treatment. Pemoline (Cylert) has fallen out of favor because of this drug’s potential for causing liver toxicity. Three other classes of medications have demonstrated efficacy for ADHD: tricyclic antidepressant medications (e.g., imipramine, nortriptyline), bupropion (Wellbutrin), and antihypertensives belonging to the α2-agonist class such as clonidine (Catapres) and guanfacine (Tenex). The therapeutic effect of these alternative medications is, on balance, much less than that of the stimulants. Atomoxine (Strahera) is a promising nonstimulant option for the treatment of ADHD. Atomoxine is valuable for patients who do not tolerate or respond to stimulant medications. If stimulant therapy is initiated, the clinician needs to perform follow-up at regular intervals to assess efficacy (using such parameters as school performance, standardized behavioral checklists) and side effects (e.g., tics, tremors, hypertension, weight loss). Stimulants can cause weight loss by appetite suppression. Using the medication only on school days can minimize this effect. Because ADHD is associated with long-term dysfunction, children with this disorder are at increased risk for continuing academic underachievement and reduced occupational status in adulthood. Tic Disorders
Children with tic disorders usually present first to the primary care provider. According to the DSM-IV, tics are motor movements or vocalizations that are sudden, rapid, recurrent, nonrhythmic, and involuntary. Tics become worse during stress but may improve during activities requiring moderate (physical or mental) activity.
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Muscle spasms differ from tics because they are slower and last longer. Tics need to be differentiated from medication-induced movement disorders as well as from the abnormal movements associated with various neurologic conditions. Pathologic non-tic movements are chorea (dancing, random), athetosis (writhing, sinuous movements), dystonia (twisting, slow contractions), myoclonus (shocklike jerks), and hemiballismus (violent, unilateral motions). Simple motor tics may consist of eye blinking, neck jerking, or shoulder shrugging, whereas examples of complex motor tics are repetitive grooming behaviors, deep knee bends, and smelling of objects. Simple vocal tics may be throat clearing or grunting sounds, whereas complex vocal tics may consist of repeating inappropriate words or phrases (e.g., coprolalia—the repetitive, stereotyped vocalization of obscenities). According to the DSM-IV, conditions that make up the tic disorders are ● ●
●
transient tic disorder (motor or vocal tics of 1 year’s duration) Tourette disorder (motor and vocal tics > 1 year’s duration)
There is some evidence that group A β-hemolytic streptococcal infections are associated with pediatric autoimmune neuropsychiatric disorders (PANDAS) such as tics and obsessivecompulsive disorders (OCDs). The working criteria for a diagnosis of PANDAS are ● ● ● ● ●
presence of OCD and/or tic disorder pediatric onset abrupt onset and episodic course association with group A β-hemolytic streptococcal infections association with neurologic abnormalities, such as motor hyperactivity, choreiform movements, or tics
In children who meet these criteria, PANDAS should be considered, because antibiotic therapy may eradicate the OCD or tic symptoms. Tourette Disorder. Tourette disorder is a chronic illness consist-
ing of multiple motor and vocal tics of at least 1 year’s duration. The incidence of this condition is 4 to 5 per 10,000. In some families, this illness is inherited as an autosomal dominant condition, with 70% penetrance in female carriers and 99% penetrance in male carriers. Because of this difference in penetrance, Tourette disorder is 1.5 to 3 times more common in boys than in girls. The median age for presentation is 7 years, but some cases are reported as early as 2 years. Even though coprolalia is popularly thought to be associated with this illness, fewer than 10% of affected patients have this form of complex vocal tics. The DSM-IV criteria for Tourette disorder are 1. multiple motor and vocal tics lasting longer than 1 year with no tic-free intervals longer than 3 months 2. age of onset before 18 years 3. no medical causes (drugs, neurologic diseases) for the tics Children with chronic tic disorders frequently have other psychological conditions, such as ADHD and OCD. In addition, the tics may cause the patient’s peers to socially ostracize the patient. Because of the combination of ADHD and obsessive-compulsive behaviors with the tics, these children are not accepted by their peers and frequently frustrate their teachers and family members. This increase in stress can worsen the tics, which can further compound the problem. Because of these issues, the family may need counseling. If the symptoms are not severe, the only necessary therapy may be psychological support. If the symptoms become problematic, the patient may need to be treated with low dosages of antipsychotic drugs, such as haloperidol (Haldol) or pimozide (Orap). Risperidone (Risperdal), an atypical antipsychotic agent, has some efficacy in the treatment of Tourrette disorder. Because pimozide can cause the
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prolongation of the QT interval, an electrocardiogram should be obtained before therapy is initiated and at regular intervals. Because stimulant therapy can aggravate tics, children with both Tourette disorder and ADHD may be treated with clonidine. In patients with chronic tics and OCDs, both conditions may be treated with medications that potentiate serotonin activity (clomipramine or a selective serotonin reuptake inhibitor).
modalities (individual, group, family) are employed to improve the child’s functioning. The role of the primary care provider is early recognition and referral to a mental health specialist. Success of therapy depends on early intervention before the dysfunctional patterns are firmly established. The clinician can enhance compliance with psychotherapy by being supportive and by explaining to the family that therapy often requires months of slow progress and demands active family participation.
Treatment by Psychiatrist When treating children severely affected by disruptive behavioral disorder symptoms (or any severe psychiatric disorder), the primary care provider is best advised to team up with the local mental health “system” in providing ongoing care (see Fig. 35-2). This system might include a social worker to provide counseling therapy and overall case coordination; a chemical dependency specialist if addictions are an issue; a psychologist to provide psychometric testing and to assist with school programming, and a child and adolescent psychiatrist if there are unusually complex medication and/or psychological issues. Oppositional Defiant Disorder
Oppositional defiant disorder is a chronic condition in which the patient is stubbornly rebellious toward all authority. This behavior is more than just a reaction to a stressful situation or the normal show of independence during adolescence. According to the DSM-IV, affected patients exhibit a consistent pattern during a 6-month period of at least four or more of the following behaviors: 1. 2. 3. 4. 5. 6. 7. 8.
frequently losing temper often arguing with authority figures defying rules deliberately annoying adults blaming others for his or her actions becoming easily annoyed by others being angry being vindictive
This diagnosis should not be made if the patient meets the DSM-IV criteria for conduct disorder or if the symptoms occur during the course of a mood, anxiety, or psychotic disorder. In mood and psychotic disorders, children exhibit oppositional behavior as a reaction to their illness and hence they should be classified under their primary mood or psychotic disorder. The prevalence of ODD ranges from 2% to 16%, depending on the population. In prepubertal children, it occurs more frequently in boys; however, in adolescents, its incidence is equal in both sexes. Most children present before 8 years of age. Affected preschool-aged children sometimes exhibit increased motor activity and difficulty in being comforted, and they overreact to situations. Affected schoolaged children have low self-esteem and a low tolerance for frustration. Some of the theories on the causes of ODD are learned behavior (secondary gain from defiant behavior), fixation at a negative stage of behavior development (the “terrible twos”), and poor parenting skills. There may also be a genetic component because the disorder commonly occurs in families with mood or psychotic disorders (especially with maternal depression) and with chronic disruptive behaviors (ADHD, conduct disorder). Children with ODD are at marked risk for other psychological disorders. Because of the association of ADHD with ODD, children with ODD should also be evaluated for ADHD. In addition, these patients may be at increased risk for conduct disorder, antisocial personality disorder (as adults), substance abuse, major depressive disorder, and suicide. Because of the difficulty in treating ODD, mental health professionals are the ones who usually manage this condition. Therapy is directed toward treating comorbid disorders (ADHD, substance abuse, suicide ideation). In addition, various psychotherapeutic
Conduct Disorder
Children who chronically violate the rights of others may be diagnosed as having conduct disorder. According to the DSM-IV, a child has conduct disorder if he or she has repetitively violated the rights of others and of society. Children with this diagnosis have performed three or more of the following behaviors within the past year with at least one occurring in the previous 6 months: 1. aggression toward people or animals (intimidation, initiation of fights; use of weapons; cruelty to people; cruelty to animals; rape; confrontational theft [“mugging”]) 2. destruction of property (arson, vandalism) 3. deceitfulness (nonconfrontational theft [house breaking, “conning”]) 4. serious violation of rules (curfew violation, running away, truancy before age 13) For running away to qualify as a symptom, it must occur twice (or once if it was lengthy) and must not be an attempt to escape sexual or physical abuse. Conduct disorder is subdivided into childhood onset (symptoms occur before 10 years of age) and adolescent onset (symptoms occur at or after 10 years of age). It is also subdivided by severity of the offense, such as mild (truancy), moderate (vandalism, nonconfrontational theft), and severe (rape, confrontational theft). The prevalence of conduct disorders is higher among males than females. Children initially present with lying, initiating of fights, and truancy; as they get older, they progress to more violent acts. Boys are more likely to exhibit acts of violence (fighting and stealing) than are girls, who are more likely to exhibit truancy, runaway behavior, and sexual promiscuity. Of concern is that 50% of these children may develop antisocial personality disorder, which is a severe conduct disorder of adulthood that is usually associated with criminal activity; the earlier the onset of conduct disorder, the greater is the risk of developing antisocial personality disorder as an adult. These children have a high frequency of depression (suicide ideation), personality disorders, anxiety disorders, ADHD, and substance abuse. Although the cause of conduct disorder is unknown, both genetic and psychosocial factors play a role. The psychosocial factors associated with conduct disorder are parental rejection, difficult infant temperament, physical or sexual abuse, early institutional living, and lack of appropriate discipline. A biochemical or genetic cause for this condition has been postulated because of the high prevalence of this condition in families with psychiatric disorders, ADHD, and conduct disorder. Therapy is best managed by mental health professionals. The therapy consists of individual and/or family psychotherapy, judicious use of residential treatment centers, and treatment of comorbid conditions (substance abuse, ADHD, depression). The behavior in children with conduct disorders can markedly improve if their ADHD is treated with stimulants and their depression is treated with antidepressants. The success of therapy depends on early recognition and intervention before the destructive behaviors are firmly established. The role of the primary care provider is early recognition, referral, and enhancement of compliance with treatment. Unfortunately, there is no compelling evidence to suggest that any treatment is effective for severe conduct disorder. As a result, behavioral containment and control to protect the individual and society may be the most feasible goals.
Chapter 35 Unusual Behaviors Substance Use
The presence of unusual disruptive behaviors can be the result of the intoxication or the withdrawal of a psychoactive agent. Some of these behaviors are belligerence, mood lability, and cognitive impairment. As many as 90% of high school seniors have tried psychoactive drugs (nicotine or ethanol), and almost 60% have tried illicit drugs. Almost 20% of high school seniors drink ethanol to the point of intoxication on a weekly basis. More than half of adolescents who drink do so in automobiles. Some of the illicit drugs used are tetrahydrocannabinol (THC, found in marijuana), central nervous system (CNS) depressants (benzodiazepine, phenobarbital), hallucinogens (lysergic acid diethylamide [LSD], methylenedioxymethamphetamine [MDMA or “ecstasy”], phencyclidine piperidine [PCP]), opiates (heroin), stimulants (sympathomimetics, amphetamine, cocaine), and inhalants (toluene, Freon, nitrous oxide). The DSM-IV divides the diagnoses attributable to drugs into substance use (dependence and abuse) and substance-induced disorders (intoxication, withdrawal). Substance dependence according to the DSM-IV consists of three or more symptoms occurring at the same time during a 12-month period: 1. tolerance (higher doses of the drug are needed to achieve the same effect) 2. withdrawal (the drug is needed to suppress symptoms) 3. drug use that entails taking larger amounts or use over a longer period than intended 4. desire or effort to cut down use 5. drug-seeking activity 6. social or occupational impairment 7. continued use despite physical or psychological complications Substance abuse is considered present when any drug use leads to significant adverse consequences, such as repetitive absences from work or school, expulsion from school, driving while impaired, and arrests. The diagnosis of substance abuse does not require tolerance or withdrawal. The role of the primary care provider is to identify the patients who are using or abusing drugs. This identification can be made by the patient history, the results of the physical examination, and urine toxicology testing. Because of the high prevalence of substance use, the clinician should have a high index of suspicion in any patient who presents with psychiatric symptoms, high-risk behaviors (runaway, delinquency), unexplained somatic complaints, and acute changes in behavior or mental status (Tables 35-3 and 35-4). The interview should begin without the presence of the parents and should be conducted in a manner that does not make the patient defensive. The interview may begin with the clinician asking whether the patient’s friends have ever tried drugs and whether the patient has ever partied with these friends. One series of questions that may assist the clinician in determining whether a patient has a substance use disorder is the so-called CAGE questionnaire (Table 35-5). The CAGE questionnaire has a sensitivity of 90% and a specificity of 79% for detecting ethanol abuse. This questionnaire may also be used for other substances. If there is suspicion of substance abuse, urine and blood toxicology testing should be performed. Some of the physical findings associated with drug use (see Tables 35-3 and 35-4) are ●
● ● ● ● ●
red skin (anticholinergic drugs, jimson weed, LSD, THC, MDMA, alcohol withdrawal) dilated pupils (stimulants, hallucinogens, withdrawal syndromes) pinpoint pupils (opiates) ataxia (CNS depressants, MDMA) lateral nystagmus (CNS depressants) vertical nystagmus (PCP)
The general time after ingestion in which a drug may be detected in the urine depends on the drug, the amount ingested, and the
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chronicity of use. The following drugs are listed with the times after use in which the drugs may be detected: ● ● ● ● ● ●
alcohol: 12 hours heroin: 24 hours cocaine: 4 to 6 days, as benzoylecgonine marijuana: single use, 5 days; long-term daily use, 30 days phenobarbital: 33 days PCP (overdose): 9 days
If a clinician identifies a patient as a substance user, the unusual behavior should not be attributed solely to the drug. Instead, the clinician must consider other psychiatric conditions associated with drug use: ADHD, ODD, conduct disorder, schizophrenia, and mood disorders. The clinician must also consider the complications associated with drug use: human immunodeficiency virus infection, hepatitis B infection, cerebrovascular accidents (resulting from stimulants), bacterial endocarditis (resulting from intravenous use), asthma (resulting from THC use), and injuries from violence, accidents, or suicide attempts. If the clinician suspects substance use, the patient should be referred to a mental health specialist. The treatment of drug use or abuse consists of detoxification, treatment of comorbid conditions, and psychological intervention to help maintain sobriety. Detoxification involves the termination of use of the substance as well as the management of potential withdrawal symptoms (from opiates, amphetamines, barbiturates, and, less often, cocaine). Sobriety maintenance is attempted by addressing coexisting psychiatric disorders and implementing psychosocial interventions. Although pharmacologic treatment for abuse prevention is sometimes used in adults (such as disulfiram for alcohol abuse), this form of intervention is not often employed with adolescents.
Central Serotonin Syndrome
Central serotonin syndrome results from excessive serotonin activity in the CNS from dietary supplements (L-tryptophan) or use of drugs that enhance CNS serotonin levels (serotonin reuptake inhibitors [SRIs] or selective serotonin reuptake inhibitors [SSRIs]). Certain drugs increase synaptic serotonin release (amphetamine, cocaine, MDMA, fenfluramine, mescaline, psilocin, L-dopa); others are serotonin agonists (lithium, LSD) or inhibit serotonin degradation (monoamine oxidase inhibitors, MDMA). In addition to SRRIs and SRIs, other drugs that inhibit serotonin reuptake include tricyclic antidepressants, meperidine, dextromethorphan, and MDMA. The triad of cognitive-behavioral, autonomic nervous system, and neuromuscular signs and symptoms are characteristic of the central serotonin syndrome. Patients frequently manifest behavior alterations that include confusion, disorientation, agitation, and irritability. Coma, anxiety, seizures, hallucinations, and hypomania are less common. Autonomic features include hyperthermia, diaphoresis, and tachycardia; hypertension, mydriasis, and tachypnea are less common. Neuromuscular features include myoclonus, hyperreflexia, tremor, rigidity, restlessness, hyperactivity, and ataxia. Other toxic ingestions (salicylates, sympathomimetic agents, or anticholinergic drugs), other withdrawal symptoms, and neuroleptic malignant syndrome are included in the differential diagnosis (see Table 35-3). Serum drug levels are usually normal if the patient has been prescribed an SSRI or SRI. Management includes stopping the drug and treating complications such as hyperthermia with cooling, benzodiazepines (clonazepam), and mechanical ventilation. Some physicians administer propranolol or cyproheptadine, a nonspecific postsynaptic 5-HT1A and 5-HT2 inhibitor. The mortality rate is 10% to 15%; most patients recover within 24 hours of discontinuing the agent.
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Table 35-3. Immediate Effects of Substance Abuse
Substance
Alcohol
Immediate Effects
Respiratory depression, central nervous system (CNS) depression, ataxia, slurred speech, hypoglycemia
Duration of Action
Toxicity
Depends on Cirrhosis, amount gastrointestinal, ingested and hemorrhage, adolescent’s thiamine and folate tolerance deficiency, CNS depression, impaired motor performance and mental function, stupor, deep anesthesia, death Amphetamine, ↑ Blood pressure 2-8 hr Agitation; ↑ heart other stimulants (BP), activity, and rate, BP, and alertness; temperature; tachycardia; hallucinations; insomnia, anorexia; paranoia, psychosis; ↓ fatigue, euphoria; convulsions; death, excitation; aggression; arrhythmias hostility Nicotine ↑ BP and heart Minutes CNS stimulation rate; ↓ temperature; CNS stimulation, skeletal muscle relaxation Cocaine, crack ↑ Alertness, 15-30 min Agitation; ↑ exultation, temperature, pulse, euphoria, insomnia; and BP; tremors; ↓ appetite; ↑ BP convulsions, and heart rate; tachyarrhythmias; aphrodisiac, paranoia, psychosis; local anesthesia cerebral hemorrhage; myocardial infarction; death Inhalants Respiratory 5-30 min Arrhythmias, (solvents, depression, CNS hallucinations, seizures, gasoline) depression, ataxia, encephalopathy, renal slurred speech, tubular acidosis, bradycardia hepatitis, peripheral neuropathy, lead poisoning, sudden death LSD, other Dysphoria; 2-12 hr; can Long intense hallucinogens hallucinations; produce “trips”; psychotic anxiety; paranoia; exhaustion reactions not always psychosis; ↑ BP, lasting for reversible; heart rate, and days flashbacks; suicide temperature; attempts; deaths dilated pupils; with some drugs incoordination; ↑ creativity Marijuana, Euphoria, ↓ reaction 2-4 hr Dysphoria, acute anxiety hashish time, ↓ inhibitions, attacks, acute psychosis, ↑ appetite fatigue, paranoia, lack of motivation PCP and PCP Ataxia, nystagmus, Hours to days Psychosis; convulsions, analogues ↑ BP, slurred coma, seizures, ↑ or ↓ speech, dysphoria, BP, muscle rigidity; hallucinations, paranoia; flashbacks; aggression, suicide attempts, paranoia, confusion, accidents hyperthermia
Signs and Symptoms of Withdrawal
Treatment of Overdose
Insomnia, restlessness, anxiety, tremulousness, hypertension, tachycardia, diaphoresis; auditory or visual hallucinations or both, seizures, delirium tremors are rare in adolescents Apathy, hallucinations, irritability, excessive sleep, depression, psychosis, suicidal thoughts, sudden death
Supportive ventilation if needed
Restlessness, anxiety, insomnia, agitation, nausea, headache, ↑ appetite, inability to concentrate Apathy, long periods of sleep, irritability, depression, suicidal thoughts, disorientation
None
Rare: chills, hallucinations, headache, abdominal pain, muscle cramps, delirium tremens None
Paranoia with haloperidol; seizures with diazepam
Paranoia with haloperidol; seizures with diazepam; cooling for hyperthermia; nitroprusside, labetalol for hypertension Organ-specific therapies
Reassurance; haloperidol
Insomnia, hyperactivity, Psychological ↓ appetite support None
Haloperidol, diazepam, cooling for hyperthermia
Continued
Chapter 35 Unusual Behaviors
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Table 35-3. Immediate Effects of Substance Abuse—cont’d
Substance
Immediate Effects
Duration of Action
Toxicity
Signs and Symptoms of Withdrawal
Opioids
Euphoria, ataxia, slurred speech, miosis, stupor, respiratory depression
Hours
Respiratory depression, hypothermia, hypotension, pulmonary edema, apnea, coma, death
Sedativehypnotics
Respiratory depression, coma, hypotension
Variable by drug type and class
Alcohol enhances toxicity of benzodiazepines
γ-Hydroxybutyrate (GHB)
Sedation, respiratory depression, “date rape drug” Potent sedative benzodiazepine; as per GHB
1-2 hr
Death if taken with alcohol or other intoxicants Amnesia
Uncertain
Amphetaminelike effects (see those for amphetamines)
4-5 hr
↑ BP, ↑ temperature, seizures, hyponatremia, cerebral infarction, arrhythmias, hepatic or renal failure, behavioral effects, death
Uncertain
Flunitrazepam (Rohypnol) (“Roofies”) MDMA (“Ecstasy”)
4-6 hr
Increased sympathetic nervous system activity, hunger, antisocial behavior gooseflesh, diaphoresis, rhinorrhea, diarrhea, yawning Irritability, anxiety, depression
Uncertain
Treatment of Overdose
Naloxone; ventilation
Supportive ventilation; Flumazenil* for benzodiazepines Supportive ventilation if needed Supportive ventilation if needed Treat hyperthermia by cooling, dantrolene
Data from Jones RL: Substance abuse. In Shearin RB (ed): Handbook of Adolescent Medicine. Kalamazoo, Mich: Upjohn Company, 1983, pp 133-152; Abramewicz M (ed): Treatment of acute drug abuse reaction. Med Lett 1987;29:83; Kreipe RE, McAnarney ER: Adolescent medicine. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 244. *Flumazenil is a benzodiazepine antagonist that may produce vomiting, acute withdrawal symptoms, or seizures. It should be used cautiously after an airway is secured. LSD, lysergic acid diethylamide; PCP, phencyclidine; MDMA, 3,4-methylenedioxymethamphetamine.
EPISODIC (RECENT) DISRUPTIVE BEHAVIORS Episodic disruptive disorders may be either an acute presentation of an illness in a previously healthy individual or an episodic flare-up of a chronic disorder. These conditions may be subdivided according to the patient’s mental status (confusion or delusion), emotional state (labile or pervasive), and the best expert to treat the condition (primary care provider or mental health specialist) (see Figs. 35-3 and 35-4). Mental Status Changes Delirium
Delirium is characterized by deficits in cognition and consciousness that develop over a short time (Table 35-6). According to the DSM-IV, the criteria for the diagnosis of delirium are 1. a disturbance of consciousness with reduced ability to focus or sustain attention 2. a change in cognition (drowsiness, disorientation) or perceptual disturbances (illusions, hallucinations) 3. an onset over a short period of time 4. a medical cause for the symptoms The symptoms of delirium develop acutely and fluctuate throughout the course of the illness. Besides altered sensorium, the patient also has reversal of the sleep/wake cycle and may exhibit disruptive behaviors consisting of psychomotor agitation or retardation. Delirium is caused by global cerebral dysfunction. Hence, any agent that can cause coma can also cause delirium. Some of
these causes are represented by the mnemonic AEIOU-TIPS, which stands for alcohol, encephalopathy (lead, Reye syndrome, inborn errors of metabolism, encephalitis), insulin (hypoglycemia or hyperglycemia), opiates, uremia, trauma, infection, poisonings, and seizures. Because the aforementioned causes of delirium are potentially life-threatening, an expedient and comprehensive medical evaluation is needed. Children with delirium present with perceptual disturbances consisting of misinterpretations (hearing a sound and thinking it represents something else), illusions (visual misinterpretations), and hallucinations (seeing something that is not actually there). The hallucinations of delirium are different from those of psychoses (e.g., schizophrenia) because they are usually visual and acute in onset, whereas those resulting from psychoses are usually auditory and subacute or chronic. The hallucinations occurring with psychoses may have a delusional component. The treatment of delirium is directed toward the underlying medical problem. Some patients with delirium may be aggressive and assaultive. A psychiatric consultation may be helpful in differentiating the hallucinations into medical versus psychotic causes and in assisting in the pharmacologic and behavioral or environmental management of the agitated patient. Benzodiazepines, high-potency antipsychotic agents (haloperidol), or both may reduce the agitation; however, the dosages must be carefully titrated to prevent the side effects of these medications from contributing to the patient’s altered sensorium. Because patients with delirium are frightened and confused, their agitated behavior may respond to frequent reassurances, implementation of expected routines, a consistent environment, and frequent reorientation.
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Table 35-4. Long-Term Effects, Adulteration, and Methods of Administration of Substances that Adolescents Abuse Dependence Substance
Alcohol
Amphetamine, other stimulants (speed) Tobacco
Cocaine, crack
Inhalants (solvents, gasoline, “white out,” etc.) LSD, other hallucinogens
Marijuana, hashish PCP and PCP analogues
Opioids
Long-Term Effects
Blackouts; behavioral changes; ↑ accidents; homicide; suicide; gastritis; peptic ulcer; alcoholic hepatitis; fatty liver; pancreatitis Weight loss, insomnia, anxiety, paranoia, hallucinations; skin abscesses and amphetamine psychosis after injections ↑ Risk of chronic bronchitis, heart disease, and cancer (oral cancer with smokeless tobacco) Nasal perforation with snorting, weight loss, insomnia, anxiety, paranoia, hallucinations, soft tissue abscesses with injections Liver damage with toluene, trichloroethylene, gasoline; anemia with tetraethyl lead; leukemia with benzene; kidney damage with trichloroethylene Flashbacks, pronounced personality changes, ↑ risk of chronic psychosis
Great variety involving several body systems; ↓ motivation Personality disorders, flashbacks, catatonia, neuropsychological disturbances, increased risk of schizophrenia ↓ Motivation, antisocial behavior, crime to support habit, skin abscesses, endocarditis, osteomyelitis, nephritis, hepatitis, HIV, amenorrhea
Tolerance
Psychological
Physical
Adulteration or Substitution
Method of Administration
Yes
Yes
Yes
Methanol
Ingested
Yes
High
Yes
Ingested, injected
Yes
Yes
Yes
More than 90% of speed is adulterated with caffeine, asthma medicatons, PCP, LSD, strychnine, sugars No
Yes
High
Yes, Local anesthetics, especially sugars, PCP after smoking or injection
Snorted, smoked, ingested, injected
Yes, especially with toluene
Yes
Yes
Yes, crosstolerance with mescaline, DMT, and psilocybin Yes
Degree No unknown
Sniffing rags soaked with the compound, inhaling fumes through the mouth Ingested, injected, sniffed
Yes
High
Degree unknown
Often added to other drugs or advertised as other drugs
Ingested, injected, smoked
Yes
Yes
Yes
Quinine, sugar
Ingested, injected subcutaneous (skin-popping), intravenous
Degree No unknown
None
Sold as tablets, in liquids, in microdots in many colors; often adulterated with or substituted for other drugs With PCP
Smoke inhaled, snuff dipping, chewed
Smoke inhaled, ingested
Modified from Jones RLK: Substance abuse. In Shearin RB (ed): Handbook of Adolescent Medicine. Kalamazoo, Mich: Upjohn Company, 1983, pp 133-152; Kreipe RE, McAnarney ER: Adolescent medicine. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 245. DMT, dimethyltryptamine; HIV, human immunodeficiency virus; LSD, lysergic acid diethylamide; PCP, phencyclidine.
If the underlying medical condition for delirium is promptly treated before irreversible CNS damage develops, the patient should make a full recovery. However, if damage has occurred, the patient may develop dementia. Dementia is a chronic, irreversible, and possibly progressive disease that includes memory impairment and
one of the following symptoms: 1. aphasia (inability to name an object) 2. apraxia (inability to carry out motor activities despite understanding the task and having intact motor abilities) 3. agnosia (inability to recognize objects)
Chapter 35 Unusual Behaviors Table 35-5. CAGE Questionnaire*
Table 35-7. Approach and Red Flags for Psychoses
C: Have you ever tried to Cut down on drinking? A: Have you ever been Annoyed by criticism of your drinking? G: Have you ever felt Guilty about your drinking? E: Have you ever had a morning Eye-opener (a drink to prevent withdrawal symptoms)?
General Strong family history of symptoms or disorders Delusions Comorbidities should be ruled out Increased suicide risk
*CAGE questioning has a sensitivity of 90% and a specificity of 79% for detecting alcohol abuse.
4. problems with executive function (inability to engage in ageappropriate planning, organizing, sequencing, abstracting) In children, dementia can also manifest as a loss of developmental milestones or deteriorating school performance. Schizophrenia
Schizophrenia is a chronic disorder that may flare into an active phase of very disruptive behavior (Table 35-7). This disruptive behavior consists of delusions, hallucinations, disorganized speech, and catatonic behavior. According to the DSM-IV, the diagnostic criteria for schizophrenia are two or more of the following present for a 1-month period: 1. 2. 3. 4. 5.
delusions hallucinations disorganized speech catatonic behavior negative symptoms, such as flat affect
These characteristic signs and symptoms must appear in the context of significant social and educational dysfunction. There must also be continuous indications of the disturbance for at least 6 months (prodrome, active phase, residual period). Medical causes and mood disorders need to be excluded. The diagnosis of schizophrenia is further subdivided by the primary symptom complex into the following types: paranoid, disorganized, catatonic, residual, and undifferentiated. During the prodromal phase, the patient may develop increasing negative symptoms, such as social withdrawal, flattening of affect, alogia (speaking in brief sentences), and avolition (lack of desire to do anything). The flat affect may consist of a reduction in body language, lack of eye contact, and emotional unresponsiveness. During this period, the patient may also have unusual beliefs that are not of the magnitude of true delusions or hallucinations. The patient may have magical thinking or may perceive that someone is talking to him or her, but no words are hallucinated. This prodromal state must be present for 6 months before the diagnosis of schizophrenia can be made. During the acute phase of schizophrenia, the patient has at least two characteristic symptoms (or one characteristic if the delusions are bizarre) for more than 1 month, unless the symptoms have been
Table 35-6. Approach and Red Flags for Delirium
1. 2. 3. 4.
Symptoms evolve in hours Level of consciousness waxes and wanes Urgent medical evaluation (AEIOU-TIPS) is required All poisons and medications in the home should be reviewed 5. Hallucinations are usually visual or tactile
AEIOU-TIPS, alcohol, encephalopathy, insulin, opiates, uremia-trauma, infection, poisonings, seizures.
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Schizophrenia Declining function unless treated Duration of symptoms > 6 mo Symptoms: hallucinations, disorganized speech, flat affect, disorganized/catatonic behavior Bipolar Disorders* Past episodes of mania or hypomania Should be considered for any disruptive behavior that does not respond to treatment Major Depressive Disorders* Can manifest with behavioral problems and irritability instead of depressed mood Should not be overattributed to a stressor Risk for developing bipolar disorders *Bipolar and some depressive disorders are classified as mood disorders, but in severe cases patients may show psychotic features.
shortened by treatment. The most common delusions (erroneous beliefs) in this disorder are persecutory (patient is being spied on) and referential (events or comments are directed toward the patient). Other less common delusions are somatic (internal organs are replaced by others), religious, and grandiose. The most common hallucinations are auditory, but they may emanate from any sensory modality. For hallucinations to support the diagnosis of schizophrenia, the patient must have a clear sensorium. The disorganized speech may be incomprehensible, and the patient may be unable to organize a logical conversation. The behavior problems consist of inappropriate dress, disheveled appearance, unprovoked aggression, and catatonia (decreased response to the environment). If symptoms have not been present for 6 months, the provisional diagnosis of schizophreniform disorder is used. Approximately two thirds of patients with schizophreniform disorder have symptoms that last longer than 6 months and hence are reclassified as having schizophrenia. The prevalence of schizophrenia ranges from 0.5% to 1.0%. Even though some cases have been reported in children as young as 5 years of age, most cases of schizophrenia manifest between the late teens and early 30s. Results of monozygotic twin studies support both an environmental cause and a biologic cause for schizophrenia. Among children who have a first-degree biologic relative with schizophrenia, there is a 10-fold increase in schizophrenia over the incidence in the general population. Neuroimaging studies have consistently noted increased ventricular size in the brains of schizophrenics in comparison with normal persons. The differential diagnosis of schizophrenia consists of the same medical causes of delirium and dementia plus the mood disorders and pervasive developmental disorders. In addition, ingestions (e.g., amphetamines, cocaine, PCP, hallucinogens) may produce similar symptoms. The prognosis of schizophrenia is guarded, with significant morbidity and mortality (suicide, especially early in the illness). This chronic disorder is associated with exacerbations and remissions. Even with optimal therapy, patients with schizophrenia have significant social deficits, poor initiative, and abnormal thought processes.
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The treatment of schizophrenia consists of the use of atypical antipsychotic agents (risperidone, olanzapine, clozapine in treatmentresistant cases), psychotherapy, and educational interventions. The patient often benefits from socialization groups plus individual and/or group therapy. The families of patients with schizophrenia also need emotional support and guidance. Because of the abnormalities in the thinking process and the neuropsychological deficits, patients often need an individual educational program. This disease is difficult to treat, and therefore the therapy is managed best by a psychiatrist. The primary care provider may assist in the management by conducting the medical evaluation and by educating the family. Families often confuse schizophrenia with dissociative identity (or multiple personality) disorder; they are unrelated. Bipolar Disorders
Bipolar disorder, formerly called manic-depressive disorder, is a mood disorder. The most common mood disorder is major depressive disorder. Bipolar disorder manifests acutely, with severe problems in thinking and behavior that lead to significant impairment in functioning (see Table 35-7). Disturbances in thinking associated with mania include racing thoughts (rapidly changes topics), distractibility, and delusions of grandeur. Problematic behaviors during a manic episode include recklessness (excessive participation in social activities, promiscuity, buying sprees), agitation, decreased sleep, and excessive talkativeness. The bipolar disorders are divided into the following categories: ●
●
●
●
bipolar I disorder (episodes of mania usually with episodes of depression) bipolar II disorder (major depression with only hypomanic episodes) mixed bipolar disorder (daily occurrence of both manic and depressive features) cyclothymic disorder
Cyclothymic disorder is a chronic, cyclic illness of hypomania and depressive symptoms (no major depressions). Approximately 15% to 50% of patients with cyclothymic disorder will eventually develop bipolar I or II disorder. According to the DSM-IV, a manic episode consists of an abnormally elevated (euphoric), expansive, or irritable mood for at least 1 week unless treated. This mood disturbance is associated with at least three (four if patient is irritable) of the following symptoms: 1. 2. 3. 4. 5. 6. 7.
grandiosity decreased desire for sleep talkativeness racing thoughts distractibility excessive goal-directed activity (or psychomotor agitation) reckless pursuit of pleasure
Hypomanic episodes consist of the same symptoms except that the symptoms are present for a shorter time (4 days), are not associated with any psychotic activity (delusions or hallucinations), and are not severe enough to cause major social or academic dysfunction. About 10% of patients with hypomania progress to mania. The differential diagnosis of bipolar disorders includes the medical conditions that cause coma or delirium. Some specific medical conditions whose presenting symptoms resemble bipolar disease are thyroid disorders (hypothyroidism or hyperthyroidism), Cushing disease, and multiple sclerosis. Substance-induced mood disorders (e.g., cocaine, tricyclic and SSRI antidepressants) must also be considered. The clinician should obtain a detailed family history because of the high prevalence of these disorders in parents of children with bipolar disorders. Because the condition is often undiagnosed in parents, the questions should be directed toward the presence of the symptoms for bipolar disorders. Some of the psychiatric disorders that frequently occur with bipolar disorders are eating disorders, ADHD, conduct disorders, panic
disorders, social phobias, adjustment disorders, and substance-related disorders. These conditions may manifest with symptoms that imitate bipolar disorders (e.g., distractibility of ADHD instead of mania). The clinician must decide whether the symptoms are caused by a bipolar disorder or by some other psychiatric disorder. ADHD can be differentiated from mania because the hyperactive behavior of ADHD is more likely to manifest in childhood and progress to restlessness in the teenager, whereas teenagers with mania present acutely with excessive activity. Because patients with bipolar disorders can also present with hallucinations and delusions, schizophrenia must be ruled out. Likewise, patients with initial diagnoses of schizophrenia have been found after years of follow-up to have bipolar disorders. The lifetime prevalence of bipolar I disorders is 0.4% to 1.6%, and that of bipolar II disorders is 0.5%. Approximately 15% of adolescents with recurrent major depression eventually develop bipolar illnesses. A 2- to 15-fold increase of bipolar disorders in children of affected parents supports a biologic determinant for this condition. Manic patients have biologic abnormalities in neuroendocrine function (increased cortisol production, absence of dexamethasone nonsuppression) and in neurotransmitter systems. Although bipolar disorders can develop in childhood, the average age of onset is 20 years for men and women. The natural history of bipolar disorders is a chronic illness with episodes of mania, hypomania, and major depression; 15% of patients have four or more episodes per year. Risk factors for initiation of a manic episode are disruption of the normal sleep cycle (crossing multiple time zones), the postpartum period, and recent onset of major depression (about 70% of manic or hypomanic episodes are associated with recent major depression). With therapy, many patients recover fully between episodes; however, 30% of patients with bipolar I disorder and 15% of those with bipolar II disorder have persistent interpersonal and occupational disorders. Ten percent to 15% of patients with bipolar disorders eventually commit suicide. Because of the severe morbidity and mortality with this disorder and the complexities of treatment, psychiatrists manage bipolar disorders. Treatment consists of medications and psychotherapy. Medications used to treat bipolar disorder include lithium carbonate, carbamazepine, valproic acid, benzodiazepines, and antipsychotic agents. Various forms of psychotherapy are often employed in conjunction with a close liaison with schools to promote scholastic success as well as to maximize the patient’s well-being. The role of the primary care provider in the management of bipolar disorders is early detection. Mixed (manic and depressed) states with marked dysphoric, agitated affect and explosive anger occur more frequently in youths than in adults. Guidelines that may lead to early diagnosis are as follows: 1. Know and recognize the symptoms for mania and hypomania. 2. Remember that depressed patients often have bipolar disorders. 3. Obtain a thorough family history to look for symptoms of mood disorders. 4. Consider bipolar illnesses in patients with any disruptive disorder that does not respond to treatment. 5. Assess for drug and/or alcohol use (may induce bipolar disorder and is frequently a comorbid condition). Once the primary care provider suspects bipolar disorders, the patient should be referred to a psychiatrist. Because of the manic symptoms (elation, angry outbursts when thwarted, delusions of grandeur) that accompany this disorder, these patients may vigorously argue and refuse referral. Family members must often be enlisted to insist on referral. Labile Emotions Adjustment Disorder
Adjustment disorder (see Fig. 35-3) is an excessive or maladaptive response to stress. A recognizable stressor must be present in
Chapter 35 Unusual Behaviors order to make this diagnosis. Some of the typical stressors for children and adolescents are separations, painful injuries, illness, treatment of an illness (hospitalization, surgery), parental divorce, change of residency, academic failure, and conflict with peers. The DSM-IV criteria for adjustment disorder are as follows: 1. 2. 3. 4. 5.
The symptoms develop within 3 months of the stressor. Significant impairment (social, academic) results. The symptoms do not meet criteria for mood or anxiety disorder. The symptoms do not represent bereavement. The symptoms abate 6 months after termination of the stressor.
This disorder is further subdivided by the patient’s symptoms, such as depressed mood, anxiety, and/or conduct disorder. The prevalence of adjustment disorder ranges from 10% to 30% in mental health clinics. Besides the morbidity secondary to the social and/or academic impairment, these patients may be at increased risk for suicide. If the stressor is an illness or treatment, the morbidity of the medical condition may increase as a secondary consequence of noncompliance. The differential diagnosis of adjustment disorder is mood or anxiety disorder, exacerbation of a personality disorder, or post-traumatic stress disorder. The primary care provider may intervene with advice, insight, reassurance, and, if necessary, a referral to a mental health professional for short-term counseling.
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negative connotations for many health care professionals, and these connotations can be so stigmatizing that they might interfere with the quality of care; and (2) the entire process of differential diagnosis is much more difficult in adolescence because the developmental shifts typical of this phase are dramatic enough to blur the boundaries between borderline personality disorder and its common comorbid conditions, particularly the mood disorders (unipolar and bipolar), psychotic disorder, and post-traumatic stress disorder. The presence of substance abuse and family turmoil, which are frequently associated with borderline personality disorder, adds other layers of complexity to the diagnostic picture. Nevertheless, the diagnosis is appropriate and valid for some adolescent patients who show a pervasive pattern of instability and impulsivity and have a history of significant maltreatment (physical, sexual) in childhood. Borderline personality disorder is difficult to treat. Even though the patients are very reasonable and appealing between the crises, the primary care provider should refer them to a mental health specialist because of the serious mortality and morbidity associated with this chronic recurrent disorder. Treatment consists of psychotherapy and the use of psychotropic agents to treat target symptoms. The course of treatment is often lengthy, with frequent exacerbations and remissions. Pervasive Emotions
Borderline Personality Disorder Major Depressive Disorder
Borderline personality disorder (see Fig. 35-3) is a chronic personality disorder characterized by intense mood lability, impulsivity, and identity disturbances. Patients with this disorder also have unstable and intense interpersonal relationships. According to the DSM-IV, the diagnosis of this condition requires five or more of the following features: 1. frantic efforts to avoid abandonment 2. intense interpersonal relationships alternating between extreme idealization and devaluation 3. unstable self-image 4. impulsivity 5. recurrent suicide attempts and/or self-mutilating behaviors 6. marked mood reactivity (short periods of intense anxiety or dysphoria) 7. feelings of emptiness 8. difficulty in controlling anger 9. stress-related paranoia The prevalence of borderline personality disorder in the general population is 2%, occurring predominantly in females. Risk factors for this illness include abuse, neglect, and early parental loss. A fivefold prevalence among children with affected parents, coupled with the social risk factors, suggests both a genetic and a psychosocial cause. This disorder usually manifests during adolescence or early adulthood as a fulminant crisis around an unstable and intense relationship. These crises often involve a suicide attempt because of severe impulsivity and mood lability. Approximately 10% of affected patients commit suicide. The morbidity is compounded by the physical sequelae from these multiple attempts (scarring, mutilation, brain anoxia). In addition to their suicide attempts, these individuals commonly quit school, relationships, or work just before reaching a goal, even when success is imminent. Other comorbid conditions associated with borderline personality disorder are mood disorders, substance abuse, eating disorders (especially bulimia), ADHD, and post-traumatic stress disorder. The suicide attempts, the failed life opportunities, and the comorbid conditions all add to the overall morbidity of this condition. Although borderline personality disorder may be diagnosed in patients younger than 18 years, most child and adolescent psychiatrists are reluctant to do so. There are two reasons for this diagnostic circumspection: (1) borderline personality disorder has decidedly
Because of the associated risk of suicide and significant social and academic impairment, depression is a serious condition. Even though a child may be pervasively sad, he or she may also present with behavior problems and irritability (see Table 35-7). According to the DSM-IV, major depressive disorder consists of at least a 2-week period of a depressive mood (irritability in some children) or loss of interest in pleasurable activities that results in significant impairment. During this period, the patient has at least five of the following symptoms: 1. 2. 3. 4. 5. 6. 7. 8.
depressed mood (irritability in some children) loss of interest/pleasure loss of appetite or overeating sleep disorders fatigue feeling of worthlessness or guilt (patient may be delusional) poor concentration suicidal ideation or thoughts of death
These symptoms should not be secondary to bereavement, medical conditions, substance abuse, or bipolar disorders. Patients may also present with somatic complaints, psychosis, or both. The psychotic symptoms are typically auditory hallucinations and delusions of guilt, medical illnesses, or deserving punishment. The occurrence of major depressive disorders in adolescence from a community-screened population is 4% to 5%. There is also a threefold increase of major depression in children whose parents have the disorder. Other evidence suggesting a biologic component to the illness includes abnormalities on polysomnograms (reduced latency to onset of rapid eye movements in early sleep) and abnormal levels of neurotransmitters. The differential diagnosis of major depression encompasses various medical disorders, including neurologic disorders (causes of coma or delirium), endocrine disorders (hypothyroidism, hyperparathyroidism), side effects from medications (H2 blockers, isotretinoin [Accutane]), and substance abuse or use. The patient should be screened for thyroid or parathyroid disorders and for substance abuse. Numerous psychiatric conditions are comorbid with major depression. In children, these conditions are ODD, conduct disorder, ADHD, and anxiety disorders. In adolescents, these illnesses are ODD, conduct disorder, ADHD, anxiety disorders, eating disorders, and substance abuse or use.
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Major depressive disorders can manifest at any age; however, the average age of presentation is the mid-20s. Children usually present with somatic complaints, social withdrawal, and irritability, whereas adolescents often present with psychomotor retardation, negative self-cognition of guilt and worthlessness, and excessive sleep. Approximately 10% to 15% of children with major depression eventually develop bipolar disorders. Fifty percent of children with major depression have multiple episodes, frequently associated with significant stressors. Approximately 25% of patients with certain chronic medical conditions (cancer, diabetes) develop major depressive disorder during the course of illness. Beyond the social and academic dysfunction caused by the major depression and its associated comorbid conditions (ADHD, behavior disorders), 15% of patients eventually commit suicide. The main difficulty in diagnosing major depression is that the gravity of the depressive mood is often not apparent to the parents and the clinician. Unlike patients with bipolar disease, these patients do not present with disruptive behaviors. Instead, they present with irritability, sullenness, or meanness. The parents and/or clinician may attribute this behavior to normal adolescence (“just going through a phase”). These children do not appear sad and deny having any problems. The clinician should have a high index of suspicion of major depression in any child who presents with sullenness and irritability. Guidelines for evaluating such a patient are as follows: 1. Assess suicidal ideation and ensure the patient’s safety. 2. Interview multiple sources (coaches, teachers) to determine the child’s function and symptoms. 3. Obtain a thorough family history for symptoms and diagnoses of mood disorders. 4. Rule out bipolar disorders (mania and hypomania). 5. Investigate primary or comorbid conditions (e.g., substance abuse). 6. Consider the role of life stressors in relationship to the symptoms. Emotional reaction to adverse stressors is a normal part of life. The clinician must decide whether the reaction to the stressor is normal, an adjustment disorder, or major depression. Treatment of major depression is usually conducted by a psychiatrist and consists of psychotherapy and/or psychopharmacologic interventions. The SSRIs such as sertraline (Zoloft) and fluoxetine (Prozac) are the first-line medications for juvenile depression. When major depression causes significant impairment in function, a trial of antidepressants should be considered. Besides medications, psychotherapy (individual, group, and family) is beneficial in treating depressed children. Because major depression often interferes with academic performance, a close liaison with the school system is important. The role of the primary care provider is early recognition and referral. Because children with major depression often do not present with problematic behavior, the family is reluctant to seek psychiatric care. The primary care provider is a trusted advisor who can encourage a referral to a mental health provider. Anxiety Disorders
Anxiety disorders (see Fig. 35-4) are the most prevalent psychiatric disorders in children and adolescents. These disorders are characterized by intense episodes of distress, which consist of fear, worry, avoidance, or terror. The anxiety disorders are ● ● ● ● ● ● ● ●
panic disorder separation anxiety disorder specific phobia social phobia OCD post-traumatic stress disorder acute stress disorder generalized anxiety disorder
Some of the medical conditions that manifest with anxiety symptoms and hence must be ruled out are metabolic disorders (hypoglycemia), endocrine disorders (thyroid or parathyroid), neurologic diseases, ingestion of stimulants (caffeine, psychostimulants), drug withdrawal, and catecholamine-producing tumors (pheochromocytoma, carcinoid). The SSRIs have enhanced the treatment of childhood anxiety disorders; these medications include fluoxetine, sertraline, fluvoxamine (Luvox), and citalopram (Celexa). The SSRIs are very similar in most respects and are generally well tolerated. Some children become behaviorally activated in response to a SSRI. This activation/ agitation side effect usually responds to a dosage adjustment or changing to a different SSRI medication. Another anxiolytic medication that is well tolerated and safe is buspirone (BuSpar); it is often not quite as effective as the SSRIs, but it is a useful alternative. Although the SSRIs were initially marketed as antidepressants, they have nonspecific antianxiety properties that are useful in treating all of the anxiety disorders. Panic Disorder. According to the DSM-IV, panic disorders consist
of recurrent unexpected panic attacks, during which one of the attacks is followed by a concern of having additional attacks, worry about the implications of the attack (loss of control), or a significant change in behavior (social avoidance). A panic attack consists of at least four of the following symptoms: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
palpitations (tachycardia) sweating shaking shortness of breath sensation of choking chest pain nausea dizziness emotional detachment paresthesia chills fear of dying fear of “going crazy”
These symptoms may result in hyperventilation syndrome, which causes respiratory alkalosis, tetany, paresthesia, dizziness, or fainting. Panic attacks occur suddenly, peak within 10 minutes, and may occur with agoraphobia. Agoraphobia is an intense anxiety about having a panic attack in a place from which the person cannot escape or in which help may not be available. Because of this anxiety, the individual either avoids the situation (being outside the home alone) or endures the situation with marked distress. The 1-year prevalence rate of panic disorders ranges from 1.5% to 3.5%. Thirty percent to 50% of individuals with panic disorder also have agoraphobia. The age of onset is bimodal, with the largest peak occurring in adolescence and a smaller one in the mid-30s. Panic disorder in prepubertal children occurs but is rare. Patients with panic disorders have a high degree of comorbid conditions. Fifty percent to 65% of patients may have major depressive disorder. Patients with panic disorder are also at great risk for substance abuse because they often seek pharmacologic agents (THC, alcohol, benzodiazepines) to reduce their symptoms. There is a relatively high frequency of other anxiety disorders such as social phobia (in 15% to 30% of patients), OCDs (in 8% to 10%), and generalized anxiety disorders (in 25%) that occur with panic disorders. The physical complaints that accompany this disease often cause patients to miss work or school and seek medical care, which adds to the financial cost of the disorder. Many adolescents with panic disorder can be treated in the primary care setting. SSRIs such as sertraline and citalopram are very effective in blocking panic attacks and are well tolerated. Patients with many comorbid conditions, severely impaired patients, and younger patients should be referred to a child psychiatrist.
Chapter 35 Unusual Behaviors Generalized Anxiety Disorder. In this condition, the child
displays excessive worries and concerns over many issues. According to the DSM-IV, the diagnostic criteria for a generalized anxiety disorder are 1. anxiety and worry about various issues for more than 6 months 2. difficulty in controlling the worry 3. significant dysfunction In addition, affected children have one of the following symptoms: fatigue, restlessness, irritability, sleep disturbances, poor concentration, and muscle tension. Patients may also have symptoms of depression or somatic complaints (abdominal pain, headaches). The lifetime prevalence of generalized anxiety disorder is 5%; most cases develop during childhood and adolescence. The clinical course of this disorder is chronic and fluctuating and worsens with stress. It is also associated with mood disorders, other anxiety disorders, and substance abuse. Once the condition is recognized, the treatment consists of reducing stress in the environment, psychotherapy, and medication. The psychotherapy focuses on helping the child obtain a sense of control over this emotional state. As an adjunct to psychotherapy, many children benefit from the use of SSRIs. Separation Anxiety Disorder. In this condition, there is excessive anxiety at the separation from home or a loved one that is developmentally inappropriate. According to the DSM-IV, the symptoms are present for more than 4 weeks, occur before the age of 18 years, and consist of at least three of the following:
1. 2. 3. 4. 5. 6. 7. 8.
distress with separation (home, loved one) worry about losing loved ones worry about an event (kidnapping) causing separation refusal to go to school reluctance to be alone refusal to fall asleep alone repeated nightmares of separation somatic complaints
These symptoms may worsen when the child anticipates a separation. The prevalence of separation anxiety disorder is 4%; the onset is usually during early childhood. Affected patients are often demanding and intrusive, which leads to family conflict. Major depressive disorders and panic disorder with agoraphobia are common comorbid conditions. For simple and uncomplicated cases, the primary care provider may institute simple behavioral techniques, such as initiation of brief separations so that the child may see that separation does not lead to catastrophic consequences. Parents, who are anxious and fearful about upsetting the child, often complicate the situation. For more complex and severe cases (family strife or comorbid condition present), the patient should be referred to a psychiatrist. The treatment includes behavioral and supportive psychotherapy. Many cases can be successfully treated without resorting to medications. If the psychosocial treatment stalls, a trial of an SSRI (e.g., sertraline, citalopram) may help. Obsessive-Compulsive Disorder. This disorder consists of recurrent behaviors over which the patient has little control. According to the DSM-IV, obsessions are recurrent thoughts that are inappropriate and cause marked anxiety. Some common obsessions are ● ●
● ● ●
contamination (acquiring an illness from someone or something) doubts (needing to check and recheck the stove many times to make sure it is off; even so the patient is riddled with doubt that it is actually off) order (distress with asymmetry) aggression sexual acts
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Compulsions are repetitive and excessive acts designed to reduce anxiety (hand washing and checking behaviors are two common examples). According to the DSM-IV, the obsessive-compulsive behaviors are time consuming (take >1 hour per day) or significantly interfere with the patient’s function. The lifetime prevalence in a communitybased sample for OCD is 2.5%. The origin of this condition is unknown; however, there is a higher predominance among children whose parents have either Tourette syndrome or OCD. There is some evidence that group A β-hemolytic streptococcal infections are associated with PANDAS such as tics and OCD. In younger children with sudden onset of OCD, this diagnosis should be considered, because antibiotic therapy may eradicate the symptoms of OCD. The presentation usually occurs earlier in male patients (6 to 15 years of age) than in female patients (20 to 29 years of age). Children may present with anxiety, stress, poor concentration, or declining school performance. The differential diagnosis includes anxiety disorders, major depression, hypochondriasis, and tic disorders. Conditions commonly comorbid with OCD include major depression, anxiety disorders, eating disorders, and Tourette disorder. In addition, the obsessions and compulsions may lead to social avoidance, frequent visits to the doctor, and substance abuse. In this chronic disorder, 80% of patients have waxing and waning symptoms with exacerbations secondary to stress, 15% have a progressive deterioration in function, and 5% have occasional episodes with minimal symptoms. The treatment is usually directed by a psychiatrist and consists of cognitive-behavioral therapy and psychotropic medications. Cognitive-behavioral interventions are designed to provide patients with a sense of control over their thoughts and behaviors. Medications that potentiate serotonin activity (clomipramine, fluoxetine) may be successful in alleviating the symptoms. The response to treatment is quite variable: Some patients experience a complete remission, whereas others remain significantly disabled. OCD may manifest as a dermatitis that has resulted from excessive washing behaviors. Post-traumatic Stress Disorder. In this condition, the patient has a severe reaction to an extremely threatening stressor. According to the DSM-IV, the characteristics of this syndrome may be summarized by the mnemonic TRAUMA, which stands for traumatic event, reexperience, autonomic, symptoms of longer than 1 month’s duration, and avoidance. The traumatic event must be very severe (e.g., life-threatening) and cause fear and horror in the victim. This event is then reexperienced as thoughts, dreams, or flashbacks (which occur when the patient is awake). The patient also experiences intense distress (psychological and/or physiologic) when exposed to a situation that resembles the traumatic event. The autonomic symptoms consist of sleep disturbances, irritability, poor concentration, or hyperventilation. The avoidance consists of either avoiding circumstances associated with the event (certain people, places, and activities) or withdrawal from relationships (emotional detachment, diminished interest, inability to love). Children’s symptoms are similar to those of adults, except that their dreams are frankly nightmares, their fear is manifested in disorganized or agitated behavior, and their reenactment may consist of repetitive play (airplane crash reenacted as throwing a toy plane against the wall). In addition, children frequently complain of somatic complaints (e.g., headaches). The lifetime prevalence of post-traumatic stress disorder in a community ranges from 1% to 14%; however, it is three to four times higher among those exposed to extreme stress (disaster victims). Patients with this condition have an increased risk for panic disorders, social phobia, substance abuse, OCD, somatization disorder, and major depressive disorders. The differential diagnosis includes adjustment disorders, panic disorders, OCDs, and psychoses (flashbacks versus hallucinations). In adjustment disorders, the stressor must be recognizable, whereas
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Section Five Development/Psychiatric Disorders
in post-traumatic stress disorder, it must be extreme. In acute stress disorder, the symptoms can simulate post-traumatic stress disorder except that the symptoms occur soon after an event ( 4 weeks, associated worries of separation, significant
dysfunction), they may represent an early manifestation of separation anxiety disorder (see section on disruptive behaviors). The symptoms of school avoidance may involve any organ system but are usually abdominal pain, headaches, or both. These pains are worse in the morning (especially on Mondays). In more severe cases, the symptoms may develop on Sunday evenings. Anxiety about attending school and the pattern of gain are quickly apparent. The cause of the anxiety may be a conflict with a teacher or classmates. In adolescents, the anxiety may be caused by a recurrent stressor, such as an embarrassing situation (e.g., gym class) or conflict with peers. Some factors that may contribute to the development of this disorder are fear of losing one’s parents, reduction of fear when the patient stays at home, parental sharing of their emotional distress, recent family tragedy, and an increasing understanding of death (i.e., that it is universal, permanent, and unpredictable). Patients with school avoidance may also have an anxiety disorder (social phobia) or major depressive disorder. Establishing the differential diagnosis of school avoidance is often difficult and complex. Treatment of simple school avoidance consists of correction of school-based fears (e.g., about a teacher or peers) by parental intervention with the school, reassurance, education of the parents regarding their inadvertent reinforcement of separation anxiety, and immediate return to school. The longer the absence, the harder it is for the child to return. To get the child back to school, the parent may have to either accompany the child to the classroom or institute a stepwise return to the classroom (e.g., beginning in the principal’s office, then going to the library, and finally returning to the classroom). The child should be referred to a psychiatrist if there is an underlying psychiatric disorder (anxiety or depressive disorder); if a grade school–aged child does not return to school within approximately 1 week; or if a child in junior high/middle school does not return within a few days. If there is a significant anxiety or depressive component, the psychiatrist may prescribe a temporary course of benzodiazepines or SSRI antidepressants.
Conversion Disorders
According to the DSM-IV, the diagnostic criteria for conversion disorders are symptoms associated with voluntary motor or sensory function (not factitious symptoms or pain symptoms), preceded by a recent stressor, unexplained by a medical evaluation, and causing significant distress or prompting medical evaluation. In children younger than 10 years, the typical presenting symptoms are either pseudoseizures or gait disturbances. Older individuals may present with such symptoms as paralysis of a limb, paresthesias, blindness, or aphonia. These symptoms are relatively easy to identify because they do not follow an anatomic nerve distribution, nor do the actions fit the symptoms (a “blind” person never bumping into anything). Pseudoseizures are more difficult to document and may require continuously videotaped electroencephalographic telemetry. The patient may react to the symptoms either with indifference (la belle indifference) or in a dramatic manner. The prevalence of conversion disorder is 1 to 30 per 10,000 in the general population. The onset is usually in late adolescence to early adulthood. A typical episode is acute, follows a recent stressor, and is of relatively short duration ( 6 months’ duration) and somatoform disorder not otherwise specified (one symptom < 6 months’ duration). The prevalence of somatization disorder is 0.2% to 2% in girls and less than 0.2% in boys. Associated comorbid conditions are major depressive disorder, panic disorder, substance abuse, and personality disorders (borderline personality disorder and antisocial personality disorder). This is a chronic condition that rarely remits. The psychiatric differential diagnosis is extensive and includes mood disorders (major depression), schizophrenia with somatic delusions, panic disorders (symptoms occur only during an attack), generalized anxiety disorder, and factitious disorder. Recognition is the major problem in the management of this condition. These patients are often referred to multiple medical subspecialists for reassurance purposes. If the underlying psychological problem is not addressed, reassurance is rarely successful. Proper management consists of an appropriate medical evaluation to rule out medical causes for the symptoms, recognition of this psychological disorder, and prompt referral to a mental health specialist.
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Treatment of pain disorder consists of an appropriate medical evaluation and prompt referral to a mental health professional. The psychological treatment is similar to that for conversion disorder.
DELAYED DEVELOPMENT Delayed development (see Chapter 32) is a broad category of illnesses that can cause specific or general delay. The causes of developmental delay encompass many conditions; in more than half the cases, a medical condition has caused the delay. These medical conditions include genetic disorders (5%); alterations of embryonic development (30%), perinatal or prenatal disorders (10%), and other medical illness of childhood (5%). Another 15% to 20% of cases are caused either by deprivation or by severe mental disorders (pervasive developmental disorders). Specific developmental delays may be secondary to a medical condition such as cerebral palsy or to learning disorders (reading, mathematics, written expression disorders); to communication disorders (expressive and/or receptive); to developmental coordination disorder; or to psychiatric disorders (selective autism). This part of the chapter concentrates on the psychiatric causes of general and specific delay (Fig. 35-7). PSYCHIATRIC CAUSES OF GENERAL DELAY Pervasive Developmental Disorders Pervasive developmental disorders cause severe impairment in social development, language development, and/or imaginative play. In addition, these disorders are often associated with severe to profound mental retardation (intelligence quotient < 50). The pervasive developmental disorders are ● ● ● ●
autistic disorder Rett syndrome childhood disintegrative disorder Asperger syndrome
The diagnosis of pervasive developmental disorder not otherwise specified may be used if the patient does not fulfill the diagnostic criteria for the aforementioned disorders.
Pain Disorder
Autistic Disorder
Pain disorder is a somatoform disorder in which the patient has significant pain that leads to medical attention. According to the DSM-IV, this pain is related to stress and causes significant dysfunction. In addition, it is neither self-inflicted nor related solely to a medical condition. The symptoms may occur with or without a previous (but resolved) medical condition. Psychological factors and a medical condition, acting in concert, commonly play roles in the development of pain disorder. The actual prevalence of pain disorder is unknown; however, it appears to be quite common. The comorbid conditions associated with pain disorders are substance abuse (to alleviate symptoms), mood disorders (usually with chronic pain), and anxiety disorders (usually with acute pain). Sometimes a parent or other relative has served as a “pain model” for the young person. Two methods by which this syndrome may manifest are the “continuation” syndrome and the “let-down” syndrome. In the continuation syndrome, the symptoms from the medical disease persist even after the biologic abnormalities have completely resolved. The let-down syndrome occurs in highly successful and hard-working students who are under a lot of stress. These symptoms provide them with a legitimate excuse to escape the rigorous demands imposed by themselves or others. The patient’s recognition of the conflict over ambition is important in the resolution of this condition.
According to the DSM-IV, the diagnosis of autism is made if the patient has six or more symptoms in the following three categories: social interaction (at least two symptoms), communication (at least one symptom), and repetitive, stereotypic behavior (at least one symptom). In addition, the symptoms need to occur before the patient is 3 years of age. The problems with social interactions are sparsity of nonverbal communication (body gestures), failure to develop peer relationships, lack of sharing or showing things to others, and lack of emotional reciprocity. In early infancy, parents may notice that these infants do not cuddle well. Affected infants fail to respond to voice to the point that the parent worries that the child is deaf. The language and symbolic impairments include a delay or a lack of any verbal communication, difficulties in sustaining a conversation, echolalia or nonsensical words, and lack of imaginative play. The degree of language impairment and overall intelligence are two of the best predictors of prognosis. The stereotypic and repetitious behavior of these children includes intense preoccupation with an interest (mimicking an actor), inflexible adherence to routines (behavioral outbursts when the routines are not adhered to), repetitive motor movements (rocking), and preoccupation with parts of an object. The prevalence of autistic disorder is 2 to 5 per 10,000; more than 75% of cases occur in boys. This disorder is biologically based
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TYPE OF DELAY
GENERAL
SPECIFIC
NONPSYCHIATRIC CAUSES
NONPSYCHIATRIC CAUSES
Heredity
Medical Insult
Embryonic Development
Learning Disorder
Prenatal/Perinatal Insult Childhood Medical Illness PSYCHIATRIC CAUSES
Reading Mathematics Writing
Figure 35-7. Evaluation of developmental delay.
Communication Disorders
Pervasive Developmental Disorders Autistic Disorder Rett Disorder Childhood Disintegrative Disorder Asperger Disorder
Expressive Receptive Developmental Coordination Disorder PSYCHIATRIC CAUSES Selective Mutism
because of the neurochemical and neuroanatomic abnormalities occurring in it, coupled with the increased risk of the disorder among siblings in affected families. Some of the medical conditions associated with autistic disorder are encephalitis, phenylketonuria, birth anoxia, and fragile X syndrome. Children with autistic disorder may be hyperactive, impulsive, and aggressive and may engage in self-injurious activities. These children may also have unusual reactions to stimulation, such as an oversensitivity to touch or a high pain threshold. As these children become older, they may show some willingness to passively engage in social encounters. Older children may also have extraordinary long-term memory (e.g., for songs, baseball statistics) but use the information inappropriately. The comorbid conditions of autistic disorder are significant: 25% of affected patients have seizures, and 75% have moderate to profound mental retardation (intelligence quotient < 50). As adults, about 30% may have some degree of independent living. Because of the severity of the symptoms, depression is common in less cognitively impaired patients who have some insight into their condition. The differential diagnosis of autistic disorder includes the other pervasive developmental disorders, communication disorders, schizophrenia, and mental retardation. The cornerstone of treatment is to foster the patient’s ability to communicate, to develop the patient’s social skills, and to facilitate learning. These interventions are usually performed in special education settings. Pharmacologic interventions are sometimes used to address specific behavioral problems such as aggressiveness or sleep disruption. SSRIs are frequently prescribed to reduce the intensity of restrictive, repetitive behaviors and interests.
movements (hand wringing), poor gait or truncal movements, loss of social engagement, and severely impaired language development with psychomotor retardation. This condition is extremely rare and has been reported only in girls. The loss of skills is persistent and progressive, ending in severe and profound mental retardation. As the patients approach adolescence, there may be some improvement in social interests and developmental milestones. Seizure disorders frequently complicate this disorder, and many patients with Rett syndrome die prematurely.
Rett Syndrome
The diagnostic features of Asperger syndrome consist of severe impairment in social interactions coupled with restrictive, repetitive behaviors. According to the DSM-IV, the diagnostic criteria for Asperger syndrome consist of at least two impairments of social interactions (poor nonverbal communication, failure to develop peer
Infants with Rett syndrome are normal until 5 months of age. Between 5 and 48 months of age, the toddler exhibits decelerated growth of the head circumference, loss of purposeful hand
Childhood Disintegrative Disorder
In this condition, the child is normal until at least 2 years of age. Between 2 and 10 years of age, the patient loses at least two of the following skills: language, social skills, motor skills, bowel or bladder control, and the ability to play. The child also has problems in two of the following areas: social interaction, communications, or repetitive behavior. Autistic disorder differs from childhood disintegrative disorder in that it occurs earlier (usually in infancy) and causes significant problems in all three areas. Childhood disintegrative disorder is a very rare condition. The origin is unknown; however, occasionally, a disorder causing developmental regression (metachromatic leukodystrophy) may be associated with it. After the loss of skills, this condition plateaus, from which there may be a slight improvement. Childhood disintegrative disorder is also complicated by severe mental retardation and an increased frequency of seizure disorders. Asperger Syndrome
Chapter 35 Unusual Behaviors relationships, lack of sharing, lack of emotional reciprocity) coupled with one or more repetitive, stereotypic patterns of behavior (repetitious motor movements, preoccupation with parts, inflexible adherence to rituals, intense preoccupation with a topic). Asperger syndrome differs from autistic disorder in that there are no impairments in cognitive function, including language. In addition, patients with Asperger disorder are curious about the environment and develop appropriate self-help and adaptive (other than social) behaviors. Asperger syndrome and autistic disorder are almost certainly closely related, differing primarily in severity, with autism at the more severe end of the spectrum and Asperger syndrome at the milder end (although the social relatedness impairment remains significant). The prevalence of Asperger syndrome is unknown. Affected preschool-aged children may have motor delay and clumsiness. As the patient gets older, difficulties with social interactions and empathy arise. The duration of this disorder is probably lifelong. PSYCHIATRIC CAUSES OF SPECIFIC DELAY Selective Mutism The patient with selective mutism has a persistent failure to speak in certain situations (for instance, the classroom), even though the individual can speak in other situations (at home). These symptoms last for at least 1 month (but not limited to the first month of school). In addition, the symptoms are not caused by embarrassment from a speech problem (stuttering) or unfamiliarity with a language. Affected children are excessively shy and withdrawn and fear social embarrassment, whereas at home they may be controlling, seeking proximity to the parents, or completely normal. The differential diagnosis includes communication disorders (not restricted to certain situations), pervasive developmental disorders (absence of language is in all settings), and social phobia. Patients with social phobia may present with selective mutism. Although patients with selective mutism do exhibit a specific and persistent delay in speaking in social, extrafamilial situations, many experts now consider selective mutism to be a childhood variant of social phobia, an anxiety disorder. Behavior therapy applied both at home and at school appears to be the most effective intervention. There is some suggestion that the addition of an SSRI (fluoxetine, sertralin, ritalopram) may augment the impact of behavioral interventions.
SUMMARY AND RED FLAGS Unusual behaviors are common in children. The primary physician is charged with recognizing and treating the most common of these and with recognizing and referring those that are serious or unusual (see Table 35-1). Suicide is the third leading cause of death in adolescents. When thoughts of suicide have escalated to threats or attempts, the patient’s life is in danger (see Fig. 35-1). Delirium and psychoses may be either an acute manifestation of a new illness or a recurrent episode in a chronic disorder (see Tables 35-6 and 35-7). Many psychiatric illnesses have comorbid psychiatric and medical conditions necessitating a diligent and collaborative approach to management (see Figs. 35-2 to 35-4). Red flags include risk-taking behavior, violence, poor school performance, poor attention to personal appearance and hygiene, deteriorating social interaction, suicide attempts without remorse, reduced appetite, weight loss, reduced or excessive sleeping, and hallucinations. REFERENCES General References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.
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Dulcan MK, Martini DR: Concise Guide to Child and Adolescent Psychiatry 2. Washington, DC: American Psychiatric Press, 1999. Klykylo WM, Kay J, Rube D: Clinical Child Psychiatry. Philadelphia, WB Saunders, 1998. Werry JS, Aman MG: Practitioner’s Guide to Psychiatric Drugs for Children and Adolescents. New York: Plenum Press, 1999. Suicide Brent DA: Risk factors for adolescent suicide and suicidal behavior: Mental and substance abuse disorders, family environmental factors, and life stress. Suicide Life Threat Behav 1995;25:52-63. De Wilde EJ, Kienhorst I, Diekster R, et al: The specificity of psychological characteristics of adolescent suicide attempters. J Am Acad Child Adolesc Psychiatry 1993;32:51-59. Hergenroeder AC, Kastner L, Farrow J, et al: The pediatrician’s role in adolescent suicide. Pediatr Ann 1986;15:787-798. Pfeffer CR, Klerman G, Hurt S, et al: Suicidal children grow up: Rates and psychological risks of suicide attempts during follow-up. J Am Acad Child Adolesc Psychiatry 1993;32:106-113. Pilowsky DJ, Wu Li-Tzy, Anthony JC: Panic attacks and suicide attempts in mid-adolescence. Am J Psychiatry 1999;156:1545-1549. Chronic Disruptive Behaviors American Academy of Pediatrics, Committee on Substance Abuse: Role of the pediatrician in prevention and management of substance abuse. Pediatrics 1993;91:1010-1013. Burd L, Kerbeshian PJ, Barth A, et al: Long-term follow-up of an epidemiologically defined cohort of patients with Tourette syndrome. J Child Neurol 2001;16:421-437. Cantwell DP: Attention deficit disorder: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:978-987. Garfinkel BD, Amrami KK: Assessment and differential diagnosis of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin North Am 1992;1:311-324. Herrerias CT, Perrin JM, Stein MT: The child with ADHD: Using the AAP clinical practice guidelines. Am Fam Physician 2001;63:1803-1810. Kazdin AE, Bass D, Siegel T, et al: Cognitive-behavioral therapy and relationship therapy in the treatment of children referred for antisocial behavior. J Consult Clin Psychol 1989;57:522-535. Leckman JF, Hardin MT, Riddle MA, et al: Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1991;48:324-328. Leonard HL (ed): New research on atomoxetine for ADHA. Brown University Child and Adolescent Psychopharmacology Update 2003;5:1,5,6. Loeber R, Burke JD, Lahey BB, et al: Oppositional defiant and conduct disorder: A review of the past 10 years, part I. J Am Acad Child Adolesc Psychiatry 2000;39:1468-1484. Mannuzza S, Klein RG, Bessler A, et al: Adult outcome of hyperactive boys: Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 1993;50:565-576. Mayfield D, McLeod G, Hall P: The CAGE questionnaire: Validation of a new alcoholism screening instrument. Am J Psychiatry 1974;131: 1121-1123. Moffitt TE: Adolescent-limited and life course persistent antisocial behavior: A developmental taxonomy. Psychol Rev 1993;100:674-701. The MTA Cooperative Group: A 14-month randomized clinical trial of treatment strategies for attention deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073-1086. Smith HE, Margolis RD: Adolescent inpatient and outpatient chemical dependence treatment: An overview. Psychiatr Ann 1991;21:105-108. Stokes A, Bawden HN, Camfield PR, et al: Peer problems in Tourette’s disorder. Pediatrics 1991;87:936-942. Episodic Disruptive Behaviors Acute reactions to drugs of abuse. Med Lett 2002;44:21-24. Arnold DH: The central serotonin syndrome: Paradigm for psychotherapeutic misadventure. Pediatr Rev 2002;23:427-432. Bernstein GA, Borchardt CM, Perwin AR: Anxiety disorders of childhood and adolescence: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:1110-1119. Birmaher B, Ryan ND, Williamson DE, et al: Childhood and adolescent depression: A review of the past 10 years, part I. J Am Acad Child Adolesc Psychiatry 1996;35:1427-1439.
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Birmaher B, Ryan ND, Williamson DE, et al: Childhood and adolescent depression: A review of the past 10 years, part II. J Am Acad Child Adolesc Psychiatry 1996;35:1575-1583. Famularo R, Fenton T, Kinscherff R: Child maltreatment and the development of post traumatic stress disorder. Am J Dis Child 1993;147: 755-760. Geller B, Luby J: Child and adolescent bipolar disorder: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1997;36: 1168-1176. March JS, Leonard HI: Obsessive-compulsive disorder in children and adolescents: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:1265-1273. Marenco S, Weinberger DR: The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave. Dev Psychopathol 2000;12:501-527. Moreau D, Weissman MM: Panic disorder in children and adolescents: A review. Am J Psychiatry 1992;149:1306-1314. Murphy ML, Pichichero ME: Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med 2002;156:356-361. Petti TA, Vela RM: Borderline disorders of childhood: An overview. J Am Acad Child Adolesc Psychiatry 1990;29:327-337. Pfefferbaum B: Posttraumatic stress disorder in children: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1997;36:1503-1511. Snider LA, Seligman LD, Ketchen BR, et al: Tics and problem behaviors in schoolchildren: Prevalence, characterization and associations. Pediatrics 2002;110:331-336. Volkmar FR: Childhood and adolescent psychosis: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996;35:843-851. Wagner KD: Generalized anxiety disorder in children and adolescents. Psychiatr Clin North Am 2001;24:139-153. Weller EB, Weller RA, Svadjian H: Mood disorders. In Lewis M (ed): Child and Adolescent Psychiatry: A Comprehensive Textbook, 2nd ed. Baltimore: Williams & Wilkins, 1996, pp 650-665. Hallucinations Nagera H: The imaginary companion. Psychoanal Study Child 1969; 24:165-196. Schreier HA, Libow JA: Acute phobic hallucinations in very young children. J Am Acad Child Adolesc Psychiatry 1986;25:574-578. Unexplained Physical Complaints American Psychiatric Association: Practice guidelines for eating disorders. Am J Psychiatry 1993;150:207-228. Benjamin PY: Psychological problems following recovery from acute life-threatening illness. Am J Orthopsychiatry 1978;48:284-290.
Eminson DM, Postlewaite RJ: Factitious illness: Recognition and management. Arch Dis Child 1992;67:1510-1516. Fluoxetine Bulimia Nervosa Collaborative Study Group: Fluoxetine in the treatment of bulimia nervosa: A multicenter, placebo controlled, doubleblind trial. Arch Gen Psychiatry 1992;43:139-147. Fritz GK, Fritsch S, Hagino O: Somatoform disorders in children and adolescents: A review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1997;36:1329-1338. Hill K, Maloney M: Anorexia nervosa and bulemia. In Klykylo WM, Kay J, Tube D (eds): Clinical Child Psychiatry. Philadelphia: WB Saunders, 1998, pp 279-288. Lehmkuhl G, Blahz B, Lehmkuhl U, et al: Conversion disorder (DSM-III-R 300-1), symptomatology and course in childhood and adolescence. Eur Arch Psychiatry Neurol Sci 1989;238:155-160. Levy JC: Vulnerable children: Parents’ perspectives and the use of medical care. Pediatrics 1980;65:956-963. Maisami M, Freeman JM: Conversion reaction in children as body language: A combined child psychology/neurology team approach to the management of functional neurological disorder in children. Pediatrics 1987; 80:46-52. Meadows R: Management of Munchausen’s syndrome by proxy. Arch Dis Child 1985;60:385-393. Rosenberg D: Web of deceit: A literature review of Munchausen’s syndrome by proxy. Child Abuse Negl 1987;2:547-563. Turgay A: Treatment outcome for children and adolescents with conversion disorder. Can J Psychiatry 1990;35:585-587. Wachsmuth JR, Garfinkel PE: The treatment of anorexia nervosa in young adolescents. Child Adolesc Psychiatr Clin North Am 1993;2:145-160. Wentz E, Gillberg I, Gillberg C, et al: Ten-year follow up of adolescent onset anorexia nervosa: Physical health and neurodevelopment. Dev Med Child Neurol 2000;42:328-333. Delayed Development Cook EH, Rowlett R, Jaselskis C, et al: Fluoxetine treatment of children and adolescents with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992;31:739-745. Klin A, Volkmar FR: The pervasive developmental disorders: Nosology and profiles of development. In Luthar SS, Burack JA, Cichetti D, Weisz JR (eds): Developmental Psychopathology: Perspectives on Adjustment, Risk and Disorder. New York: Cambridge University Press, 1997, pp 208-226. Tanguay PE: Pervasive developmental disorders: A 10-year review. J Am Acad Child Adolesc Psychiatry 2000;39:1079-1095. Volkmar FR: Childhood disintegrative disorder: Issues for DSM-IV. J Autism Dev Disord 1992;22:625-642. Volkmar FR, Nelson DS: Seizure disorder in autism. J Am Acad Child Adolesc Psychiatry 1990;29:127-129.
36
Child Abuse
Robert M. Reece
58.4%; physical abuse, 21.3%; sexual abuse, 11.3%; and miscellaneous forms making up the balance. These figures represent a decline of 19.2% from 1993. However, not all states report these statistics, and the various states have widely variable procedures for screening in reports, investigating reports and substantiating cases. The figures from 1993 and 1999 were collected by different methods. Until uniform data collection systems are in place, the trends that are reported must be viewed with some skepticism.
DEFINITIONS Local statutes define for local jurisdictions what should legally be considered child abuse. Public Law 93-247, the Child Abuse Prevention and Treatment Act of 1974, defines child abuse as “the physical or mental injury, sexual abuse, negligent treatment, or maltreatment of a child under the age of 18 years by a person who is responsible for the child’s welfare under circumstances which indicate the child’s health or welfare is harmed or threatened thereby.” Kempe (1978) succinctly defined child physical abuse as “nonaccidental physical injuries as a result of acts or omissions on the part of the child’s parents or guardians.” Child care lapses in environmental control, repetitive accidental poisonings, and failure to provide food, shelter, clothing, medical care, emotional support, or education should all be included as manifestations of maltreatment. Definitions of child sexual abuse depend on the context because there are legal, psychosocial, medical, and cultural situations within which it can be defined. Definitions are often omitted from descriptions of child sexual abuse, with the manifestations of the abuse serving to illustrate the phenomenon, thereby avoiding the task of drawing a line between abuse and other events. It is often left to observers, who must claim that they “know it when they see it.” However, definitions do exist, and several are presented here to allow some delineation of this epidemic. The National Center on Child Abuse and Neglect of the U.S. Department of Health and Human Services defines child sexual abuse as “contacts or interactions between a child and an adult for the sexual stimulation of the perpetrator or another person or [as] sexual contacts or interactions between a child and a significantly older child who has power or control over the [younger] child.” The definition of child sexual abuse proposed by Kempe (1978) is “the involvement of children and adolescents in sexual activities they do not understand, to which they cannot give informed consent or that violate social taboos.” Legal definitions describe “sexual activity” as being divided into two categories: (1) sexual conduct, or intercourse, and (2) sexual contact, or the touching of the erogenous zones of another person for the purpose of sexually arousing or gratifying either person. Local jurisdictions then define levels of severity attached to the sexual activities described, taking into account the act itself, the age of the victim, and his or her capacity to object or defend against the act.
SEXUAL ABUSE DIAGNOSTIC STRATEGIES A child who has been sexually abused may come to the attention of a physician by having told someone of the abuse or by exhibiting behavioral or physical signs and symptoms. Historical information may be derived from several sources: 1. Witnessed events: The observation of sexual activity by an adult with a child may be seen by another child or adult. The details of this witnessed event should be clear as to time, the nature of the activity observed, and the positive identification of the individuals involved. 2. Admission by the perpetrator. 3. Disclosure by the victimized child: This disclosure may be proximate in time to the event or events, but it is often delayed, sometimes for months or even years after the last episode. It may be disclosed to an adult caretaker, a trusted friend, or an authority figure (police, child protection worker, teacher, physician, therapist, or other health care provider). 4. Previous medical encounters: In some cases, previous medical examinations will have been performed, and this information can provide important data. Medical History A complete medical history, including the prenatal history, obstetric and perinatal events, childhood illnesses and hospitalizations, surgical procedures, and other contact with medical professionals, should be detailed. A careful review of systems may reveal symptoms referable to the current complaint. This exercise helps to avoid the pitfalls of misattribution of medical conditions to sexual abuse, and it also demonstrates good medical diagnostic work if the case comes to trial, in which the strength of the legal case may rest on the medical evidence.
PREVALENCE In 1999, on the basis of data contained in “Child Maltreatment 1999: Reports from the States to the National Child Abuse and Neglect Data System,” the Department of Health and Human Services estimated that there were 2,974,00 referrals of possible maltreatment and, after investigation, 826,000 cases of substantiated child maltreatment. This is a prevalence of 11.8 per 1000 children. The distribution of the forms of maltreatment was as follows: neglect,
Family and Social History It is the province of the examining physician to gather pertinent family and social history. This should include a description of the social and economic milieu. The marital status of the caretaking parent, the identity of the other members of the household, and the status of adult partners and friends who are occasional members of 611
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the household should be learned in order to understand the ecology of the allegation. Inquiries into a history of abuse in the childhood of the adult caretaker or current domestic violence should be made. Is there exposure to high risks of violence, drugs or alcohol, nutritional problems, or diseases? Are there psychiatric disorders apparent in the caretaker or in those with him or her at the time of the visit? Is there a history of emotional disorder in the caretaker or the child? Has there been previous involvement with law enforcement or social service agencies? The occurrence of allegations of sexual abuse within the context of divorce or custody disputes has brought this situation to the forefront in the public mind. Examination of peer-reviewed literature indicates a very low incidence of sexual abuse in all divorce and custody cases (2%) and a higher incidence of proven “malicious” false allegations (5% to 14%). Nonetheless, all allegations of sexual abuse must be taken seriously and warrant thorough investigations. The emotional landscape of divorce is such that there may also be an increased incidence of all types of abuse perpetrated against the children trapped in these struggles. Behavioral Signs and Symptoms Nonspecific signs and symptoms can occur in a child reacting to a wide range of stresses and conflicts (enuresis, encopresis, disturbed sleep or eating patterns, changes in school performance, mood swings, or just depression, irritability, temper outbursts). These can be present in sexually abused children but are not diagnostic for sexual abuse. Specific symptoms or signs of sexual abuse are the byproduct of inappropriate sexual exposure and are associated with sexual function in some way. Thus, unexpected knowledge in young children about sexual matters, unusual curiosity about sexual or excretory functions, asking others to engage in sexual acts, acting out sexually with toys or other children, or abnormal masturbatory activities are examples of behavioral symptoms suggestive of sexual abuse. Research has cast some doubt on the specificity of sexualized behaviors, and these behaviors must therefore be put into the context of the total information about each case. Physical Signs and Symptoms There are also specific and nonspecific physical manifestations and important legitimate reasons for certain presenting complaints that must be taken into account when a child is evaluated for possible sexual abuse. A child may have an innocent injury to private parts through play (straddle injury, penetrating injury); may have dysuria, abdominal pain, proctitis, vaginitis, or vulvitis from nonsexually acquired infections (streptococcal cellulitis, intravaginal foreign body); or may have a nonsexual dermatologic problem (lichen sclerosus et atrophicus, severe contact dermatitis secondary to poor hygiene, seborrheic dermatitis). The 4-year-old who has a foulsmelling vaginal discharge not caused by a foreign body, has vaginal bleeding, or demonstrates decreased anal tone with accompanying fecal soiling, however, has physical signs that suggest sexual abuse until careful evaluation proves otherwise. The Medical Interview Because of the nature of the information involved, the medical interview in a possible sexual abuse case may intimidate otherwise self-assured pediatricians. The examiner must derive information from the child about what may be confusing, painful, and frightening to him or her that may be perceived by the child in a completely different way than by adults. The objectives of the interview are to determine ● ● ● ●
the elements of the abuse who was involved when and how often it occurred where it occurred
The initial goal is to make the child comfortable and unafraid. The child and the adult bringing the child for the session should be informed of what will happen during the visit. It is often helpful to address children’s universal fear of pain by assuring them that they are not going to have “shots” or any painful procedure during the course of the examination. In girls, the caregiver should be told that the examination does not involve the type of gynecologic examination used for adults and that nothing is to be inserted into the child’s vagina. The child can be reassured that the trusted adult with whom he or she came can be present during the examination. The caregiver should be interviewed separately from the child, and the interview with the child should be conducted after rapport has been established with him or her. The first step in interviewing the child is to explain in simple terms that the examiner is a “kid’s doctor” and that at first the examiner just wants to get to know the child. This can be done by “making friends” with the child in the form of “getting to know you” questions about his or her friends, pets, neighborhood, school, or interests (sports, television, music, or hobbies). Allowing the child to select a beverage or a treat before the interview can enhance this process. In some clinics, younger children are presented with a choice of small stuffed animals to take home with them, and the animal is used for demonstration of the elements of the examination. The stuffed animal can be used to familiarize the child with the colposcope, allowing the child to look at the toy through the colposcope and then to take a picture of the animal with the flash attachment. This engages the child with the instrument and serves to demystify the process. The interview must not involve leading questions, must be openended, and must include various forms of projective techniques for eliciting information. Projective techniques can include drawing, playing with toys in the room, and using dollhouses and dolls. The use of anatomically detailed dolls is controversial. Many sexual abuse evaluation centers have turned to other means of conducting these interviews. The interviewer should be supportive, unrushed, and friendly, and the interview should be conducted in a child-friendly environment. If more than one session is required, the same interviewer should conduct all sessions. Eliciting information should start with general questions and proceed to more specific ones. Using an approach suggesting ignorance or puzzlement on the part of the examiner instills selfconfidence in the child, and it allows the examiner to ask clarifying questions in the form of “I don’t really understand what you said about...” or “I’m not really sure about one thing that you told me.” Establishing the routines in the child’s family environment can be a transition from the general discussion about the world outside of the home to the world within the home. It also allows a subtle transition to the more private areas of the child’s life: Where do you sleep? Who puts you to bed? Who helps you with your bath? Once rapport has been established, greater focus can be brought to the issues of possible sexual abuse. The child may be asked whether he or she knows the reason for this visit and whether he or she could help make the examiner understand what might have happened. This can be augmented by a discussion of “good touch, bad touch” or by asking the child to identify body parts on a picture. The language used by the interviewer influences the success of eliciting accurate information. The interviewer should use developmentally sensitive language that includes short, single-clause questions; the active voice; the clear use of names over pronouns; single negatives; short, understandable words; simple verbs; and direct statements. The child should be praised for the effort in the interview but not for the content. The use of phrases such as “some children have told me that...” or indicating in some other way that this discussion does not necessarily relate to the child but to other people is of use by giving the topic at hand an impersonal, abstract cast.
Chapter 36 Child Abuse These techniques may elicit the exposition of the events in graphic and lengthy detail or may cause shutdown. The posing of the questions that turn from nonthreatening to threatening requires a sense of timing that experienced interviewers acquire and use intuitively. Most children, if comfortable, will disclose a clear and credible description of their experience. The Credibility of Children’s Histories of Sexual Abuse
From medical, psychosocial, and legal perspectives, it is necessary to evaluate the credibility of a child’s recounting of what happened to him or her if sexual abuse is a consideration. Because children are often eager to please and wish to provide the “right” answer, it is important that the examiner use clearly worded questions that encourage children to provide answers that will be viewed nonjudgmentally. The interviewer should not suggest correct answers or scenarios, because children are prone to suggestibility. The issue of lying in childhood has been studied and may be classified according to the reasons for lying. Reasons for lying include avoidance of punishment; getting something that the child could not get otherwise; protection of friends from trouble; selfprotection; winning the admiration or interest of others; avoidance of embarrassment; maintenance of privacy; and demonstration of the child’s power over an authority. Children do not lie to get into trouble, and the disclosure of sexual abuse, especially because the perpetrator has often intimidated or threatened the child not to tell about “their secret,” puts the child at distinct risk. Consequently, when a child discloses sexual abuse to someone who has gained his or her trust, it usually represents the child’s desire to escape from further harm and should be accepted as a truthful representation of the events described. In rare instances, however, a child can be programmed to tell a lie about sexual abuse by an unscrupulous caretaker whose motive is other than the child’s best interests. Skilled interviewers are able to detect such prevarication, and careful questioning leads to the exposure of this attempted deception. The issue of children’s competency in testifying to the events around a sexual abuse allegation becomes a legal question; persons performing the medical evaluation are responsible for gathering information in the most objective manner, using the best techniques available, and for delivering this information clearly and without bias at the time of legal proceedings. Disclosure information obtained during the conduct of a medical examination is admissible in court according to the “hearsay exception” rule. The Physical Examination Usually, permission for the performance of an evaluation for sexual abuse should be obtained from the legal guardian. If the legal guardian is suspected of being the perpetrator, is shielding the perpetrator, or is for some other reason obstructing the evaluation of the child, some legal consultants believe the authority to perform necessary evaluations is covered under the child abuse reporting statutes. It is advisable in questionable cases to obtain legal advice before proceeding. The site of the examination and the time of the alleged event or events determine, to some extent, the approach to the physical examination. If the alleged sexual abuse is thought to have occurred within the past 72 hours and to have involved contact with the perpetrator’s genitalia, the collection of forensic evidence should be considered as an adjunct to the examination (see Chapter 29). If more than 72 hours have elapsed since the alleged contact and the child is being seen in an emergency setting or where the examiners are inexperienced in conducting such evaluations, the child should be examined with attention given to treatable acute injury (bleeding, tissue damage necessitating surgical care) or to signs or symptoms of infection necessitating culture analysis and treatment. If these services are not present and the child is otherwise healthy and is in
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no danger of being reexposed to the perpetrator, the child can be examined at a scheduled appointment by professionals familiar with sexual abuse evaluations. This approach avoids needless duplication of interviewing and examinations. The goals of the physical examination are as follows: 1. 2. 3. 4.
“Primum non nocere”: “First, do no harm.” Diagnose and treat, when necessary, injured tissue. Diagnose and treat sexually transmitted diseases (STDs). Diagnose and make decisions regarding pregnancies for patients in the childbearing years. 5. Thoroughly examine and document medical forensic evidence when indicated. 6. Make decisions about disposition and further diagnosis or therapy. 7. Document the findings with a consideration of both medical and legal aspects. The elements of the physical examination should be explained again to the caregiver and to the child after the medical interview. This explanation can be made to the child in the presence of the caregiver so that reassurances can be made to the caregiver and interpretation by the caregiver to the child can enhance the compliance of the child. If photographic colposcopy is to be done, it should be explained to both the child and the caregiver that only numbers identify any pictures taken and that no one will be able to recognize who is in the pictures. The absence of painful procedures during the examination should be stressed, and the child should be assured that he or she has control over the procedure. Children should be told that the examiner is going to listen to their heart and lungs; look at their eyes, nose, and ears; check to see whether they have any lumps in their tummies; and look at their knees, toes, and “bottom” to “make sure they are OK.” The examiner can also state that “if anytime during the examination you want me to stop, just tell me, and I’ll stop, and we’ll talk about what I’m doing.” It is important to tell children that this kind of examination should be done only by a doctor or nurse when their mother (or other trusted caregiver) is present. They should be told that no one else is allowed to perform this kind of examination. The child should be encouraged to ask questions about the examination before it is begun and anytime during the examination. Offering to let the child listen to his or her heart with the stethoscope is also helpful in establishing trust. If a colposcope is to be used, allowing children to look through the lens and to photograph a toy gains their interest in the instrument. Some colposcopes have been equipped with a long cable so that the child can actually trip the shutter when photographs are to be taken, and this focuses the child’s attention on this activity. A general physical examination should then proceed, with note of any medical findings relevant to the sexual abuse issue and to general medical conditions. During the examination, the child can be told what the examiner has seen or heard and what will be done next. Carrying on a conversation with children about subjects of interest to them builds rapport and makes the next phase of the examination easier. Under no circumstances should the child be forced to undergo any part of the examination. If the child is unable to cooperate after several attempts, the examination can be rescheduled. If two attempts at an examination have failed, an examination with the child under anesthesia may be scheduled. Equipment
The success of an anogenital examination depends on the availability of necessary equipment. Although the colposcope is increasingly used in these evaluations and has been successful in augmenting knowledge about normal and abnormal anogenital findings, its use is not mandatory. It is necessary, however, to have adequate examination tables, optimal lighting, some form of magnification (hand lens or otoscope), and a child-friendly environment for the examination.
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Figure 36-1. Supine frog-leg position for genital examination. (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 69.)
It is also desirable to be able to provide the child with toys or distracting objects. In addition, the requisite laboratory materials for the collection, transport, culturing, and confirmation of specimens involved in diagnosing STDs; a microscope and wet mount materials; and experienced medical assistants with knowledge of the need to preserve the chain of evidence are essential. When forensic evidence is needed, a sex crimes kit is necessary, along with expertise in collecting and delivering such evidence so that the legal chain of evidence is maintained. Positions for Examination
Most specialists in sexual abuse have children assume the supine frog-leg and the knee-chest positions, either alone or in combination, during examination. The frog-leg position is arguably more comfortable for the prepubertal child and more frequently employed (Fig. 36-1). The child can assume this position on a flat table surface with or without stirrups. As the child approaches adolescence, the use of stirrups makes the examination more acceptable because the adductor muscles of the thigh may be less pliant. The knee-chest position is less natural and comfortable; it is less stable when the examiner tries to focus for colposcopic photography (Fig. 36-2). However, some investigators maintain that without employing both positions, the posterior rim of the hymen may be incompletely evaluated.
Figure 36-2. Knee-chest position for genital examination of the prepubertal child, to supplement examination in the supine frog-leg position. (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 71.)
In both the frog-leg and the knee-chest positions, separation and traction of the labia are necessary to visualize the introitus and the edges of the hymenal membrane. Simple lateral movement by the thumbs and forefingers of the examiner can accomplish this (Fig. 36-3). The labia majora should be drawn downward and outward (traction) (Fig. 36-4). Various movements during this traction enable the floor of the perineum to open, allowing good visualization. Examination of the anus can be done with the child in these same positions or in the left lateral decubitus position (Fig. 36-5). The appearance of the normal anatomy of a prepubertal girl is shown in Figure 36-6. An example of penetrating sexual abuse is noted in Figure 36-7. Types of Sexual Abuse Sexual abuse occurs by way of a variety of sexual contacts. Fondling (passing the whole hand over the buttocks or genitalia) usually produces no physical findings, but when it progresses to digital contact and ultimately penetration, the resulting trauma can range from erythema to abrasion or laceration of the vaginal walls, depending on the amount of force, the penetrating object (finger,
Figure 36-3. Examination of female external genitalia by simple lateral movement by the thumbs and forefingers of the examiner. (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 73.)
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The determination of normal and abnormal in the examination of sexually abused prepubertal girls has been difficult. One classification of medical findings in child sexual abuse examinations includes the following (Table 36-1):
Figure 36-4. Examination of female external genitalia with the labia majora drawn downward and outward (traction). (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 72.)
Class 1: Normal. Variations in the appearance of the hymen, perihymenal tissues, and perianal tissues are documented in more than 10% of the subjects in studies of nonabused children. Class 2: Nonspecific. Findings may be the result of sexual abuse but may also be the result of other nonabusive causes. Class 3: Suspect. Findings are rarely seen in nonabused children and have been noted in children with documented abuse but have not been clearly proven to occur only as a result of abuse. Class 4: Suggestive of abuse or penetration. Findings, or a combination of findings, can be reasonably explained only by postulating that sexual abuse or penetrating injury has occurred. This type of finding mandates a report to law enforcement and a child protective service, even if the child is unable to give a clear history of molestation, under the assumption that there is no clear and consistent history of accidental penetrating injury. Class 5: Clear evidence of penetrating injury. Findings can have no explanation other than penetrating trauma to the hymen or perianal tissues. The assessment and likelihood of abuse are noted in Table 36-2.
penis, instrument), and the degree of penetration involved. Chronic digital abuse can be manifested by changes in the hymenal contour, healed transections, or the attenuation of the hymenal membrane until it is barely visible. When acute penile contact occurs, it can produce erythema, edema, bruising of the vulvar and perivestibular tissue, hymenal distortion, transections, vaginal edema, erythema, or abrasions. In long-standing cases, the vaginal orifice may take on a distinctly dilated character (see Fig. 36-7). Oral-genital contact by the perpetrator can cause petechiae, edema, bruising, and abrasions, but in most instances, no residual trauma is seen. Anal findings are even more nonspecific because of the natural distensibility of the anal sphincter. Bruising, laxity of the anal sphincter, and immediate dilation of the anus during the examination (especially in the absence of stool in the rectum) are worrisome findings. Major forced trauma to the anus and perianal structures produces more significant injuries; findings of this magnitude are rare. The perpetrators of child sexual abuse generally intend not to produce discernible injuries, because they want continuing access to their victims. Classification of Anogenital Findings in Children with Suspected Abuse
Laboratory Evidence Prepubertal children with STDs are considered the victims of sexual abuse (see Chapter 29). The most common STDs acquired through sexual abuse are gonorrhea, syphilis, and chlamydial infection (Table 36-3). Other STDs associated with sexual abuse are herpes simplex, condyloma acuminatum, trichomoniasis, human immunodeficiency virus (HIV) infection, and pediculosis pubis. Several studies have indicated low yields when cultures are obtained from all children who are having sexual abuse evaluations. Most investigators now obtain cultures from children when there is evidence of vaginal discharge, when there is known contact with the genitalia of an infected perpetrator, or when there is a history of vaginal discharge. The Centers for Disease Control and Prevention recommend that the following be obtained from selected child sexual abuse victims at high risk: ●
●
● ● ●
Most sexually abused children will have negative findings of medical examinations (range of positive findings, from 2% to 20%).
gonorrheal cultures from pharyngeal, anal, and urethral or vaginal sites chlamydial cultures from vaginal and anal sites in girls and from anal and urethral sites in boys serologic testing for syphilis, HIV, hepatitis B examination for anogenital warts or ulcerative lesions in girls, culture or wet mounts of vaginal secretions for microscopic examination for Trichomonas species and bacterial vaginosis
Figure 36-5. Hand placement for separation of the buttocks to view external anal tissues with the child in the left lateral decubitus position. (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 74.)
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Anterior commissure Prepuce
Clitoris Labia majora Urethral orifice Labia minora Para-urethral duct orifice (skene) Hymenal membrane
Greater vestibular glands of Bartholin
Hymenal orifice (vagina)
Figure 36-6. Normal anatomy of female external genitalia. (From Giardino AP, Finkel MA, Giardino ER, et al: A Practical Guide to the Evaluation of Sexual Abuse in the Prepubertal Child. Newbury Park, Calif, Sage Publications, 1992, p 32.)
Fossa navicularis (vestibular fossa) Posterior fourchette (frenulum of labia)
●
●
in adolescents, cultures for gonorrhea and chlamydia from all sites of penetration or attempted penetration, testing for Trichomonas species and bacterial vaginosis repeat serologic testing 2, 6, 12, and 24 weeks after the assault
Although histories from children, especially the young, cannot supply adequate information as to the type of contact, older children are often able to give quite accurate histories of the events of sexual contact. More selective testing can be based on the epidemiology of diseases in a given locale. The safest course of action is to adhere to strict guidelines, but clinical judgment based on the circumstances of each individual case should be applied. For information on specific therapy for STDs, see Chapter 29. Collection of Forensic Materials
Five conditions should be adhered to before the collection of specimens: 1. Specific details of collection, labeling, and packaging of specimens should be determined with the processing laboratory. 2. A specimen collection protocol should be used to ensure that all appropriate specimens are collected. 3. Collection kits should be standardized. 4. The procedures for collecting specimens should be explained in advance to the child and to his or her caretaker. 5. Proper consent should be obtained before performing the collection. If forensic evidence is to be gathered, it should be done within 72 hours of the event, because material is rarely recoverable after that time (Table 36-4). The handling of collected specimens
should be documented to maintain a chain of evidence and to prevent legal challenges about confusing specimens from different patients. DIFFERENTIAL DIAGNOSIS The correct diagnosis of sexual abuse in children can lead to intervention that is sometimes life-saving. In many cases, the recognition of abuse provides the opportunity for the child to enter a new, protected, and nourished life. The long-term outcome for some adults in whom the diagnosis was not made in childhood is a life of mistrust, maladjustment, and a multitude of psychogenic medical complaints. We do not know the outcome in children in whom a misdiagnosis of child sexual abuse has occurred. Such an error sets in motion a process that is, at the very least, disruptive and, in the worst case, tragic. It behooves the diagnostician to be aware of possible diagnoses that may be confused with sexual abuse (Table 36-5). DIAGNOSTIC FORMULATION Few cases of alleged sexual abuse follow a smooth course from the chief complaint to a firm and unassailable diagnosis. Individuals who provide clear and convincing disclosure information, exhibit behavioral signs and symptoms known to be induced by sexual abuse, and demonstrate definitive anatomic changes secondary to the trauma of sexual abuse may not have their cases supported by the protective and judicial systems. Children who provide disclosure information that is borderline or equivocal may nonetheless be the victims of abuse. The evaluators must be able to gather meaningful
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Table 36-1. Proposed Classification of Anogenital
Findings in Children Normal (Class 1) Periurethral (or vestibular) bands Longitudinal intravaginal ridges Hymenal tags Posterior (inferior) hymenal rim measuring at least 1 mm wide Estrogen changes (uniformly thickened, redundant hymen) Hymenal clefts in the anterior (superior) half of the hymenal rim: on or above the 3- to 9-o’clock line, patient supine Hymenal bumps or mounds Diastasis ani (smooth area) at 6 or 12 o’clock position in the perianal area Anal tag/thickened fold in midline Increased perianal pigmentation
Figure 36-7. View of the genitalia of a 7-year-old girl sexually molested by her father and uncle; labial traction method. Narrow hymenal rim (arrow a) with exposed ridges (arrows b) at the 3- and 9-o’clock positions, anterior column (arrow c), and enlarged hymenal orifice. Colposcopic photographs (magnification, ×10). (From McCann J: Use of the colposcope in childhood sexual abuse examinations. Pediatr Clin North Am 1990;37:863-881.)
information and to analyze and synthesize it so that a balanced, accurate, and holistic appraisal of the case is accomplished. The three critical components of diagnosis of child sexual abuse are 1. the disclosure information 2. the physical and behavioral signs and symptoms 3. the positive results of the medical examination Foremost in importance are the quality and credibility of the child’s description of the events and the techniques used in eliciting the information. A disclosure statement is theoretically possible in all cases if sexual abuse has occurred in a verbal child. This is the best and most reliable evidence. The diagnostic value of physical and behavioral signs depends on the specificity of those factors for sexual abuse. Such physical and behavioral signs/ symptoms are variably present and can be legally challenged if it is possible to cast doubt about their origin. The finding of definitive diagnostic anatomic changes is of great value but occurs in a low proportion of cases (15% to 30%). Positive culture or serologic results for STDs have value in direct proportion to the STD involved, the detection method used, and the specificity of the STD for sexual abuse.
Nonspecific (Class 2) Erythema of vestibule or perianal tissues Increased vascularity of vestibule or hymen Labial adhesions Vaginal discharge Lesions of condyloma acuminata in a child younger than 2 yr old Anal fissures Flattened anal folds Anal dilation with stool present Venous congestion of perianal tissues Suspected for Abuse (Class 3) Enlarged hymenal opening (>2 standard deviations above mean for age and position) Immediate venous congestion of perianal tissues with edema and/or distorted anal folds Anal dilation of at least 20 mm with stool not visible in rectal vault Posterior hymenal rim less than 1 mm in all views Condyloma acuminata in a child older than 2 yr of age Acute abrasions or lacerations in the vestibule or on the labia (not involving the hymen) Suggestive of Abuse/Penetration (Class 4) Combination of two or more suspected anal findings or two or more suspected genital findings Scar of fresh laceration of the posterior fourchette Perianal scar Clear Evidence of Penetrating Injury (Class 5) Areas in the posterior (inferior) half of the hymenal rim with an absence of hymenal tissue, confirmed in knee-chest position Obvious hymenal transections Perianal lacerations extending beyond (deep to) the external anal sphincter Recent hymenal-vaginal lacerations Lacerations through the hymen and posterior fourchette or perineum
REPORTING CHILD ABUSE In all 50 states, there exist uniform statutes mandating that physicians report to the child protective services bureau in their local jurisdiction all cases in which there exists a “reasonable” suspicion that child abuse has occurred. Absolute certainty is not required, and in many cases, more information needs to be elicited by the child protection agency to decide whether a case is founded. The person
who reports is immune from legal action by caretakers, unless it can be proved that malicious intent was present; there are both civil and criminal penalties for failing to report when suspicion exists. Consultation is usually readily available from child protection agencies by telephone on a 24-hour basis if there is doubt about the need to report.
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Table 36-2. Overall Assessment of the Likelihood of
Sexual Abuse Class 1: No Evidence of Sexual Abuse 1:1 Normal examination, no history, no behavioral changes, no witnessed abuse 1:2 Nonspecific findings with another known cause, and no history or behavioral changes 1:3 Child considered at risk for sexual abuse but gives no history and has nonspecific behavioral changes 1:4 Physical findings of injury consistent with accidental trauma with history given Class 2: Possible Abuse 2:1 Class 1, 2, or 3 findings in combination with significant behavioral changes, especially sexualized behaviors, but child unable to give history of abuse 2:2 Presence of condyloma or herpes simplex type I (genital) in the absence of a history of abuse, with otherwise normal examination findings 2:3 Child has made a statement but given no detailed or consistent history 2:4 Class 3 findings with no disclosure of abuse Class 3: Probable Abuse 3:1 Child gives a clear, consistent, detailed description of molestation, with or without other findings present 3:2 Class 4 or 5 findings in a child, with or without a history of abuse, in the absence of any convincing history of accidental penetrating injury 3:3 Culture-proven infection with Chlamydia trachomatis (child >2 yr of age) in a prepubertal child; also, culture-proven herpes simplex type 2 infection in a child or documented Trichomonas infection Class 4: Definite Evidence of Abuse or Sexual Contact 4:1 The finding of sperm or seminal fluid in or on child’s body 4:2 A witnessed episode of sexual molestation; this also applies to cases in which pornographic photographs or videotapes are acquired as evidence 4:3 Nonaccidental, blunt penetrating injury to the vaginal or anal orifice 4:4 Positive, confirmed cultures for Neisseria gonorrhoeae in a prepubertal child, or serologic confirmation of acquired syphilis 4:5 Pregnancy
Problems in diagnosis are noted in Table 36-6, and indications for consultation with other experts are noted in Table 36-7.
PHYSICAL ABUSE Two separate domains exist in cases of suspected physical abuse. The first domain, which is a strictly medical one, requires a traditional medical or surgical approach to diagnosis and management. The second domain requires a decision as to whether the observed phenomenon is the result of inflicted injury, a medical disease process, or an accidental injury. Standard medical and surgical approaches are the central concerns in the first domain, with optimal management necessary to obtain the best short-term outcome. Within the second domain lies the challenge of securing the best comprehensive outcome for the child and family. This requires the skills and wisdom of the interdisciplinary team at both the hospital and the community levels.
ACCIDENT OR ABUSE? An accident is defined as an event that occurs incidentally, casually, or by chance. It is presumed that such an event was at least consciously unintentional and that if such circumstances were under conscious control, an attempt would have been made to avert the anticipated event. An intentional event or action is one that occurs voluntarily and is under conscious, or perhaps even unconscious, control, reflecting an underlying conflict or impulse. In possible child abuse cases, there is a continuum from what appears to be a volitional act to what appears to be a chance event. The distinction must be made, taking into account the setting of the event (social context, location of encounter), the biases of the observer and the reporter, the type of injury (likelihood of observed injury or injuries being caused by an accidental mechanism), and the future risk to the child, if it is at all predictable. The approach both to the medical or surgical diagnosis and to the determination of the cause of the observed condition, however, is a traditional medical one: accurate and comprehensive historical investigation, thorough physical examination, and discerning selection of laboratory and imaging studies. Several questions help to distinguish accidental from inflicted injury: 1. What is the age of the patient? Developmental stages of childhood determine what kinds of injuries are likely to be seen. The motor skills of the child determine what the child could have done to incur injury. What are the normal behaviors of a child at this particular age? What is this child developmentally capable of doing? Is the child “hyperactive” either in the eyes of his or her caretakers or in actuality? Is the child a “daredevil”? Is the child obstreperous, combative, or “annoying” and therefore more likely to be disciplined harshly? 2. Is the history plausible? Could this injury have been sustained in the manner described? 3. Does the history change with changing information supplied to the caretaker? Adjustments in the account of the injury may be made by caretakers to fit the evolving information, which indicates that the history is being tailored to fit the new information. 4. Does the history change when related in subsequent accounts by other family members? 5. Are there nonfamilial eyewitnesses to the injury? 6. Was the injury unwitnessed by the caretaker? The lack of information as to how a serious injury has occurred should raise the index of suspicion for an abusive origin. 7. Is the caretaker’s demeanor defensive, belligerent, hostile, or passive and not in keeping with the seriousness of the patient’s condition? 8. Is the social situation in which the injury occurred a high-risk environment? The presence of community or intrafamilial violence, substance abuse, chaotic living arrangements, poverty, social isolation, transient lifestyles, mental health problems, or discord among family members should serve as a red flag. 9. Can the described mechanism of injury account for the observed injury? The concept of the discrepant history is a central one in distinguishing between accidental and inflicted injury. Often the injury is explained by claims that it was caused by a fall. According to a large literature, falls from short distances are discounted as being responsible for serious injuries, but short falls down steps, off beds, off couches, off tables, and in baby walkers are often offered as the mechanisms of serious injuries in actual abuse cases. The role of torsion must be considered in fractured bones, and it should be remembered that for a torsion injury to exist, one end of a long bone is twisted in the opposite direction of the other by a large force. The issue of how much force is required to produce injuries is often raised. Information derived from the medical literature helps to answer this question.
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Table 36-3. Incubation, Diagnosis, and Implications of Sexually Transmitted Diseases (STDs) in Prepubertal Children STDs
Incubation
Gonococcal infection Syphilis Chlamydial infection Human papillomavirus Trichomoniasis Herpes simplex virus type 2 infection Herpes simplex virus type 1 infection Bacterial vaginosis Genital mycoplasma HIV infection
2-7 days 10-90 days Variable 1-9 mo (? 20 mo)
Relationship to Sexual Abuse
Diagnosis
Certain* Certain* Probable* Probable*
4-20 days 2-14 days
Culture confirmed by two or more confirmatory tests RPR or VDRL test confirmed by FTA-ABS or MHA-TP test Culture only: rapid techniques lack adequate specificity Inspection, application of acetic acid, or biopsy and viral typing infection Wet mount of discharge, culture more sensitive Culture with viral typing
2-14 days
Culture with viral typing
Possible
7-14 days? 2-3 wk? 6 wk–18 mo
“Clue cells” on wet mount and positive “whiff” test Culture ELISA confirmed by Western blot
Uncertain Uncertain Uncertain
Probable* Probable*
From Finkel MA, De Jong AR: Medical findings in child sexual abuse. In Reece RM, Ludwig S (eds): Child Abuse: Medical Diagnosis and Management. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 207-286. *Except when perinatal transmission is documented. ELISA, enzyme-linked immunosorbent assay; FTA-ABS, fluorescent treponemal antibody absorption; HIV, human immunodeficiency virus; MHA-TP, microhemagglutinationTreponema pallidum; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratory.
10. What else might produce the clinical picture? The development of a differential diagnosis is critical in investigating all possible causes for the clinical and radiographic findings. HEAD INJURIES More fatalities and long-term morbidity are due to abusive head injury than to any other form of maltreatment. The types of abusive head injuries range from asymptomatic tissue swelling to mild or moderate bruising to skull fracture to intracranial bleeding, diffuse axonal shearing injury, and brain swelling resulting in stupor, coma, and death. When a child younger than 3 years of age comes for medical care with a serious head injury without a readily apparent major trauma history (motor vehicle accident, fall from heights over 10 feet), the chances that this is an inflicted injury are quite high. Data Collection While a seriously head-injured child is being evaluated and treated medically, it is crucial for a detailed, analytic, but not challenging or accusatory history to be obtained from the caretakers. The person collecting the history should ideally be someone with experience in child abuse cases who does not have immediate responsibility for the medical treatment required by the child. As a rule, abusing parents tell a misleading story about how the “accident” happened and are sometimes quite inventive in describing the event. Gentle probing, with inquiries and request for clarification about questionable portions of the history, often elucidates the mechanism of injury and shows discrepancies in the history. The interviewer should establish a timeline of events beginning with the last time the caretakers believed that the child was completely “normal.” A thorough description of all events involving the child after that time up to and including the injury event, the caretakers’ response to the event, and the solicitation of medical care should be sought. This helps to determine when the child became symptomatic and who had physical access to the child. The history of the pregnancy, labor and delivery, and neonatal course and a family history of medical diseases are important, with particular attention to bleeding and clotting disorders, neurologic
diseases, metabolic and bone diseases, or other genetic conditions of the family. This comprehensive evaluation eliminates the necessity of returning to the caretakers for missing data as the case progresses. The medical history of the child, including previous injuries and serious illnesses or hospitalizations, along with a review of systems, should be obtained. Exploration of the social milieu with attention to the living arrangements and the relationships of household members should be done. Physical Examination The physical examination of the child with a head injury involves the risk of ignoring less urgently compromised organ systems (see Chapter 40). Ignoring bleeding visceral organs is the most glaring and potentially disastrous omission, but overlooking cutaneous injuries can deprive the diagnostician of important clinical data because of the fleeting nature of these injuries. Likewise, inspection of the oral cavity for intraoral lesions is important, as is a search for scalp lesions hidden under the hair. The neck should be carefully inspected for signs of injury (strangulation, hand- or finger-inflicted bruising). The presence of bruises on the back or thighs or in the perineum should also be noted. Photodocumentation of such injuries is highly desirable. The use of digital cameras is becoming widespread. All forms of photodocumentation have been challenged legally, but if the images produced are said to represent what the examiner saw at the time of the examination, these legal maneuvers are answered. The examination of the fundi is of utmost importance. This should ideally be carried out by pupillary dilatation and indirect ophthalmoscopic inspection or, in lieu of that capability, by direct ophthalmoscopy. Although retinal hemorrhages are the most common finding in child abuse, other lesions may also be seen. These include retinal detachment, optic nerve injury, and cupping of the optic nerve secondary to raised intracranial pressure. Although retinal hemorrhages are not pathognomonic for inflicted head trauma, they are present in a high percentage of abuse cases, are not present in most accidental head trauma cases, and are seldom seen in children who have undergone cardiopulmonary resuscitation. The presence of widespread, bilateral, multilayered retinal hemorrhages extending to the periphery of the retina are highly specific for inflicted head injury.
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Table 36-4. Collecting Forensic Specimens in Sexual Abuse Cases
1. Obtain 2-3 swabbed specimens from each area of body assaulted (for sperm, acid phosphatase, P30, MHS-5 antigen, blood group antigen determinations). The number of swabs required depends on local laboratory. Most laboratories request air-dried specimens, which require drying for 60 min before they can be packaged. 2. Mouth: Swab under tongue and buccal pouch next to upper and lower molars. These areas are locations where seminal fluid is most likely to be persistent. 3. Vagina: Use dry or moistened swab or 2 mL saline wash. Remember that overdilution of secretions may produce false-negative results of tests for acid phosphatase. Secretions may also be collected with a pipette or eyedropper. 4. Rectum: Insert swab at least 1/2 to 1 inch beyond anus. 5. Specimens should be taken from any other suspicious site on the body. Saline- or sterile water-moistened swabs may be used to lift any stains suspected to be dried seminal fluid or blood. An alternate method is to scrape off the dried stains with the back of a scalpel blade into a clean envelope or tube. 6. Make saline wet mount of specimens from all assaulted orifices and examine immediately for presence of motile and nonmotile sperm. 7. Some forensic laboratories request a dry smear of each secretion sample using clean glass microscope slides; others prefer to prepare their own slides from swab specimens. 8. Collect saliva specimen to determine the victim’s antigen secretion status. Saliva may be collected using 3-4 sterile swabs or a 2 × 2 gauze pad that the victim placed in the mouth. 9. Obtain a venous blood sample from the victim for antigen secretor status. This sample from the victim will be used in the analysis of the identity of the perpetrator. 10. Save torn or bloody clothes or any clothing when semen staining is suspected, using Wood lamp. Semen may fluoresce with a blue or green color under the ultraviolet light of the Wood lamp, although fluorescence under UV light is nonspecific. Various skin infections; congenital or acquired skin pigmentary changes; and chemicals, including systemic and topical medications, cosmetics, soaps, and industrial chemicals, may fluoresce under UV light. 11. If the victim was wearing a tampon, pad, or diaper during the assault or if a fresh tampon, pad, or diaper was used after the abuse, save this for analysis; seminal fluid products may be found on these items. Plastic bags should be used only on dry specimens and only if so directed by the laboratory. Sealed plastic may promote the growth of Candida and other organisms that might destroy some of the evidence. 12. Save any foreign material found on removal of clothing. Fiber analysis or trace analysis may provide evidence that links the specimens to the perpetrator or the location of the abuse. 13. Collect samples of combed pubic hair or scalp hair and fingernail scrapings. These procedures are often considered optional. Pubic hair, scalp hair, or skin fragments from scratching may be used to help identify the perpetrator. Control samples of the victim’s body or scalp hair are collected for comparison. Usually, it is recommended that the hairs be plucked rather than cut, although the additional trauma of plucking 10 to 20 hairs from a child may not be warranted unless foreign hair material is found on the child’s body. Some protocols recommend considering cutting hairs or collecting plucked hairs at a later time if needed. 14. Specimens should also be taken to screen for sexually transmitted diseases. The recommended procedures are detailed in the text. Swabs should not be air dried because air drying kills the organisms and causes the cultures for these diseases to be falsely negative. Specimens for culture should be sent quickly to a microbiology laboratory for processing and not be included with the materials to be processed in the forensic laboratory. From Finkel MA, De Jong AR: Medical findings in child sexual abuse. In Reece RM, Ludwig S (eds): Child Abuse: Medical Diagnosis and Management. Philadelphia, Lippincott Williams & Wilkins, 2001, p 268. MHS-5, mouse antihuman semen-5; UV, ultraviolet.
Laboratory Studies Children with head trauma severe enough to warrant admission to the hospital should also undergo laboratory studies to support diagnoses of associated trauma in other organ systems, to anticipate hematologic and biochemical alterations sometimes attendant to head trauma, and to document and monitor their neurologic status. These studies are listed in Table 36-8.
Imaging Studies In most instances of moderate to severe head injury, the first imaging modality should be computed tomography (CT) scanning without contrast media, because it is readily available in most hospitals and can be performed safely with life support systems operating during the procedure (Figs. 36-8 and 36-9). Bone windows should be employed along with the standard scan. Plain radiographs of the skull usually show existing skull fractures better than do CT scans but are of no value in demonstrating intracranial bleeding or parenchymal brain injury. Magnetic resonance imaging (MRI) is
ordinarily used as a confirmatory test rather than as an initial one because of the longer scan times and need for life support, but MRI shows parenchymal changes and smaller subdural hematomas in superior detail (see Fig. 36-8). Some of the newer techniques in MRI are gaining acceptance, and in time MRI may supplant CT scanning as the imaging modality of choice. CT scans of the abdominal viscera are valuable when there is elevation of liver and pancreatic enzymes or when there is reason to believe hepatic or pancreatic damage is present. If splenic or renal laceration is suspected, CT scans delineate these injuries. Skeletal radiologic surveys are recommended for serious head trauma, because the diagnosis of abuse may be made or supported if unsuspected traumatic injuries are found in other parts of the skeleton. Such accompanying skeletal fractures are seen in some cases of abusive head injury. Posterior rib fractures and the classic metaphyseal lesions at the ends of long bones provide strong evidence in favor of an abusive origin. Subtle acute posterior rib fractures may be difficult to visualize on the initial skeletal survey but can be demonstrated with bone scan scintigraphy or with followup thoracic films in 10 to 14 days, which reveal callus formation at the fracture site (Fig. 36-10).
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Table 36-5. Conditions Confused with Child Sexual Abuse
Dermatologic Conditions Erythema and excoriations Diaper rash Poor hygiene Candida infection Pinworms Allergy/irritants Bruises Hematologic disorders Mongolian spots Hypersensitivity vasculitis Purpura fulminans Coining and other folk practices Phytodermatitis Other Lichen sclerosus Seborrheic, atopic, and contact dermatitis Lichen planus Lichen simplex chronicus Psoriasis Congenital Conditions Midline pits, fusion defects, shiny areas Prominent median raphe Midline tags Linea vestibularis Diastasis recti (depressed fan-shaped areas) Genital hemangiomas Injuries Straddle injuries Violent abduction of the legs Motor vehicle accidents Self-destructive behavior in retarded children Female circumcision Anal Conditions Severe or chronic constipation and megacolon Postmortem anal dilation Neurogenic patulous anus (myotonic dystrophy)
Anal Conditions—cont’d Fistula Inflammatory bowel disease Pinworms Lichen sclerosus Hemolytic-uremic syndrome Rectal polyps or tumor Eversion of the anal canal/rectal prolapse Urethral Conditions Prolapse Caruncle Hemangioma Polyps Papilloma Cyst Condyloma Sarcoma botryoides Prolapsed bladder or ureterocele Infections Vaginitis with organisms not sexually transmitted Group A β-hemolytic streptococcus Shigella species Pinworms Nonpathologic Neisseria species Haemophilus species Varicella Molluscum Perinatally acquired Chlamydia Syphilis Herpes simplex virus (HSV) Human papillomavirus (HPV) infection Autoinoculation HSV type 1 HPV (warts) Infection with cyclic/idiopathic neutropenia Non–sexually transmitted disease causes of genital ulcers
Adapted from Bays JA: Conditions mistaken for child sexual abuse. In Reece RM, Ludwig S (eds): Child Abuse: Medical Diagnosis and Management. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 287-306.
The types of injuries in serious abusive head injury include skull fractures, subdural or subarachnoid bleeding (see Fig. 36-8), cerebral edema (see Fig. 36-9), diffuse axonal injury, parenchymal tears and contusions, and injuries to the cervical spinal cord. The shaken-baby syndrome/shaken-impact syndrome (SBS/SIS) occurs mainly in infants, usually younger than 1 year, but has been described in older children as well. In fact, there have been reports of shaken-adult syndrome, with the signs, symptoms, and clinical and radiographic findings identical to those seen in SBS. A key factor in these cases is the disparity in size between the perpetrator and the victim. Perpetrators are men in 75% of cases and women in 25%. Parents, baby sitters, other relatives, and unrelated adults have all been implicated. It is highly unlikely that children younger than 5 years could be perpetrators of SBS/SIS. Shaking alone or shaking with impact by slamming the child against a hard or soft surface with resultant deceleration and hypoxia are the responsible factors producing the subdural hematoma, diffuse axonal injury, and consequent cerebral edema leading to raised intracranial pressure. Whether shaking alone or shaking plus impact is required to cause the damage is debated. The clinical picture is one
of neurologic devastation, resulting in death in approximately 25% of the victims and long-term neurologic morbidity in the majority (57% to 65%) of the survivors. The most important consideration in SBS/SIS is that the lesions are injuries to the brain and that the attendant subdural and subarachnoid bleeding are only markers of the traumatic and hypoxic injuries. Retinal hemorrhages are seen in the majority of the cases, and the types of retinal hemorrhages— extensive, multiple, involving numerous layers of the retina—are almost never seen in any other condition and thus can be said to be diagnostic unless another major accidental injury can be demonstrated (e.g., major motor vehicle crash, falls from five stories). ABDOMINAL AND THORACIC INJURIES Abdominal and thoracic injuries are the second most common cause of death in child abuse (Table 36-9). They account for 6% to 8% of all injuries in physical abuse, and most of these are abdominal injuries. Reported fatality rates are between 40% and 50%.
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Section Five Developmental/Psychiatric Disorders
Table 36-6. Pitfalls in Child Abuse Evaluation:
12 Costly Errors 1. A desire not to make the diagnosis 2. Failure to assemble past information on medical conditions and medical encounters 3. Too great a reliance on the information developed by others 4. Transference-countertransference with custodial parent (formation of alliances or development of hostilities) 5. Overinterpretation or underinterpretation of signs and symptoms 6. Overinterpretation or underinterpretation of physical findings 7. Failure to know about conditions mistaken for sexual abuse 8. Faulty laboratory techniques resulting in either false-positive or false-negative reports 9. Use of techniques easily challenged in court 10. Impatience about arriving at a diagnostic conclusion 11. Failure to understand normative data with regard to psychosexual development 12. Failure to prepare adequately for court appearances
The following features help distinguish abusive from accidental abdominal injuries: 1. Abusive injuries are more common in younger children (median age 2.6 years versus 7.8 years in accidental cases). 2. Vague histories often account for the abusive injuries. In contrast, accidental injuries are often witnessed or otherwise well documented: 70% of the injuries in the accidental group are caused by motor vehicle accidents and 20% by falls from great heights.
Table 36-7. When to Seek Consultation
1. If clinician is not prepared to work in an interdisciplinary group 2. If clinician is not prepared to see the case through from initial encounter through the investigation and ultimate legal resolution 3. If clinician’s knowledge base about any of the components of the evaluation is too narrow 4. If there are areas of uncertainty about the diagnosis
Table 36-8. Laboratory Studies in Physical Abuse Cases
Complete blood cell count with morphology analysis; serial hematocrit levels Serum electrolytes, blood urea nitrogen, creatinine, serum and urine osmolality Urinalysis Liver function studies (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase) Serum amylase Creatine phosphokinase Cultures of blood, urine, cerebrospinal fluid (if safe to perform lumbar puncture) Prothrombin time, partial thromboplastin time, platelet count Stool for blood Arterial blood gases
Figure 36-8. Images in a 6-month-old with seizures. A, Axial unenhanced computed tomographic image reveals a focal acute high-density hematoma over the right cerebral convexity. There is generalized enlargement of the extracerebral spaces, reflecting either chronic subdural hematoma or brain atrophy. B, Coronal T1-weighted magnetic resonance image shows the acute right convexity subdural hematoma as a mass with high signal intensity. A subacute subdural hematoma with lower signal intensity surrounds the acute lesion. There is also generalized brain atrophy with increased extracerebral space; the normal cerebrospinal fluid over the left cerebral convexity is of lower signal intensity than is the subacute hematoma over the right convexity. (From Merten DF, Carpenter BLM: Radiologic imaging of inflicted injury in the child abuse syndrome. Pediatr Clin North Am 1990;37:815-839.)
3. Delay in seeking medical care is seen in abusive injuries, in contrast to the accidental group, in which care is typically sought promptly. 4. Abusive injuries occur to hollow viscera most often, whereas a solid organ is more often injured in accidents. 5. The mortality rate from abuse is higher (>50%) than in accidental injuries (~20%).
Chapter 36 Child Abuse
Figure 36-9. Unenhanced computed tomographic image in an abused 3-month-old infant reveals generalized right-sided decrease in brain density caused by diffuse cerebral edema. The right lateral ventricle is effaced, and there is a shift of midline structures to the left. Posterior and anterior subdural interhemispheric hemorrhages are also present. (From Merten DF, Carpenter BLM: Radiologic imaging of inflicted injury in the child abuse syndrome. Pediatr Clin North Am 1990;37:815-839.)
There is a hierarchy of injury to the abdominal organs, with hollow viscera being the most commonly affected. Ninety percent of hollow visceral injuries are seen in the duodenum or jejunum; the remainder are in the terminal ileum. The second most common organ for abusive injury is the liver, particularly the more midline portion, and the third most common is the pancreas. Clinical Manifestations The manifestations of abdominal injury can be quite striking, with distention, exquisite tenderness, vomiting, shock, or unconsciousness. However, most children with abdominal injuries, either inflicted or accidental, have no obvious abdominal wall cutaneous injuries. Some children have only minimal signs and symptoms; florid symptoms develop only after several hours. Often there are injuries to other parts of the body, making attention to the abdomen less of a perceived priority. Rapid deterioration can occur if blood loss is not identified and treated. Laboratory Studies The pertinent laboratory studies are listed in Table 36-8. Imaging Studies The initial imaging study to diagnose abdominal or thoracic injury is plain radiography. Two frontal views of the abdomen, one with the patient supine and one with the patient erect, are recommended. If the child is too ill for an erect view to be obtained, a horizontal beam cross-table lateral view can be used. This technique usually identifies obstruction, perforation (pneumoperitoneum), hemoperitoneum, or
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Figure 36-10. Chest radiograph in a 7-month-old infant with an “accidental” skull fracture also reveals multiple healing fractures of the right sixth through ninth ribs adjacent to the costovertebral junctions. (From Merten DF, Carpenter BLM: Radiologic imaging of inflicted injury in the child abuse syndrome. Pediatr Clin North Am 1990;37:815-839).
ascites. If there is obstruction, contrast media can be used to localize the lesion. Barium is the preferred contrast medium unless perforation is suspected, in which case a water-soluble contrast medium should be used. A frontal view of the chest is recommended for possible thoracic injuries, including rib fractures. A skeletal survey should also be obtained at the earliest possible opportunity, especially in severely injured children, because future opportunities may not occur and important forensic evidence may be lost. Contrast studies of the genitourinary tract have been rarely indicated since the advent of CT scanning, but voiding cystourethrography may be needed if lower urinary tract rupture needs delineation. The CT scan is the most useful imaging technique for evaluation of solid organ injuries. Contrast studies are better for showing hollow organ lesions; the contrast CT scan may demonstrate extravasation or a leakage of contrast material, which is usually an indication for surgical exploration. Most intramural hematomas without perforation do not necessitate intervention but resolve with supportive care unless there are bleeding complications. Abdominal ultrasonography also helps identify solid organ trauma and hematoma formation (liver, spleen, pancreas, kidney). Clues to thoracic and abdominal trauma are noted in Table 36-9. SKELETAL INJURIES The actual incidence of skeletal injuries in child abuse is unknown, although an estimate of fractures in abused children younger than 1 year of age is as high as 70%. Nearly 50% of these fractures are clinically unsuspected, and almost 50% involve more than one bone.
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Table 36-9. Types of Abdominal and Thoracic Injuries Organ
Injury
Hypopharynx Esophagus
Traumatic perforation Traumatic perforation
Stomach
Traumatic perforation
Duodenum
Blunt abdominal trauma
Jejunum, ileum
Blunt trauma
Colon, rectum
Liver
Blunt trauma Anal penetration Sexual abuse Sadistic abuse Blunt trauma
Spleen
Blunt trauma
Pancreas
Deep epigastric blunt trauma
Genitourinary tract
Signs/Symptoms/Diagnostic Findings
Feeding difficulty, drooling, palatal abrasion, sloughing lesion pharynx Coughing, blood-tinged sputum Interstitial emphysema, emesis, mediastinitis, rib fractures on radiographic study Shock and collapse Distended abdomen Free peritoneal air on plain radiographic study High intestinal obstruction Gastric dilatation Vomiting Possible peritonitis secondary to perforation Obstruction Lower abdominal pain Pain, constipation Bruising, abrasions, tears of external genitalia Rupture of bladder Abdominal distention Shock, collapse Elevated aspartate aminotransferase, alanine aminotransferase, bilirubin CT or ultrasound evidence of injury Peritoneal irritation, left shoulder pain Blood loss, shock Associated rib fractures CT or ultrasound evidence of injury Abdominal distention, tenderness Elevated amylase CT or ultrasound evidence of injury
CT, computed tomography.
Most abuse fractures (80%) are seen in children younger than 18 months, and only 2% of all fractures in this age group are of accidental origin. The skeletal survey, especially in children with head and visceral injuries, is extremely important in suspected abuse of children younger than 2 years because of the high likelihood that it will reveal unsuspected fractures. The differential diagnosis of skeletal trauma is noted in Table 36-10. Types of Fractures
often affected by transverse or oblique/spiral fractures. There are no specific types or locations for abusive fractures, which emphasizes the need for careful history taking, attention to the age of the child, and use of the skeletal survey for children younger than 2 years. Toddler fractures or oblique fractures of the tibia in children aged 9 months to 3 years are common accidental injuries that can occur without the knowledge of caretakers. They produce symptoms of limp, disinclination to bear weight on the affected leg, or pain on standing. Fractures resulting from abuse may also involve the forearms and, rarely, the clavicle. Fractures of the hands and feet, scapulae, and pelvis are unusual in child abuse.
Extremity Fractures Rib Fractures
These are the most common abusive fractures; certain types of extremity fractures are more specific for abuse. The “classic metaphyseal lesion” of the long bones has long been identified as the most specific for inflicted injury and is considered pathognomonic for abuse (Fig. 36-11). This so-called corner fracture, bucket-handle fracture, metaphyseal flag, or metaphyseal fragmentation fracture is a planar fracture through the primary spongiosa region of the end of the long bones, producing a disk-like fragment at this site. The fractured portion of the bone, depending on the projection of the x-ray beam, appears as a fragment (corner fracture) or a semilunar loop (bucket-handle fracture). The torsional forces necessary to produce these lesions are those associated with SBS or the application of rotational vectors to the long bones. The most common long bone fracture in child abuse involves the diaphysis, occurring four times more frequently than metaphyseal fractures. The femur, humerus, and tibia are the long bones most
Often unsuspected clinically and discovered through skeletal surveys, rib fractures nevertheless constitute 25% of fractures seen in abuse (see Fig. 36-10). Most of these are posterior fractures, occurring near the costovertebral articulation. They result when the rib arcs rotate poteriorly across the vertebral transverse process, producing a levering effect on the rib. The second most common location for rib fractures is in the midaxillary line. The fracture line in posterior fractures is usually on the anterior (visceral) surface of the rib, whereas the fracture line in the midaxillary fracture is on the outer surface of the rib. Because these fractures are produced by compressions of the thorax while the child is being held during shaking or when the child is forcefully picked up in anger by a caretaker, they are often multiple and bilateral. Overlying bruises of the thoracic wall may be observed but are often absent. Unless the fractures have been present long enough to produce callus, they
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Table 36-10. Differential Diagnosis of Skeletal Trauma
Obstetric trauma Prematurity Nutritional-metabolic defects Scurvy Rickets Secondary hyperparathyroidism (renal osteodystrophy) Menkes syndrome Mucolipidosis type II (I-cell disease) Methotrexate osteodystrophy Prostaglandin therapy Hypervitaminosis A Congenital syphilis Osteomyelitis Congenital insensitivity to pain Cerebral palsy-myelodysplasia Skeletal dysplasias Osteogenesis imperfecta Infantile cortical hyperostosis (Caffey disease) Leukemia Metastatic neuroblastoma Histiocytosis X Toddler fracture Normal variant Physiologic periosteal new bone Adapted from Brill PW, Winchester P, Lachman PS, et al: Differential diagnosis of child abuse. In Kleinman PK: Diagnostic Imaging of Child Abuse. St. Louis, Mosby, 1998, pp 178-236; and Radkowski MA: The battered child syndrome: Pitfalls in radiological diagnosis. Pediatr Ann 1983;12:894.
may not be discernible on plain radiography; in these cases, bone scintigraphy is most useful. Vertebral Body Fractures
These fractures are being diagnosed more frequently and may be common. They are anterior vertebral body compression fractures and are thought to be caused from hyperflexion during shaking or other violent handling. Skull Fractures
Figure 36-11. Metaphyseal fracture. A, Lateral view of the knee in a 5-month-old infant reveals a complete metaphyseal fracture of the tibia and an incomplete fracture of the fibula. There are corner fractures of the femur. B, Bucket-handle fracture of the tibia in a 3-month-old infant. (From Merten DF, Carpenter BLM: Radiologic imaging of inflicted injury in the child abuse syndrome. Pediatr Clin North Am 1990;37:815-839.)
Skull fractures are classified as simple and complex. Simple fractures are linear and do not cross suture lines; complex fractures are multiple, cross suture lines, are displaced, are comminuted, are diastatic, or are depressed. Complex fractures do not result from trivial trauma, and although they can be the result of accidental trauma, such trauma nearly always has a consistent history. Complex skull fractures alleged to have been acquired by falls from short heights or in unwitnessed falls are highly suspect for abuse.
Table 36-11. Elements of the Skeletal Survey
Skull: Frontal and lateral (lateral to include the cervical spine) Spine: Frontal and lateral thoracolumbar spine (lateral to include the sternum) Chest: Frontal (for rib and spinal detail) Extremities Upper: Frontal (to include shoulder and hands*) Lower: Frontal (to include lower lumbar spine, pelvis, and feet†)
Imaging Techniques The skeletal survey is the preferred diagnostic technique for fractures in suspected child abuse. Although radionuclide scintigraphy has certain useful applications (acute subtle fractures, rib fractures), it is not without inherent technical shortcomings and is dependent on the level of competence of the radiologist interpreting it. Table 36-11 details the views recommended for the skeletal survey.
From Cooperman D, Merten DF: Skeletal manifestations of child abuse. In Reece RM, Ludwig S (eds): Child Abuse: Medical Diagnosis and Management. Philadelphia, Lippincott Williams & Wilkins, 2001, p 125. *Separate views of the hands and feet in larger infants and children. †
At least two views of each fracture should be obtained.
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Dating of Fractures Physicians are often asked to pinpoint the time of injury in child abuse cases. The ability to narrow the time frame is limited, but there are some precepts of value (Table 36-12). CUTANEOUS INJURIES The most common manifestations of child abuse are cutaneous injuries. These types of lesions include bruises, abrasions, lacerations, petechiae, ecchymoses, and burns (Figs. 36-12 and 36-13). The characteristics of skin lesions important for distinguishing inflicted injuries from accidental ones are the location (Table 36-13), pattern, presence of multiple lesions of different ages, and failure of new lesions to appear during hospitalization or after removal of the child from the caretaker. The inflicting instrument may be discerned from the shape of the skin lesion (Fig. 36-14). The typical lesion left by a looped electric cord used for whipping may appear elliptic; a belt, buckle, or wire coat hanger leaves a bruise conforming to its shape; the human hand may leave parallel linear stress petechiae, representing the spaces between the fingers, or scalloping lesions conforming to the metacarpal-phalangeal junction; adult human bites leave characteristic lesions, which can be measured and compared with the dentition of the alleged perpetrator; gags leave down-turned lesions at the corners of the mouth; lesions around the neck suggest ligatures applied in that location; ligatures applied to wrists and ankles to restrain the child leave rope burns or pressure lines to those structures; bruises of the upper arms or in the rib cage suggest encirclement bruises resulting from hard pressure applied during shaking or violent handling. Dating of bruises is imperfect because of the variability of skin color, location of the bruise, healing characteristics, and varying age groups of the children involved in abuse. Color photography of bruises, with clear identification of the patient, color card, and the date the photograph is taken, can be of great value for documenting bruises. BURNS
Figure 36-12. Lash marks from an electric cord. Such marks are distinctive. The deep lacerations, which are looped if the cord is looped, result in deep tissue damage, and there is a potential for keloid formation on healing. (From Johnson CF: Inflicted injury versus accidental injury. Pediatr Clin North Am 1990;37:791-815.)
Between 12% and 30% of burns in children are nonaccidental, and burns represent approximately 10% of all abuse cases; 87% of inflicted burns are scald burns, and 13% are flame injuries. The peak age of burn victims is 13 to 24 months. The classic lesion is the immersion burn involving the buttocks and ankles, sustained when a child is held down in extremely hot water. There is often a doughnut lesion of the buttocks, sparing the portion of the buttocks
Table 36-12. Dating Fractures Category
1. Resolution of soft tissues 2. Periosteal new bone 3. Loss of fracture line definition 4. Soft callus 5. Hard callus 6. Remodeling
Early (Days)
Peak (Days)
Late (Days)
2-5
4-10
10-21
4-10 10-14
10-14 14-21
14-21
10-14 14-21 3 months
14-21 21-42 1 yr
42-90 2 yr to epiphyseal closure
From O’Connor JF, Cohen J: Dating fractures. In Kleinman PK (ed): Diagnostic Imaging in Child Abuse. St. Louis, Mosby, 1998, p 176.
Figure 36-13. Marks from burns. (From Johnson CF: Inflicted injury versus accidental injury. Pediatr Clin North Am 1990;37:791-815.)
Table 36-13. Location of Cutaneous Injuries Inflicted
Upper arms Trunk Upper anterior legs Side of face Ears and neck Genitalia
Accidental
Shins Hips (iliac crest) Lower arms Prominences of spine Forehead Under chin
Adapted from Pascoe JM, Hildebrandt HM, Tarrier A, Murphy M: Patterns of skin injury in nonaccidental and accidental injury. Pediatrics 1979;64:245.
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Figure 36-14. Marks from objects. (From Johnson CF. Inflicted injury versus accidental injury. Pediatr Clin North Am 1990;37:791-815.)
resting against the relatively cooler porcelain of the tub. Sharp demarcation lines are typically seen at the borders of burned and spared skin. These lesions, plus the stocking-glove immersion burns, represent easy diagnoses, because they are so obviously caused by restraint of the child. Likewise, burns of the palms and soles are diagnostic for inflicted injury unless the caretaker has an unusually convincing history of a mechanism of injury. Table 36-14 summarizes the distinguishing characteristics of inflicted versus accidental burns. Nonaccidental burns also seem to carry a higher correlation with social pathologic disorders than do other forms of child abuse. In most inflicted burn cases, the children either are known to the state’s protective service agencies or have been previously admitted to the hospital with a variety of diagnoses, including failure to thrive, poisoning, lead intoxication, fractures, head injuries, and previous burns.
Table 36-14. Inflicted versus Accidental Burns Inflicted
History
Burns attributed to sibling Unrelated adult seeks medical care Differing accounts of injury Treatment delay >24 hr Prior “accidents” No parental concern Lesion incompatible with history Location Buttocks, perineum, genitalia Ankles, wrists Palms, soles Pattern Sharply demarcated edges Stocking-glove distribution Full thickness Symmetrical Burns older than history indicates Burn neglected, infected Numerous lesions of varying ages Pattern of burn consistent with instrument Large area of uniform, dry contact burn
Although reports of intentional poisoning of children are small in number, the true incidence is difficult to determine. Repetitive accidental poisoning in childhood may have no relationship to home safety but is intimately associated with parental psychopathologic disorders and disturbed family relationships. The clinical indicators of abuse by poisoning are noted in Table 36-15. Poisonous substances may include household agents (salt, pepper, talc, water, caustic agents, air freshener, laxatives), drugs of misuse (cocaine, ethanol or isopropyl alcohol, opiates, barbiturates, lysergic acid diethylamide [LSD], phencyclidine [PCP], marijuana), prescription drugs (barbiturates, anticonvulsants, insulin, imipramine, opiates, phenothiazines), or others (arsenic, ipecac, acetaminophen, aspirin, mineral oil, Epsom salt, ethylene glycol) (see Chapter 40). MUNCHAUSEN SYNDROME BY PROXY Munchausen syndrome by proxy (MSBP) is a bizarre form of child abuse in which the child is the victim of a form of mental illness of the mother, the psychodynamics of which are poorly understood. The condition is defined as a circumstance in which 1. Illness is simulated or produced by a parent (almost invariably the mother) or someone who is in a caretaker role. 2. The child is brought persistently for medical assessment and care, which results in multiple medical and sometimes surgical procedures. 3. The perpetrator denies knowledge about the cause of the child’s illness. 4. Acute symptoms and signs in the child abate when the child is separated from the perpetrator (see Chapter 35). The goal of the diagnostic process is to gather evidence that the illness is simulated or faked (Table 36-16). The strategy of this process is to gather the team of caregivers in the hospital setting and discuss the evolving information on a regular basis. It is wise to alert the child protection agency, law enforcement, and prosecuting
Accidental
Compatible with observed injury
Front of body Random and injury-specific Associated irregular splash burns Partial thickness Asymmetrical
One traumatic event
Table 36-15. Clinical Indicators of Abuse by Poisoning
Age 6 months fulfilling 3 and 4 listed above for episodic tension Headache Associated with Trauma Headache Associated with Disorder of Sinuses or Other Facial or Cranial Structures From Headache Classification Committee of the International Headache Society: Proposed classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia 1988;8(Suppl 7):9-96.
analgesic medications by patients with a history of headaches can create a headache syndrome. All classes of headache medications can paradoxically cause headaches that may be worse on waking and exacerbated by activity. Stopping the medication improves the situation. PHYSICAL EXAMINATION Children with headache should have a thorough physical examination (Table 37-12). Many causes of headache, including some serious diseases early in their course, do not cause abnormal findings on physical examination (see Table 37-7). When the results of the neurologic examination are abnormal (Table 37-13), a structural brain lesion is possibly present, and a neuroimaging study is warranted.
Table 37-2. Differential Diagnosis of Headache
1. Vascular headache of migraine type a. Classic migraine b. Common migraine c. Cluster headache d. Hemiplegic and ophthalmoplegic migraine e. “Lower half ” headache 2. Muscle-contraction (tension) headache 3. Combined headache: vascular and muscle-contraction 4. Headache of nasal vasomotor reaction 5. Headache of delusional, conversion or hypochondriacal states 6. Nonmigrainous vascular headaches a. Systemic infections b. Miscellaneous: hypoxic states, carbon monoxide poisoning, chemical vasodilator effects (e.g., nitrates), caffeine withdrawal, cerebral ischemia, postconcussion or postconvulsive states, “hangovers,” hypoglycemia, hypercapnia, hypertensive states, pheochromocytoma 7. Traction headache a. Primary or metastatic tumors: meninges, brain, or vasculature b. Hematomas: epidural, subdural, parenchymal c. Abscesses: epidural, subdural, parenchymal d. Post–lumbar puncture headache e. Pseudotumor cerebri 8. Headache due to overt cranial inflammation a. Intracranial: meningitis, subarachnoid hemorrhage, iatrogenic (postoperative, postpneumoencephalogram, etc.), arteritis, phlebitis b. Extracranial: vasculitis, cellulitis 9. Ocular headache Increased intraocular pressure, ocular muscle contraction, trauma, tumor, inflammation 10. Aural headache Trauma, inflammation, infection, tumor of the ear 11. Nasal/sinus headache Allergic, infectious, inflammatory, traumatic, tumor of the nose and/or paranasal sinuses 12. Dental headache Infection, trauma, tumor, inflammation, iatrogenic Temporomandibular joint syndrome 13. Cranial/neck headache Disorders of cervical spine, cervical nerve roots, scalp/neck muscles, tendons, ligaments 14. Cranial neuritides Traction, trauma, inflammation, infection, tumor 15. Cranial neuralgia Trigeminal Glossopharyngeal Chronic post-traumatic headache is often multifactorial, usually related to 1b, 2, and/or 13 above. Adapted from the Ad Hoc Committee on Classification of headache, National Institute of Neurological Diseases and Blindness: Classification of headache. JAMA 1962;179:717-719.
NEUROIMAGING AND LABORATORY INVESTIGATIONS There are various indications for ordering neuroimaging studies (Table 37-14). Magnetic resonance imaging (MRI) of the brain is the preferred study, although noncontrast computed tomographic (CT) scanning of the brain is useful in an emergency situation or when MRI is contraindicated. Routine blood work is not indicated in
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Table 37-3. Systemic Infection in which Headache May Be a Prominent Symptom Common Illness
Viremia Influenza Pharyngitis Otitis media Sinusitis Mononucleosis Pneumococcal pneumonia Mycoplasma pneumonia
Uncommon Illness
Uncommon, but Most Serious
Typhoid fever Tularemia Toxoplasmosis Cytomegalovirus infection Mumps Measles Poliomyelitis Psittacosis Dengue Trichinosis Q fever Legionnaires disease Leptospirosis Typhus
Meningitis (bacterial, viral) Brain abscess Retropharyngeal abscess Orbital cellulitis Cervical osteomyelitis Suppurative intracranial thrombophlebitis Subdural empyema Encephalitis Septicemia Endocarditis Rocky Mountain spotted fever Malaria
Adapted from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 90.
patients with a history suggestive of a primary headache syndrome and normal findings in physical and neurologic examination. In some instances, findings in the history, physical examination, or neuroimaging dictate laboratory evaluation (Table 37-15). SUDDEN SEVERE HEADACHE A sudden and severe headache is alarming and usually prompts a visit to the physician. The diagnostic approach (see Fig. 37-5) is different than for the patient with recurrent headaches. The physician must note that every patient with migraines (and other non– life-threatening headaches) has a first severe headache. This headache may even be associated with an abnormal neurologic state, fever, or other worrisome features. Neuroimaging (see Table 37-14) and laboratory tests (see Table 37-15) may be indicated in the evaluation of an acute, severe headache. Additional indications for neuroimaging include an abnormal finding in a neurologic examination; reduced visual acuity; poor growth; neuroendocrine manifestations (galactorrhea, secondary amenorrhea); behavioral changes; seizures; increased headache frequency; and increased pain with awakening, coughing, straining, or position changes.
Table 37-4. Secondary Headache: Systemic and
Metabolic Causes Common
Hyperthyroidism Hypothyroidism Anemia Polycythemia Hypoxemia Hypercarbia Hypoglycemia Hypertension Uremia Hyponatremia Pseudotumor cerebri
Uncommon
Carbon monoxide poisoning Toxic hemoglobinopathies Pheochromocytoma Parathyroid disease Cushing disease Addison disease Vitamin A intoxication Lead poisoning Cranial neoplasm Chronic leukemia-lymphoma Subarachnoid hemorrhage–aneurysm Glaucoma Uveitis (iritis)
Adapted from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 111.
SPECIFIC HEADACHE DISORDERS MUSCLE CONTRACTION (TENSION) HEADACHES Most children and adolescents experience an occasional muscle contraction headache, usually in response to stress, exhaustion, or hunger (see Table 37-5 and Fig. 37-1). Frequent muscle contraction headaches, also called tension headaches, occur in about 15% of older children. Younger children may also have muscle contraction headaches; however, muscle contraction headaches do not cause persistent headaches in this age group. These headaches can be annoying, painful, and disabling. A muscle contraction headache often accompanies other headache disorders or is the end result of a migraine. In addition, structural cervical or cranial musculoskeletal abnormalities may cause muscle contraction (tension) headaches.
Clinical Features These headaches have a typical pattern and are usually chronic and nonprogressing. Patients awaken feeling well, with the pain beginning gradually and escalating throughout the day. The pain is constant, squeezing, nonpulsatile, and located in a band extending from the front of the head, across the temples, and toward the occiput or neck (see Fig. 37-1). Nausea and photophobia may accompany these headaches but are not a constant feature. In patients with longstanding pain, the headaches can assume characteristics of migraines. Chronic muscle contraction headaches are defined as headaches occurring at least 15 days a month for at least 6 months. Often, the child or adolescent has daily headaches. A detailed psychosocial history is important because it may uncover the cause for the headache. Adjustment disorders and depression may be either the primary cause or a secondary reaction to chronic pain. Sleep disturbances, school absences, and chronic analgesic use are common in this group. A negative psychosocial history can also occur in patients with chronic muscle contraction headaches. In some highly motivated and successful children, the headaches may be a reaction to the stress associated with achievement. In this instance, school attendance is usually perfect and the patient continues to achieve in all realms. Patients with muscle contraction headaches have normal neurologic and physical findings except for tenderness along the affected muscles. These muscles often feel tight, and palpation can trigger the pain. There are no laboratory tests to diagnose these headaches.
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Table 37-5. Clinical Features of Most Common Chronic Headache Syndrome Feature
Classic Migraine
Common Migraine
Prodrome Quality
Visual or neurologic Throbbing, pulsatile
None (or vague) Throbbing
Location Associated symptoms Usual duration Usual frequency Patient’s typical response
Unilateral Nausea, vomiting, photophobia Several hours Several per year Hibernates in dark room Tries to sleep Frightened by prodrome
Usually unilateral Usually nausea; anorexia Several hours 1-2 per month “Sick” Can’t work
Muscle Contraction
None Tight, squeezing Sometimes throbbing Usually bilateral Depression Highly variable Daily or several per week Rarely interrupts usual activities “I can live with it”
Modified from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 101.
Treatment Patients usually do not seek the advice of a physician for the occasional muscle contraction headache because rest and over-the-counter analgesics (acetaminophen or ibuprofen) usually alleviate the pain. In contrast, patients with chronic, frequent headaches may require a multidisciplinary approach to their management. Some may benefit from physical therapy through the use of progressive rangeof-motion exercises aimed at strengthening the neck muscles. Other patients may benefit from the assistance of a psychologist. Besides addressing underlying adjustment disorders, the psychologist can assist by teaching the patient stress management (relaxation
Table 37-6. Headache History
General Medical History Presence of other acute medical problems or symptoms Chronic medical problems Current medication use or overuse Previous medication used for headaches Previous long-term medication use or overuse Intake of caffeine, vitamin A, alcohol, cocaine Pattern When did the headaches begin? Frequency and change in frequency Duration of headaches Pattern to the time of day Presence of headaches on weekends, weekdays Are headaches preceded by a warning? Description of Pain Location Quality Intensity Effects of position, Valsalva maneuver, and movement Associated Factors Trauma Are headaches associated with other activity? Does any medication make the headache better? Do the following occur before, during, or immediately after the headache: visual disturbance, vertigo, weakness, paresthesias, nausea, vomiting, changes in sensorium? Family History Migraines Aneurysm (autosomal dominant polycystic kidney disease, inherited disorders of collagen synthesis)
techniques, biofeedback). It is important for the patient to realize that certain types of stress are normal. The patient needs to know that stress is not going to be eliminated and that he or she must learn to cope. To reduce stress, the daily schedule should be regulated, with a focus on exercise, proper diet, and sleep. Because caffeine, nicotine, and alcohol may contribute to the headaches, the patient should avoid using these drugs. If the headaches are affecting the activities of normal childhood and adolescence, individual therapy, family therapy, or both are warranted. Over-the-counter analgesics are the most appropriate treatments for the occasional severe headache. Aspirin is contraindicated in children and teens because of the risk of Reye syndrome (see Chapter 40). Other medications (low-dose tricyclic antidepressants) for treating chronic headaches exist; however, the clinician must be careful to ensure that these medications are used properly and are not abused. Treating only the symptom and not the cause (stress) may actually prolong the patient’s condition and expose the patient to the potential side effects of the medications. Benzodiazepines, narcotics, and barbiturates should be avoided because of their addictive potential, although these agents can be used rationally and successfully in
Table 37-7. Headache Disorders with No Neurologic
Signs Headache Disorder
Muscle contraction Common migraine Cluster Hypertension, uncomplicated Fever Ice cream headache Anoxia Medication overuse Caffeine withdrawal Coital headache Early hydrocephalus or brain mass Cough headache, uncomplicated Meningitis, uncomplicated Sinusitis, dental or pharyngeal abscess Temporomandibular joint syndrome Postconcussive syndrome Conversion disorder
Pain Profile
CN, AI AI, CN AI AI, CN AS AS AS CN AS, AI AS, AI CP AI AS AI CN CN CN
AI, acute intermittent; AS, acute, singular (occurs only with the causative condition); CN, chronic nonprogressive; CP, chronic progressive.
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Table 37-8. The Headache Diary for Recurring
Headaches* Date Time of onset Time of resolution Maximum level of pain (mild, moderate, or severe, or 1-10) Associated phenomena: Sleep Food Position, Valsalva maneuver Medication use or overuse *If more than one type of headache exists, the types should be defined and labeled, and separate data should be recorded for each type.
the responsible patient who has infrequent and severe muscle contraction headaches. Ergot alkaloids should also be avoided because of their addictive properties and the high incidence of side effects in children. The calcium channel blockers and β blockers are helpful only if there is a significant migrainous component to the headache. Some patients may benefit from prophylactic therapy. In these patients, a single, daily standard dose of ibuprofen, naproxen, or amitriptyline may prevent headaches. Amitriptyline given at dosages far below what is effective in the treatment of depression can have an excellent effect in preventing muscle contraction headaches.
Table 37-9. Differential Diagnosis of Headaches Based
on the Time Course New Acute Severe Headache Viral syndrome Acute sinusitis, pharyngitis Migraine Migraine variant Meningoencephalitis Intracranial hemorrhage Head trauma Brain tumor Substance abuse (e.g., cocaine) Medications Carbon monoxide poisoning Ventriculoperitoneal shunt malfunction Hypertensive encephalopathy Intracranial venous sinus thrombosis
Figure 37-1. Common location of migraine (A) and tension (B) headaches. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991.)
Because amitriptyline can cause sleepiness, it is usually given as a single bedtime dose, ranging from 10 to 75 mg (adolescent age dose). In patients with chronic headaches, overuse of analgesic medications may paradoxically produce headaches. These headaches are often difficult to distinguish from tension headaches but may be
Recurrent Acute Headaches Migraine and migraine variants Tension-type headache Substance abuse Medications Postepileptic event Cluster headaches Intermittent raised intracranial pressure (e.g., from colloid cyst in the third ventricle) Chronic Progressive Headaches Hydrocephalus Brain tumor Intracranial infections (e.g., brain abscess, infection of the ventriculoperitoneal shunt, tuberculosis, cryptococcal meningitis) Chronic subdural hematoma Pseudotumor cerebri (benign intracranial hypertension) Primary or secondary central nervous system vasculitis
Figure 37-2. Periorbital headache. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991.)
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Figure 37-3. Cluster headache. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991.)
present on awakening or increase with physical activity. The treatment is to stop the medication. MIGRAINE HEADACHES Types of Migraines Common and Classic Migraines
By 15 years of age, at least 5% to 10% of children have had a migraine headache (see Fig. 37-1 and Tables 37-1, 37-5, and 37-10). Migraine and migraine variants also occur in early childhood but at
an unknown prevalence. The general description of this headache type usually makes the diagnosis straightforward. A family history of migraines and a history of motion (car) sickness are common in patients with migraines. With a few exceptions, childhood migraines are very similar to those in adults. During childhood, migraines affect more boys than girls, which is contrary to the adult experience. In children, the headaches are less frequent, are shorter in duration, and respond better to treatment. Vomiting and abdominal pain are also more common in children than in adults. Of adults, 18% of women and 6% of men have migraines. The pattern of migraines is highly variable. Migraines may be sporadic; however, they can also occur at almost any interval. Without prophylactic treatment, most patients have between 1 to 4 migraines a month. There is often no temporal pattern, although in some patients the headaches may cluster around a certain event. In postpubertal women, migraines may cluster around particular phases of the menstrual cycle. Unless the migraines tend to cluster, patients rarely have pure migraines more than twice a week. Mild or moderate headaches often occur between the more severe migraine attacks. In the classic migraine, the headache is preceded by an aura, which is caused by vasoconstriction and diminished blood flow to the affected region of the brain. The aura associated with the classic migraine is visual and may consist of blurred vision, spreading scintillating scotomas, flashing lights, zigzag lines, and hemianopsia. These features should last less than 60 minutes. Sensory auras are less common than visual auras and consist of numbness or tingling, which may be followed by weakness. Transient hemiparesis (hemiplegic migraine), aphasia, and alteration of consciousness (confusional migraine) are rare auras. With common migraines, there is no specific aura; however, the patient may feel fatigued or ill immediately before the headache. The onset of the pain is gradual and develops over minutes to an hour. Some patients, however, have a sudden onset of severe pain. Less severe migraines consist of a dull, constant pain. As the severity increases, the pain becomes throbbing. The headache is often unilateral but may be bilateral. The pain may be frontal or facial, instead of the more typical temporal location. As the headache proceeds, the pain can generalize to the entire cranium. In children with basilar artery migraines, the pain is occipital. Intense nausea and, less often, vomiting often accompany migraines. Skin pallor is also a common finding. Nasal congestion and tearing may occasionally be present.
Table 37-10. Differential Diagnosis of Commonly Confused Chronic Unilateral Headache Syndromes Feature
Prodrome Quality Location
Common Migraine
None Throbbing Hemicranial Periorbital Nausea
Associated symptoms Usual duration
3-8 hours
Usual frequency
1-2 per month
Patient’s typical response
“Sick” Quiet
Trigeminal Neuralgia
Cluster
None Ache, severe Periorbital Tearing; rhinorrhea 1 /2-2 hours 1-4 per day, during cluster† Paces the floor, agitated
None Sharp, “electric” jabs Cheek, jaw, lower lip None
Temporomandibular Joint Syndrome
10-60 seconds, repetitively over 1-3 hrs Daily‡ but episodic
None Dull ache Preauricular, jaw spreading to temple, eye, and neck Limited jaw motion or “clicking” Several hours, or constant
None Dull ache Temple, occiput and neck Depression; muscle tightness Hours-days, constant
Daily‡
Daily‡
Avoids trigger points
Depression Teeth grinding
Depression, coping
Modified from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 102. *Tension headache is usually bilateral but may be confused with these syndromes when unilateral. †
A typical cluster will last several weeks.
‡
Tension*
Frequency of these syndromes is highly variable, but daily occurrence is common.
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Table 37-12. Important Components of the Physical
Examination in the Child with Headaches General Examination Airway, breathing, circulation, and blood pressure Growth, including head circumference Mental status, behavior profile Head, neck, eye, ear, nose, and throat examination for swelling, tenderness, trauma, or infection Dental examination Skin examination for rashes, neurocutaneous lesions, pallor Evidence of external trauma External bleeding, petechia
Figure 37-4. Assessing pain in young children. A, Nine-face interval scale. Faces A through D represent varying magnitudes of positive affect; faces F through I represent varying magnitudes of negative affect. B, Linear analog scale. The child places an X on the line to identify the relative severity of headache. (Adapted from Beyer JE, Wells N: The assessment of pain in children. Pediatr Clin North Am 1989;36:846.)
Because most patients are sensitive to motion, light, and noise during a migraine attack, they search for a dark and quiet place to sleep. The patient usually awakens within 2 to 12 hours feeling fatigued but usually pain free. Certain factors are known to trigger migraine attacks in susceptible patients. Patients need to be questioned about the temporal association of their migraines with these factors because eliminating the precipitant may prevent some or all of the migraines. The most common identified precipitants to migraines are specific foods and food additives, such as chocolate, hard cheeses, onions, yeast, and beans (see Table 37-11). Because caffeine withdrawal can precipitate
Table 37-11. Possible Dietary Precipitants of Migraine
Ripened cheeses (cheddar, Emmentaler, Stilton, Brie, Camembert, brick, blue, Swiss, Gouda, Roquefort, mozzarella, Parmesan, provolone, Romano) Pickled herring Chocolate Anything fermented, pickled, or marinated Olives, pickles Sour cream, yogurt, buttermilk, chocolate milk Sauerkraut, onions Sunflower seeds Nuts, peanut butter Beans, except string beans Avocados, figs, raisins, papaya, passion fruit, red plums Alcoholic beverages
Fermented sausage and aged, canned, cured, or processed meats (bologna, salami, pepperoni, summer sausage, hot dogs), bacon Canned soups with monosodium glutamate Pizza Hot fresh yeast breads, coffee cake, doughnuts, sourdough bread Chicken livers Brewer’s yeast, meat tenderizers, seasoned salt Citrus foods Tea, coffee, cola Banana Foods containing large amounts of monosodium glutamate (Chinese foods) Corn Egg
Data from Diamond S, et al., Modern Medicine, July 1986, pp 76-86; and Mansfield LE: Food allergy and headache. Whom to evaluate and how to treat. Postgrad Med 1988;83:46. Reprinted from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 116.
Neurologic Examination Meningeal signs Fundus, eye movements, and pupillary reaction Facial asymmetry Motor strength in all extremities Deep tendon reflexes Gait Romberg sign Cerebellar signs (e.g., finger-to-nose test, rapid alternating movements, and action tremors) Palpation of shunt track if ventriculoperitoneal shunt present
a migraine attack, all caffeinated beverages should be avoided. Some of the food additives that may trigger a migraine are sulfites, nitrites, and monosodium glutamate (MSG). MSG is found in Chinese-style foods, canned and dehydrated soups, proprietary spices (seasoned salts), salad bars, and many packaged foods. Because food additives are commonly used in the food industry, susceptible patients are advised to read all labels. Aside from foods, other precipitants include menstruation, hunger, estrogen (oral contraceptives), lack of sleep, stress, heat, and exertion. Some patients with migraines are extremely sensitive to exertion, especially on hot days. Their headaches may be precipitated by strenuous activities, such as summer practice sessions for varsity sports or a marching band. The headaches may be prevented by proper dress and prophylactic indomethacin therapy. Complicated Migraine
Patients with a complicated migraine have neurologic deficits that persist during and after the headache. These deficits include hemisensory symptoms, hemiparesis, aphasia, visual loss, and alteration in consciousness. In most cases, the neurologic deficit precedes the headache. These symptoms usually last about as long as the headache but can last for days. Permanent neurologic deficits are rare but can occur if the vasoconstriction is severe and causes infarction. Complicated migraines begin in childhood and evolve into the more typical migraine pattern as the patient gets older. In some children with this disorder, their attacks are precipitated by mild head trauma, such as striking the head against a wall or using the head to hit a soccer ball. Two genetic disorders may mimic complicated migraine. Autosomal dominant familial hemiplegic migraine and episodic ataxia type 2 are caused by mutations of a neuronal calcium channel. Patients may present with hemiplegic migraine, episodic ataxia, or both. Acetazolamide is effective in treating this disorder. MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike attacks) is a mitochondrially inherited disorder, with a high frequency of hemiplegic migraine-like attacks. Recovery from attacks is variable. This diagnosis must be considered in children with coexisting epilepsy, mental retardation or regression, and myopathy. A DNA
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Table 37-13. Headache Disorders Associated with
Neurologic Signs Headache Disorder
Pain Profile
Complicated migraine
AI
Basilar artery migraine
AI
Acute confusional migraine
AI
Ophthalmoplegic migraine
AI
Vasculitis
CP, AI
Brain neoplasm or mass Hydrocephalus
CP
Pseudotumor cerebri
CP
Subarachnoid hemorrhage, ruptured aneurysm Subdural or epidural hemorrhage
AS
Sagittal sinus thrombosis
CP, AI
CP AS
Meningitis; encephalitis AS
Optic neuritis
AS
Neurologic Sign
Hemiparesis, aphasia, paresthesia, hemianopsia Ataxia, visual disturbance, vertigo, tinnitus, paresthesia Alteration in sensorium, stupor, agitation, fugue state Paresis of eye movement, dilated pupil, ptosis Seizure, changes in sensorium Papilledema, focal deficit Papilledema, bilateral sixth nerve palsies, increased motor tone, impaired upward gaze and Parinaud syndrome Papilledema, constricted visual fields, enlarged blind spot Changes in sensorium, focal neurologic signs, meningismus Focal neurologic signs, papilledema, changes in sensorium Papilledema, focal neurologic deficits, changes in sensorium, seizures Papilledema, focal neurologic deficits, changes in sensorium, seizures Papillitis, decreased visual acuity, afferent pupillary defect
AI, acute intermittent; AS, acute, singular (occurs only with the causative condition); CP, chronic progressive.
test for the most common mitochondrial mutation is available. Migraines are also common in a variety of other mitochondrial disorders. Basilar Artery Migraine
The basilar artery is more prone to involvement in childhood migraines, which leads to brainstem or occipital lobe dysfunction. The headache is usually occipital and may be intense. Neurologic abnormalities include ataxia, nausea, and vomiting. In some patients, the headache may be a minor component of the syndrome. Visual changes can also occur and can include vivid visual images. Vertigo, tinnitus, and paresthesia are less common symptoms that accompany a basilar artery migraine.
Table 37-14. Role of Neuroimaging Studies
When to Order a Neuroimaging Study The “thunderclap headache” or “worst headache of my life” The first severe headache Abnormal neurologic findings Chronic or progressive headaches Unilateral headaches that never alternate sides Headache associated, even briefly, with alteration of sensorium Presence of papilledema Meningeal signs without fever Recent worsening Advantages of Magnetic Resonance Imaging (MRI) Most vascular malformations are detected Accurate detection of tumors in temporal lobes and posterior fossa, and small tumors that obstruct CSF flow (quadrigeminal plate and third ventricular) Paranasal sinuses usually included in the examination without special request More sensitive for detecting transependymal CSF in cases of borderline hydrocephalus Diagnostic for Chiari malformations Magnetic resonance angiography can detect many aneurysms Magnetic resonance venography can detect cortical vein and dural sinus thrombosis Advantages of Computed Tomography Less expensive and easier access than MRI Shorter imaging time, important in evaluating ill patients May be used in patients with pacemakers, metal implants (surgical clips), and cosmetic tattoos (MRI may turn off pacemakers and dislodge the clips; tattoos distort the image) CSF, cerebrospinal fluid.
Table 37-15. Potentially Useful Laboratory Tests in
Children with Headaches Laboratory Test
Complete blood count CSF examination
Toxicology screen Hypercoagulation panel ESR, ANA, ANCA Genetic tests EEG VP shunt radiographic series
Possible Cause of Headache
Infection (elevated white blood cell count); bleeding diathesis (thrombocytopenia); anemia Infection, vasculitis, pseudotumor cerebri, subarachnoid hemorrhage after CT is normal Substance abuse Unexplained venous sinus thrombosis Vasculitis Familial hemiplegic migraine, MELAS Seizure disorder Malfunctioning VP shunt
ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; ESR, erythrocyte sedimentation rate; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms; VP, ventriculoperitoneal.
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Severe, acute headache No
Are neurologic examination results normal?
MRI or CT ⫺
⫹
Yes Intracranial hemorrhage SAH Brain tumor Abscess Hydrocephalus Stroke
Fever? Yes Meningeal signs Yes
History of trauma
SAH Vasculitis Meningoencephalitis Pseudo tumor cerebri
Yes
No
LP
Meningitis SAH with fever
No
LP
No MRI or CT
Sinusitis Dental abscess Pharyngeal abscess Viral syndrome
⫹ SDH
⫺
Transient neurologic deficit
Postconcussive syndrome
Yes
No
MRI or CT ⫹ Third ventricle cyst Hydrocephalus Posterior fossa mass AVM Chiari malformation
Migraine Hemicrania Hypertension Coital headache Cough headache
⫺ Complicated migraine
Figure 37-5. Evaluation of an acute, severe headache. Boxes indicate tests. AVM, arteriovenous malformation; CT, computed tomography; LP, lumbar puncture; MRI, magnetic resonance imaging; SAH, subarachnoid hemorrhage; SDH, subdural hematoma.
Acute Confusional Migraine
This disorder begins after 5 years of age and usually converts to typical migraine as the patient gets older. Acute confusional migraine begins with an alteration in consciousness, which can include varying degrees of lethargy, agitation, and stupor. A fuguelike state has also been described with these migraines. Attacks last a few hours, with the child eventually falling asleep. The child awakens without memory of the incident. Ophthalmoplegic Migraine
Cranial nerve palsies, usually of the third cranial nerve, may accompany this type of a migraine. Physical findings usually include pupillary dilatation and ptosis. Other cranial nerves involved during these headaches are the fourth cranial nerve (causing loss of downward and medial eye movement) and the sixth cranial nerve (causing loss of lateral eye movement). The ophthalmoplegia may persist for a few weeks after the headache. In younger children, a headache may not be associated with this disorder. An MRI study is warranted because ophthalmoplegia, even if transient, is associated with serious conditions, such as aneurysms and tumors. Amaurosis fugax (ophthalmic transient ischemia) manifests as monocular visual loss lasting minutes; in childhood, it is often caused by migraines. Migraine Status
Most migraines last 6 to 12 hours; however, some patients are susceptible to prolonged headaches. A prolonged headache may last
for days and is usually associated with protracted vomiting and dehydration. Diagnosis is based on a propensity for previous prolonged migraine attacks. Treatment of Migraines Treatment can help most patients with migraine headaches. If precipitating factors can be identified, they should be avoided. If medication is necessary, the physician and patient must decide whether the goal is to prevent the migraines (prophylactic management) or to stop or lessen the headache once it starts (abortive management). The choice of treatment depends on the age of the patient and the frequency and severity of the headaches. Abortive Management
Abortive management is most effective when medication is taken as soon as possible. Children may need to be able to take the medication at school. If abortive therapy is used, the medication should be taken at the first symptom, whether it is the aura or the headache. The characteristics of the headache dictate the therapeutic decision making: Patients with less severe symptoms may respond to nonsteroidal antiinflammatory drugs (NSAIDs). In contrast, patients with more severe symptoms do not need to “fail” a trial of NSAIDs before taking more effective medications. This only prolongs patient suffering and school absences, increases dissatisfaction with the physician, and leads to poor utilization of resources, with frequent emergency room and office visits. Patients with significant nausea or emesis may not tolerate an oral agent.
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Table 37-16 outlines a general approach for the acute treatment of childhood migraine. NSAIDs, such as ibuprofen or naproxen sodium, are useful for mild to moderate migraine. There are two principal benefits of adding a dopamine antagonist such as metoclopramide. First, it reduces nausea and emesis. Second, its prokinetic action improves the rate of absorption of concurrent medication, leading to faster headache relief. Metoclopramide may cause drowsiness and extrapyramidal symptoms, which are mostly transient and reversible with benzodiazepines or diphenhydramine. Other agents that combat nausea in migraine include prochlorperazine, diphenhydramine, and trimethobenzamide. The rectal form of trimethobenzamide is useful in children with intractable emesis during a migraine. If possible, patients should rest and try to fall asleep. Sleep relieves symptoms, and many patients awaken free of pain. The combination of isometheptene mucate, dichloralphenazone, and acetaminophen (Midrin), may be used in moderate migraine. The combination of aspirin, the barbiturate butalbital, and caffeine (Fiorinal) is another treatment option. The triptans are selective agonists of the serotonin (5-HT) receptors, mainly receptor subtypes 5-HT1B and 5-HT1D. Triptans are highly effective for the treatment of migraine. A wide variety of preparations are available, with different pharmacologic properties (Table 37-17). The subcutaneous (SC) form of sumatriptan is ideal for rapid-onset migraine that is associated with nausea and emesis, which precludes oral medication. Oral sumatriptan has a slower onset of action than the SC form; the onset of action of the intranasal spray is intermediate between those of the oral and SC forms. Sumatriptan also relieves migraine-associated symptoms such as nausea, emesis, photophobia, and sonophobia. Adverse effects of sumatriptan are uncommon in children. Atypical sensations such as tingling and numbness over body parts; anxious feeling; sensations of heaviness or tightness of the chest and throat; and feeling of warmth, burning, cold, or pressure are symptoms reported by patients after taking triptans and are therefore referred to as “triptan symptoms.” The symptoms are generally mild and always transient, with resolution within 1 to 2 hours. They are more common and intense with sumatriptan than with newer triptans. The reported incidences in adults are 42% with SC sumatriptan
and 8% with oral sumatriptan. The incidence in children appears to be lower. Minor pain, erythema, or tingling is also common at the injection site after SC sumatriptan. Some children may report a bad taste after intranasal sumatriptan. Cardiovascular adverse effects are rare; the incidence of coronary vasospasm and cardiac ischemia appears to be about one per million doses. Nevertheless, caution should be exercised in children with underlying heart disease, and the presence of coronary insufficiency is a contraindication. Other conditions that are contraindications to the use of 5-HT1 agonists are hypertension, peripheral vascular disease, and pregnancy. Neurologic vascular events have been reported only rarely in adults and are caused mostly by treatment of a misdiagnosed stroke in evolution. Some patient with complicated migraines may be at increased risk of developing cerebrovascular events, and therefore it is imperative that proper diagnosis of the migraine syndrome is made before 5-HT1 agonists are considered. Triptans and other vasoconstrictive agents are generally contraindicated in complicated migraine episodes such as hemiplegic migraine, basilar migraine, ophthalmoplegic migraine, and migraine attacks associated with other neurologic abnormalities. The second-generation triptans rizatriptan and zolmitriptan have several potential advantages over sumatriptan: They have better oral bioavailability, more rapid onset of action after an oral dose, increased central nervous system penetration, a longer duration of action with a lower rate of headache recurrence, and a decreased incidence and severity of “triptan symptoms.” Dihydroergotamine (DHE) is a nonselective 5-HT1 agonist, with affinity for 5-HT1, 5-HT2, 5-HT3, adrenergic, and dopaminergic receptors. Common adverse effects of DHE are nausea, emesis, abdominal pain, diarrhea, and leg cramps. DHE is available in intravenous, intramuscular, and intranasal preparations. The intravenous form is recommended for use in severe prolonged migraine and is the treatment of choice for status migrainosus. Metoclopramide or prochlorperazine can be used with intravenous DHE to ameliorate nausea and emesis. Intranasal DHE is an effective alternative to triptans for treatment of acute migraine. DHE is contraindicated in children with peripheral vascular disease and heart disease with coronary insufficiency; it should not be used concurrently with triptans or other vasoconstrictor agents.
Table 37-16. Stratification of Acute Childhood Migraine into Four Treatment Groups* Mild/Moderate Attack with No or Mild Nausea
Oral NSAID Oral metoclopramide
Moderate Attack with Nausea, with or without Vomiting
Children >12 years Oral isometheptene mucate– dichloralphenazone– acetaminophen (Midrin) Oral/intranasal sumatriptan Oral/MLT rizatriptan Oral zolmitriptan Intranasal DHE Rectal or oral antiemetics Children 12 years SC sumatriptan Intranasal/oral sumatriptan MLT/oral rizatriptan Intranasal DHE Rectal or oral antiemetics May add naproxen (Naprosyn) for longer attack Children 72 Hours (Status Migrainosus)
Children >6 years IV DHE IV metoclopramide IV ketorolac IV diphenhydramine IV prochlorperazine (>50 kg) IV hydration Children 50 kg
Initial
Max/24 hr
Initial
Max/24 hr
15 20 90
25 mg 5-10 mg 0.1 mg/kg
50 mg 10-20 mg Repeat × 1
50 mg 20 mg 6 mg
100 mg 40 mg 12 mg
3 3
50 50
5 mg 5 mg
10 mg 10 mg
5-10 mg 5-10 mg
10-20 mg 10-20 mg
3
40
2.5 mg
5 mg
2.5-5 mg
10 mg
Comments
Watch for “triptan symptoms” especially with SC form. Nasal is 5 and 20 mg/spray MLT form dissolves in mouth
Modified from Gupta A, Rothner AD: Treatment of childhood headaches. Curr Neurol Neurosci Rep 2001;1:144-155.
The physician must be aware that drug-dependent states can develop, even with nonnarcotic medications. Therefore, medication use must be monitored carefully. If a patient is using analgesics more than 1 day a week, abortive management should be considered unsuccessful and should be abandoned. Prophylactic Management
For children with frequent migraines (every 1 to 2 weeks), daily medication is a more appropriate choice (Table 37-18). The most commonly used prophylactic medications are β blockers, amitriptyline, and cyproheptadine. The goal is to prevent as many headaches as possible at a dose that has tolerable side effects. Medication should be started at a low dose to minimize sedation and other adverse effects. The dose should be increased every 1 to 2 weeks if the headaches are not controlled. If intolerable side effects develop, the medication should be tapered and another begun in its place. In the younger patient, cyproheptadine (an antihistamine with serotonin antagonist properties) should be the first choice because it is very well tolerated. The major side effects are excessive appetite and weight gain; this drug may not be acceptable to teenagers. Dose escalation is usually in 1- to 2-mg increments every 1 to 2 weeks. β Blockers (e.g., propranolol) are second-line medications and are generally well tolerated. The major dose-limiting effects include fatigue, weight gain, and cardiovascular β blockade. Because of these effects, this medication can interfere with the lifestyle of active teenagers and athletes. This group of medications is an excellent choice if the headaches are controlled at a dose below that which causes β blockade. Dose escalation of propranolol is usually in weekly increments of 10 to 20 mg. Long-acting (sustained-release) preparations are available once the headaches are controlled. Amitriptyline, a tricyclic antidepressant with serotonin antagonist properties, is usually a good choice for teenagers with migraines. In addition to controlling migraines, amitriptyline is also effective against mixed migraine–tension headache disorders. Because of the sedative properties of amitriptyline, a single daily bedtime dose is usually administered. The starting dose is 10 mg at bedtime, with dose escalation of 10 mg every 1 to 2 weeks until adequate control is achieved. Dose-limiting side effects include dry mouth, weight gain, fatigue, and constipation. Most older patients cannot tolerate more than 75 mg a day. A pretreatment electrocardiogram should be obtained because tricyclic antidepressants prolong the QT interval. This medication should not be prescribed if a prolonged QT interval is found because it may precipitate severe ventricular arrhythmias (torsades de pointes) that are refractory to treatment.
CLUSTER HEADACHES Cluster headaches rarely occur before adolescence but are common in young adults and are more common in men than in women (see Fig. 37-3). Episodes of pain are intermittent, with long periods of remission; hence the name “cluster.” Cluster pain is localized to the eyes and temples but can spread to other parts of the head. The pain begins suddenly and rapidly increases to an excruciating level; patients may think they are dying and plead for relief at any cost. Patients find it impossible to rest, and they become agitated and restless during an attack. They may yell, scream, pace around, or bang their head against the wall. This is in sharp contrast to a migraine attack where the patient is quiet and withdraws to a dark cool room for sleep. Most cluster headaches last 30 minutes to 2 hours. The headaches occur in bouts lasting from 4 to 8 weeks, with one or two bouts occurring a year. During these periods, alcohol should be avoided because it can precipitate a headache. Cluster headaches are more common in smokers. Lacrimation, rhinorrhea, sweating, and nasal stuffiness usually accompany the headache. These headaches usually occur at a particular time of day, most occurring at night. The management of cluster headaches is directed at both the prophylaxis of headaches during clusters and the treatment of acute headache. The acute headache responds to oxygen inhalation, subcutaneous sumatriptan, or parenteral DHE. A short course of steroids may help induce a prompt remission. Prophylactic agents include verapamil, lithium, prednisone, and methysergide. VASCULITIS HEADACHES Vasculitis is an important cause of headaches in adults, although in children it rarely manifests as headaches. Instead, the headaches may be part of the constellation of symptoms associated with this illness. Because of the increased risk of systemic hypertension in patients with vasculitis, it is important to include a blood pressure measurement as part of the complete history and physical examination. When systemic lupus erythematosus and mixed connective tissue disorders affect the central nervous system, children often have seizures and mental status changes. These changes can occur with or without headaches. HYPERTENSION-RELATED HEADACHES Systemic hypertension, both acute and chronic, may be associated with headaches. The pain is probably caused by alterations in the regulation of cerebral blood flow. Acute hypertension typically
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Table 37-18. Medications for Migraine Prophylaxis in Children
Class
Medication
β Blockers
Propranolol
Efficacy/ Side Effects*
4+/2+
Tricyclic Amitriptyline antidepressants
4+/2+
Nortriptyline
4+/2+
Calcium channel blockers
Verapamil
2+/1+
Antiepileptic drugs
Valproate
4+/2+
Antiserotonin
Cyproheptadine
2+/1+
NSAIDs
Naproxen (Naprosyn)
2+/2+
Vitamins
Riboflavin
2+/−
Contraindications (C/I) and Common Side Effects (SE)
Dose
Comments/Precautions
35 kg: 20-40 mg t.i.d. Max: 160240 mg/day Start 5-10 mg q.h.s., increase to 5 mg/kg/day Max dose, 100-150 mg/day
C/I: asthma, heart failure, and heart block SE: depression, decreased athletic performance, hypotension C/I: glaucoma, seizures, cardiac disorders SE: sedation, anticholinergic symptoms, arrhythmias
Start 10 mg q.h.s. Max dose, 50-75 mg/day 4-10 mg/kg/day in 3 divided doses Max adult dose, 480 mg/day 10-30 mg/kg/day in 2 or 3 divided doses Higher doses may be needed Start 2 mg q.h.s. Max doses, 2-6 yr: 12 mg/day in 3 divided doses 7-16 yr: 20 mg/day in 3 divided doses 5-20 mg/kg/dose q8-12h Max dose, 1250 mg/day for 2-4 weeks 100-400 mg/day
Similar to those for amitriptyline Less sedating C/I: heart failure, heart Sustained-release block preparation available SE: constipation, hypotension C/I: hepatic disease Monitor LFT and CBC at SE: liver toxicity, start and periodically thrombocytopenia, pancreatitis, nausea, sedation, alopecia, weight gain C/I: asthma, glaucoma, Morning doses may cause gastrointestinal or school-time sedation genitourinary obstruction SE: increased appetite and weight gain C/I: Gastrointestinal bleeding, ulcer disease SE: platelet dysfunction, tinnitus SE: Hypersensitivity, yellow discoloration of urine
Do not stop abruptly Sustained-release preparation May obtain ECG before starting treatment; do not stop abruptly, especially when on high doses for long time Monitor ECG, heart rate, and blood pressure Similar to those for amitriptyline
For prompt relief while other agent is being introduced Administer with food
Modified from Gupta A, Rothner AD: Treatment of childhood headaches. Curr Neurol Neurosci Rep 2001;1:144-155. *Efficacy and potential for side effects of medications are rated on a scale of 1+ to 5+. − is no side effect. CBC, complete blood cell count; ECG, electrocardiogram; LFT, liver function tests; NSAID, nonsteroidal antiinflammatory drug.
occurs in a child with post-streptococcal glomerulonephritis, renal failure, or collagen-vascular disease. Although hypertension is an uncommon cause of headaches in children, the diagnosis of hypertension is straightforward, and treatment of the hypertension alleviates the headaches (see Chapter 12). Many patients with hypertension have no headaches. Headaches can be part of malignant hypertension syndrome, in which case retinal exudates and microscopic hematuria are usually present. Severe hypertension can also cause an intracerebral hemorrhage. Use of cocaine causes headaches through various mechanisms, including hypertension, vasoconstriction, hypersensitivity vasculitis, and subarachnoid hemorrhage.
seen during the neurologic examination (nuchal rigidity, altered mental status) suggest that factors other than fever may be the source of the headache and must be evaluated.
FEVER-RELATED HEADACHES
CHRONIC PAROXYSMAL HEMICRANIA
Headaches are common in febrile patients, regardless of the source of the fever (see Table 37-3). The pain is usually bifrontal and bitemporal but may also involve the occiput and neck. The pain may be throbbing and may increase with neck flexion. Any abnormalities
Chronic paroxysmal hemicrania consists of frequent and intense unilateral headaches (see Table 37-9). This disorder is much more common in women than in men. Although it usually begins in adulthood, chronic paroxysmal hemicrania can affect older children and
ICE CREAM HEADACHES This common headache affects about 33% of children and 90% of patients with migraines. This disorder occurs more in the summer. Within 30 seconds of quickly ingesting a cold drink or ice cream, a severe, boring pain develops deep inside the head. The pain lasts for only several seconds to a minute. Once this condition is recognized as such, no further evaluation or treatment is necessary.
Chapter 37 Headaches in Childhood
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adolescents. The average headache lasts about 10 minutes (range, a few minutes to 45 minutes). Patients can have as many as 10 to 20 attacks a day, and the pain can awaken the patient from sleep. Sudden head movement can also precipitate an attack. This headache responds dramatically to indomethacin therapy. Relief of symptoms occurs within a few days of beginning the medication. Other NSAIDs are of no benefit. Because the symptoms of chronic paroxysmal hemicrania are similar to those of vascular malformations of the brain, a neuroimaging study should be performed to rule out these malformations before the diagnosis of chronic paroxysmal hemicrania is made.
Increased ICP causes headaches by generating traction on the dura and vessels at the base of the brain. Some processes (brain tumors, pseudotumor cerebri) result in constant headaches because ICP is continuously increased. Other conditions (colloid cyst of the third ventricle) may cause intermittent headaches through transient increases in ICP.
ANOXIA AND CARBON MONOXIDE HEADACHES
In children with headaches, a concern about a brain tumor is probably the key reason why patients request, and physicians order, an imaging study. The mechanism of brain tumors that causes headaches may be either increased ICP or direct traction on the dural or vascular structures. Headaches caused by hydrocephalus can develop rapidly, whereas traction from tumor growth causes a slow and progressive headache. However, at the time of presentation, most patients with headaches caused by tumors or hydrocephalus have chronic and progressive headaches, in which the frequency and severity of pain escalate over time. Tumors may produce hydrocephalus by obstructing cerebrospinal fluid (CSF) flow. With or without a brain tumor, hydrocephalus usually causes a generalized headache. Slowly developing hydrocephalus initially causes mild pain, whereas rapidly developing hydrocephalus causes severe pain. Most patients with hydrocephalus have morning headaches that lessen after they arise. Those who do not follow this pattern have constant pain. When the headache is solely a result of tumor without accompanying hydrocephalus, the location of the headache may or may not be related to the tumor site. Patients with posterior fossa tumors usually have occipital pain, but if hydrocephalus is also present, the pain may be generalized. It is important to note that many patients with brain tumors have no particular pattern to their headaches. Initially, their pain may be mild, and over-the-counter analgesics provide adequate pain relief. If the pain pattern is typical, the severity and frequency of pain increase slowly. Patients with brain tumors near the optic chiasm may have visual disturbances and endocrine deficiencies or galactorrhea. Diplopia may be present if the third or sixth cranial nerve is compressed (nonlocalizing signs); ptosis may also be present. The examination often reveals abnormal findings, including papilledema and neurologic deficits. Common focal neurologic findings include eye movement abnormalities, facial weakness, swallowing difficulties, hemiparesis, and ataxia. Nonlateralizing signs include increased motor tone and bilateral sixth nerve palsies. Increased motor tone may not be a constant finding and may manifest as transient shivering. Tenderness or rigidity of the neck is a sign of increased ICP. Macrocephaly is present in young children with unfused cranial sutures and in those with long-standing hydrocephalus. Other signs of hydrocephalus are a bulging fontanelle and widened cranial sutures. The head growth chart is especially important in the evaluation of children with hydrocephalus. Head growth is abnormal if the plot of sequential head circumferences crosses percentile lines. Papilledema is usually absent in children with an open fontanelle and may also be absent in children with posterior fossa tumors (with or without hydrocephalus). The Parinaud syndrome is the triad of upward-gaze paresis, poor pupillary reaction to light, and retraction nystagmus on convergence. This constellation of physical findings is seen in patients with hydrocephalus or tumors in the pineal region. The presence of Parinaud syndrome always warrants neuroimaging. Increased ICP that is caused by hydrocephalus and/or brain tumors should be suspected in any child with chronic progressive headaches, abnormal neurologic examination results, nuchal rigidity, or abnormal head growth. Patients with these signs and symptoms should undergo a neuroimaging study (see Table 37-14).
Anoxia, hypoxia, and carbon monoxide poisoning may produce headaches through dilatation of cerebral arteries, which in turn causes an increase in cerebral blood flow. In children with illnesses that predispose them to hypoxia (chronic lung disease, obstructive sleep apnea), treatment should be directed at alleviating the source of the hypoxia. High altitudes can also lead to an acute hypoxic state, in which case symptoms can be treated with altitude descent, acetazolamide, and dexamethasone. Low-level carbon monoxide poisoning should be suspected in any child with chronic headaches. The diagnosis is difficult to confirm with an arterial hemoglobin carbon monoxide (HgCO) level because the half-life of HgCO in room air is only 4 hours. Hence, the level may be normal only a few hours after exposure. One way of diagnosing and treating this condition is removing the cause of the exposure. Some sources of carbon monoxide exposure are heavy urban traffic in which the patient is a car passenger; methylene dichloride paint strippers; kerosene space heaters; a gasoline engine running in an attached garage; cigarette smoking; and faulty home furnaces. In severe carbon monoxide poisoning, the patient is treated with 100% oxygen (carboxyhemoglobin half-life, 50 minutes) or hyperbaric oxygen (2 to 3 atm; carboxyhemoglobin half-life, 30 minutes) until the HgCO level is less than 15% and both the metabolic acidosis and mental status changes have resolved. CAFFEINE WITHDRAWAL HEADACHES The threshold for withdrawal for each person is variable, but when caffeine is ingested in sufficient quantities for prolonged periods, sudden withdrawal can lead to vascular headaches. In the most common scenario, consumption occurs on weekdays, and because of schedule differences, the caffeinated beverage is not consumed on the weekend. This syndrome is easily diagnosed by history or by use of a headache diary. Treatment is removal of all sources of caffeine from the diet, such as tea, coffee, caffeinated soft drinks, “pep” pills, and diet pills. EXERTIONAL HEADACHES Coughing, running, swimming, competitive sports, or sexual activity may precipitate exertional headaches. The headaches usually begin during or after the activity and may be associated with nausea and occasional vomiting. They are generalized or localized to one side and last from 30 minutes to 12 hours. History and examination findings are usually normal. The headaches may interfere in performance of the youngster preparing for competitive sports. Indomethacin is the treatment of choice and can be used as needed before the activity or for daily treatment, if circumstances so dictate. More than 85% of patients show excellent response to indomethacin. Monitoring of side effects is important if daily long-term treatment is used. TRACTION HEADACHES One of the greatest concerns in the evaluation of a child with headaches is whether the headache is caused by increased ICP.
Persistently Increased Intracranial Pressure Neoplasms and Hydrocephalus
Section Six Neurosensory Disorders
646 Nonneoplastic Masses
Nonneoplastic masses, such as hemorrhage, cysts, and abscesses, can also cause headaches. Intracranial hemorrhage should be suspected in any child with a concussion causing amnesia or loss of consciousness or with a head injury resulting in abnormal neurologic examination results (e.g., altered mental status, focal findings). Most intracranial hemorrhages are detected by the initial neuroimaging study performed immediately after the injury; however, some subdural and a few epidural hematomas may take weeks to develop after the trauma. Cysts are classified as arachnoid, epidermoid, and dermoid. Slow-growing cysts often produce headache patterns similar to those of neoplasms. Epidermoid and dermoid cysts can have sinus tracts that communicate with the skin. If these cysts become infected, their clinical manifestation resembles a brain abscess. A brain abscess should be considered in any child with a rightto-left cardiac shunt, chronic mucosal surface infections (sinus, otitis, dental), and a recent onset of persistent, chronic headaches. Patients with a brain abscess may present with progressive neurologic dysfunction and may deteriorate quickly. Aneurysmal Rupture
Arterial aneurysms may be congenital (berry) or caused by an infectious process (mycotic). Rupture of an arterial aneurysm is rare in children. The rupture produces an excruciating headache, known as a thunderclap headache. Patients state that this is “the worst headache of my life.” The pain is acute in onset and associated with nuchal rigidity, emesis, and changes in sensorium. The neurologic examination findings may be nonfocal. CT scans reveal blood in the cisterns and meninges in 85% of cases. If the CT scan shows no pathologic process, a lumbar puncture is necessary in all patients thought to have a ruptured aneurysm. The spinal fluid in a ruptured aneurysm is bloody, xanthochromic, or both. In half the cases, patients report having previous headaches before having the headache associated with the rupture. These earlier headaches may be caused by leakage of blood from the aneurysm. If the clinician suspects a leaking or ruptured aneurysm, rapid neurologic and neurosurgical care is mandatory. Arteriovenous malformations may produce similar manifestations. Pseudotumor Cerebri
Even though pseudotumor cerebri is also known as benign intracranial hypertension, it is associated with significant morbidity. The headache in pseudotumor cerebri can be intermittent or constant and may resemble a migraine. Papilledema is usually present at the time of presentation. In severe cases, the retinal blind spot may enlarge, and the visual fields may become constricted. This syndrome is more common in older children and adolescents, girls and women, and obese individuals. The characteristic findings are chronic progressive or nonprogressive headaches, papilledema, normal neuroimaging, and raised ICP. Pseudotumor cerebri may be either idiopathic or secondary to a variety of medical conditions (Table 37-19). Because papilledema is a common finding in this syndrome, a neuroimaging study must be performed before the lumbar puncture to rule out other causes of papilledema (tumor, hydrocephalus) (see Table 37-14). The opening pressure from the lumbar puncture (in the lateral position) in pseudotumor cerebri is elevated (range, 240 to 600 mm H2O). The results of the physical examination (except papilledema, visual field changes, and occasional sixth nerve palsy), neuroimaging studies, and CSF studies are usually normal. In the evaluation of a patient with pseudotumor cerebri, a detailed history and physical examination are needed to rule out the many secondary causes of this syndrome (see Table 37-19). Specifically in young children, obstruction of the intracranial venous sinuses by
Table 37-19. Conditions Associated with Pseudotumor
Cerebri Intracranial Venous Drainage Obstruction Mastoiditis and lateral (sigmoid) sinus obstruction Extracerebral mass lesions Congenital atresia or stenosis of venous sinuses Head trauma Cryofibrinogenemia Polycythemia vera Paranasal sinus and pharyngeal infections Cervical or Thoracic Venous Drainage Obstruction Intrathoracic mass lesions and postoperative obstruction of venous return Endocrine Dysfunction Pregnancy Menarche Marked menstrual irregularities Oral contraceptives Obesity Withdrawal of corticosteroid therapy Addison disease Hypoparathyroidism “Catch-up” growth after deprivation, treatment of cystic fibrosis, correction of heart anomaly Initiation of thyroxine treatment for hypothyroidism Adrenal hyperplasia Adrenal adenoma Hematologic Disorders Acute iron deficiency anemia Pernicious anemia Thrombocytopenia Wiskott-Aldrich syndrome Vitamin Metabolism Chronic hypervitaminosis A Acute hypervitaminosis A Hypovitaminosis A Cystic fibrosis and hypovitaminosis A Vitamin D–deficiency rickets Drug Reaction Tetracyclines Perhexiline maleate Nalidixic acid Sulfamethoxazole L-Asparaginase Indomethacin Penicillin Prophylactic Antisera Miscellaneous Galactosemia Galactokinase deficiency Lyme disease Sydenham chorea Sarcoidosis Roseola Hypophosphatasia Paget disease Maple syrup urine disease Turner syndrome Adapted from Burg FD, Ingelfinger JR, Wald ER (eds): Gellis and Kagan’s Current Pediatric Therapy, 14th ed. Philadelphia, WB Saunders, 1993, p 67.
Chapter 37 Headaches in Childhood infection or dehydration and thrombosis, trauma, and chronic middle ear or mastoid infection should be considered, and magnetic resonance venogram and special views may be necessary to visualize the mastoid air cells. The goal of treatment is to lower the ICP and alleviate the headaches. Lumbar puncture is a fast, reliable, but temporary method for achieving both goals. Most patients require multiple lumbar punctures before their symptoms resolve. If the visual fields are affected, the treatment must be aggressive, with serial lumbar punctures, until the fields return to normal. If symptoms persist despite serial lumbar punctures, a lumbar-to-peritoneal drain or optic sheath decompression may be necessary to provide long-term drainage for the spinal fluid. The primary cause should be addressed when possible. In obese patients, weight loss may also be helpful. Corticosteroids provide quick relief from the headache and associated visual impairment. Because steroids can cause rapid weight gain, their use should be avoided if at all possible. Ocular findings should be monitored closely because patients may develop permanent visual impairment. Transient Increased Intracranial Pressure Cough headaches are intermittent headaches caused by transient increases in ICP that result from activities that elevate intrathoracic pressure (exertion, coughing, bending). The pain is maximum and severe at the onset of the activity and then resolves in seconds. Patients are usually asymptomatic between events. Cough headaches, which are much shorter than are exercise-induced vascular headaches, may be caused by both benign and lifethreatening conditions. Structural causes of cough headache include brain tumors and Chiari malformations. The results of the physical examination are usually normal, even when structural lesions cause this syndrome. To rule out these structural lesions, patients with cough headaches should undergo MRI. Colloid cyst of the third ventricle is another life-threatening condition that causes cough headaches. With changes in position, this cyst functions as a ball valve and intermittently impedes the flow of CSF. This obstruction causes transient increases in ICP. Sometimes, the patient may be asymptomatic during these episodes of increased ICP. At other times, the patient may experience severe intermittent headaches, increased muscle tone (posturing) that resembles shivering, coma, and death. The ICP returns to normal when position is changed or when the increased CSF pressure overcomes the obstruction. Physical findings are normal between events. The diagnosis is made by neuroimaging studies (MRI). Treatment consists of CSF diversion or removal of the cyst. Decreased Intracranial Pressure Abnormally low ICP causes headaches by the same mechanism as that of increased ICP: traction on the dura and vessels at the base of the brain. The most common cause of a headache from decreased ICP is leaking CSF after a lumbar puncture. This headache can occur after any lumbar puncture but is more commonly associated with older children, use of large-bore spinal needles, and multiple attempts at obtaining CSF. Patients describe a severe headache within seconds after assuming an upright position. The headache disappears soon after the patient lies down. Treatment consists of bed rest until the leak seals. A blood patch is used when the leak fails to seal during bed rest. This procedure consists of injecting the patient’s own blood into the epidural space, thus “patching” the dural leak. Other causes of low-pressure headaches include CSF leaks from fractures or tumors at the base of the skull. HEADACHES CAUSED BY INFLAMMATION Any inflammatory process involving the head or neck can cause headaches. The pain may be from direct inflammation of the brain
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Table 37-20. Chronic Facial Pain: Differential Diagnosis
Orbital Pain Ocular disease Migraine Cluster Sinusitis Orbital cellulitis Tolosa-Hunt syndrome Intracranial aneurysm Cavernous sinus disease Giant cell arteritis Neoplasm Graves disease Neoplasm, frontal lobe Trigeminal neuralgia Postherpetic neuralgia Zoster Ear/Periauricular Pain Chronic external otitis Relapsing polychondritis Cholesteatoma TMJ syndrome Migraine Carotidynia Glossopharyngeal neuralgia Thyroiditis Muscle contraction Carotid aneurysm Cervical spine disease Neoplasm Zoster
Nasal/Cheek Pain Sinusitis Facial cellulitis Neoplasm (nasopharynx, sinus) Vasomotor rhinitis Allergic rhinitis Trigeminal neuralgia Midline granuloma Wegener granulomatosis TMJ syndrome Dental disease Postherpetic neuralgia Atypical odontalgia Cluster Poorly Localized/Vague Sinus disease TMJ syndrome Depression Conversion reaction Neoplasm Muscle contraction Dental/Jaw Pain Toothache TMJ syndrome Sinusitis Neoplasm Trigeminal neuralgia Parotid disease Atypical odontalgia Postherpetic neuralgia
Adapted from Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 106. TMJ, temporomandibular joint.
and dura (meningitis), or it may be referred from extracranial inflammation (sinusitis, dental abscesses) (Table 37-20). Intracranial Inflammation With meningitis and meningoencephalitis, the headache is acute in onset and generalized. Fever, nuchal rigidity, alteration in sensorium, and abnormal neurologic findings usually accompany an inflammatory process of the meninges (see Chapter 52). Extracranial Inflammation The headache associated with sinusitis can be acute or chronic. The headache is frontal or ocular when the frontal or maxillary sinuses are involved. When the ethmoid or sphenoid sinuses are infected, the headache can be frontal or occipital. Some of the symptoms and signs associated with sinusitis are purulent rhinorrhea, halitosis, cough (worse at night), tenderness to palpation over the sinuses or teeth, and fever. In addition, these patients may have a medical history of allergic rhinitis or previous sinusitis. If a radiographic study is needed to confirm the diagnosis, a sinus CT scan is preferred over routine sinus roentgenograms because CT scanning is more sensitive in diagnosing sinusitis and costs the same. The headaches from dental abscesses may be aching or knifelike. Dental abscesses can be a complication of dental caries, tooth extractions, and root canal procedures. The examination results may be normal, or the examination may reveal gingival swelling, redness, or pain.
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Inflammation of the eye and orbit usually causes localized pain (see Table 37-20). The signs and symptoms of periorbital cellulitis are periorbital redness and tenderness, whereas in orbital cellulitis, the patient may have chemosis, proptosis, ophthalmoplegia, and visual loss. A corneal abrasion should always be suspected in the irritable infant and in the patient with excruciating eye pain. Diagnosis is made by fluorescein examination of the cornea (see Chapter 43). Optic neuritis (inflammation of the optic nerve) often causes ipsilateral retroorbital pain. Optic neuritis may occur as a single entity, or it can be part of the manifestation of multiple sclerosis. This disorder is rare in children but common in adolescents. The ophthalmologic examination reveals papillitis (resembling papilledema), afferent pupillary defect, and decreased visual acuity. Often, the findings may be normal except for decreased visual acuity. A neuroimaging study should be performed because of the ocular findings and to rule out multiple sclerosis. Optic neuritis is treated with intravenous corticosteroids. TEMPOROMANDIBULAR JOINT SYNDROME Malocclusion of the temporomandibular joint (TMJ) can cause chronic headaches. The pain is localized to the side of the affected joint. Some patients report constant pain, whereas others have pain only with jaw movement. An identifying “click” occurs when the patient opens the mouth. Not every person with a click has TMJ syndrome, and not everyone with TMJ syndrome has headaches. Gum chewing may exacerbate the pain associated with TMJ syndrome. In patients without TMJ syndrome, gum chewing may cause headaches through overuse of the temporalis muscles. Patients with symptomatic TMJ syndrome often find relief with the use of a bite plate worn during sleep. POSTCONCUSSIVE SYNDROME Chronic headaches can occur as part of the postconcussive or posttraumatic syndrome. The headache is generally constant and may have qualities of both chronic muscle contraction and migraine headaches. For example, some patients may have nausea, vomiting, and visual auras. Other features of this syndrome are fatigue, dizziness, vertigo, poor memory, decreased reaction times, and inability to concentrate. The neurologic findings are usually normal. Symptoms begin soon after the head injury (within 1 to 7 days) and can persist for years. About 70% of patients recover within a year, but 15% are still symptomatic after 3 years. The pathophysiologic mechanism of this syndrome is unknown. Even though postconcussive syndrome is more common in persons with a history of psychologic or psychosomatic illness, it is not an imaginary phenomenon. A neuroimaging study may be necessary to rule out the presence of a chronic subdural hematoma, which is rare. Patient education is the most important element of treatment. Some patients may also benefit from psychotherapy. NSAIDs, amitriptyline, and propranolol may be helpful, but narcotics should be avoided because of their addictive potential in the treatment of chronic headaches. OCCIPITAL NEURALGIA The greater occipital nerve is a continuation of the C2 nerve root, which innervates the posterior scalp. Irritation or inflammation of this nerve can produce occipital pain that may be intermittent or persistent. The pain is described as ranging from “pins and needles” to lancinating. On physical examination, affected patients have decreased sensation over the C2 dermatome, limitation of cervical movements, and tenderness to palpation over the posterior scalp. Whiplash injury, atlantoaxial subluxation, weight lifting, wrestling, and arthritis are associated with this syndrome. Most patients
respond to some combination of cervical collar, muscle relaxants, NSAIDs, and physical therapy. In severe cases, repeated nerve blocks with steroids and a local anesthetic provide relief. CONVERSION DISORDER Headaches associated with conversion disorders are very difficult to diagnose and treat accurately. The frequency and severity of these headaches increase without lasting relief from any pharmacologic or physical therapy. Some patients appear as if they are in pain, whereas others look perfectly normal despite claiming to be in considerable pain. Secondary muscle contraction pain can occur, which further complicates the diagnosis. The neurologic findings in conversion disorders are normal. As patient and family anxiety grows, the physician’s anxiety also increases, resulting in the ordering of many blood tests and neuroimaging studies. The two problems in treating conversion disorder headaches are (1) to convince the family that there is no physical cause for these headaches, and (2) to uncover the origin of the conversion disorder. The physician with a preestablished rapport with the family is clearly at an advantage in convincing the family that no physical cause exists for the headaches. The origins of a conversion disorder are difficult to uncover and require the finesse of an experienced therapist. Psychologic intervention is mandatory, not only to identify the source of the problem but also to offer appropriate consoling.
SUMMARY AND RED FLAGS Headaches are a common cause of morbidity in children. Although muscle contraction and migraine headaches are the most common causes of headaches in children, the clinician must rule out lifethreatening conditions in the evaluation of each patient with a headache. A thorough history and physical examination are the best diagnostic tools aiding the clinician in determining which patients have a serious and life-threatening cause for their headaches. The red flags from this evaluation are thunderclap headache, cough headache, the first severe headache, chronic or progressive headaches, persistently unilateral headaches, any persistently abnormal neurologic findings (>1 hour), meningeal signs, papilledema, and alterations of sensorium. A new headache in a patient with a chronic medical condition, particularly an immunosuppressed patient, and headaches associated with activities are other red flags. Patients with these red flags need a complete emergency evaluation that includes neuroimaging studies (see Table 37-14). REFERENCES Annequin D, Tourniaire B, Massiou H: Migraine and headache in childhood and adolescence. Pediatr Clin North Am 2000;47:617-631. Appleton R, Farrell K, Buncic JR, et al: Amaurosis fugax in teenagers. Am J Dis Child 1988;142:331-333. Becker WJ: Evidence based migraine prophylactic drug therapy. Can J Neurol Sci 1999;26:S27-S32. Caruso JM, Ferri R, Exil G, et al: The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Ann Neurol 1998;44:567. Dahlof CGH, Hargreaves RJ: Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies? Cephalalgia 1998;18:593-604. Dalessio DJ: Relief of cluster headache and cranial neuralgias. Promising prophylactic and symptomatic treatments. Postgrad Med 2001;109:69-72. Digre KB: Not so benign intracranial hypertension. BMJ 2003;326:613-614. Dodick DW, Rozen TD, Goadsby PJ, et al: Cluster headache. Cephalalgia 2000;20:787-803. Green MW: A spectrum of exertional headaches. Med Clin North Am 1085;85:1085-1092. Guidetti V, Galli F: Recent development in paediatric headache. Curr Opin Neurol 2001;14:335-340.
Chapter 37 Headaches in Childhood Gupta A, Rothner AD: Treatment of childhood headaches. Curr Neurol Neurosci Rep 2001;1:144-154. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:1-96. Jensen VK, Rothner AD: Chronic nonprogressive headaches in children and adolescents. Semin Pediatr Neurol 1995;2:151-154. Jones JS, Nevai J, Freeman MP, et al: Emergency department presentation of idiopathic intracranial hypertension. Am J Emerg Med 1999;17:517-521. Joutel A, Bousser MG, Biousse V, et al: A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 1993;5:40-45. Kaniecki R: Headache assessment and management. JAMA 2003;289: 1430-1433. Kosmorsky G: Pseudotumor cerebri. Neurosurg Clin North Am 2001;12: 775-797. Lessell S: Pediatric pseudotumor cerebri (idiopathic intracranial hypertension). Surv Ophthalmol 1992;37:155-166. Lewis DW: Headaches in children and adolescents. Am Fam Physician 2002;65:625-632. Lewis DW, Ashwal S, Dahl G, et al: Practice parameter: Evaluation of children and adolescents with recurrent headaches: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002;59:490-498. Linder SL: Treatment of childhood headache with dihydroergotamine mesylate. Headache 1994;34:578-580. Linder SL, Winner P: Pediatric headache. Med Clin North Am 2001;85: 1037-1053.
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Lipton RB, Stewart WF, Stone AM, et al: Stratified care vs step care strategies for migraine. The Disability in Strategies of Care (DISC) study: A randomized trial. JAMA 2000;284:2599-2605. Lipton RB, Stewart WF, Von Korff M: Burden of migraine: Societal costs and therapeutic opportunities. Neurology 1997;48:S4-S9. Mark AS, Casselman J, Brown D, et al: Ophthalmoplegic migraine; reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images. Am J Neuroradiol 1998;19:1887-1891. Maytal J, Lipton RB, Solomon S, et al: Childhood onset cluster headaches. Headache 1992;32:275-279. Practice parameter: The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations (summary statement). Report of the Quality Standard Subcommittee of the American Academy of Neurology. Neurology 1994;44:1353-1354. Rothner AD: Headaches in children and adolescents. Child Adolesc Psychiatr Clin North Am 1999;8:727-745. Rothner AD: Evaluation of headache. In Winner P, Rothner AD (eds): Headache in Children and Adolescents. Hamilton, Ontario, BC Decker, 2001. Senior K: New understanding into the mechanics of migraine. Lancet 2002;359:500. Soler D, Cox T, Bullock P, et al: Diagnosis and management of benign intracranial hypertension. Arch Dis Child 1998;78:89-94. Steiner TJ, Fontebasso M: Headache. BMJ 2002;325:881-886. Tronvik E, Stivner LJ, Helde G, et al: Prophylactic treatment of migraine with an angiotensin II receptor blocker. JAMA 2003;289:65-69. Winner P: Triptans in childhood and adolescence. Sem Pediatr Neurol 2001;8:22-26.
38
Hypotonia and Weakness
Saleem I. Malik Michael J. Painter*
THE HYPOTONIC INFANT
IDENTIFICATION OF MUSCLE WEAKNESS AND HYPOTONIA
CLINICAL EVALUATION Hypotonia (abnormally diminished muscle tone) may be acute or chronic, progressive or static, isolated or part of a complex clinical situation; it affects children of all ages (Table 38-1). It may or may not be associated with weakness (Tables 38-2 to 38-5). The evaluation of children with hypotonia can be simplified by a thoughtful, analytic approach to the differential clues that are useful in identifying an underlying cause (Tables 38-6 and 38-7; Figs. 38-1 to 38-3). Hypotonia is usually defined functionally as diminished resistance to movement as a limb is passively moved through a range of motion about a joint. The assessment of muscle tone can also be made by several observations, including ● ● ● ●
In an infant, historical information must include a complete obstetric history as well as accurate data about perinatal events, diet, toxic exposure, and family diseases. Muscle Strength Muscle strength cannot be measured directly in infants (Table 38-8), but numerous clinical clues allow the careful observer to identify weakness. The most important of these is the spontaneous posture. The weak infant has diminished or no spontaneous movement, often in striking contrast to the usual vigorous and plentiful movements of the infant with normal strength (Fig. 38-5). The lower extremities are abducted, and the lateral surfaces of the thighs lie against the examination table, whereas the upper extremities lie extended alongside the body or flexed in a flaccid position beside the head. With marked weakness, there are no movements that overcome the pull of gravity. The immobility of the weak infant results in flattening of the occipital bone, which is often associated with occipital hair loss. When placed in a sitting posture, the infant droops forward, the shoulders droop, the head falls forward, and the arms hang limply.
evaluation of spontaneous posture extent of mobility of joints response to flapping of distal extremities response to postural changes
The method of evaluating muscle tone and strength depends on the age of the patient. Muscle tone is defined as the resistance experienced by the examiner to movement of limbs about joints. Muscle tone is divided into postural and phasic. Postural tone is that experienced by the steady flexion or extension of a joint and is caused by the resultant uniform resistance of muscle to passive movement. Antigravity posture of muscle is caused by postural tone. Phasic tone is the catch experienced when an extremity is rapidly flexed or extended. The anatomic structures responsible for muscle tone are contained in a closed circuit formed by the muscle spindle, which is connected to the spinal cord by sensory afferent pathways. The sensory afferent fibers synapse directly or indirectly with anterior horn α and γ motor neurons. The α motor neurons end at the neuromuscular junction, and the γ motor neurons end at the muscle spindle, completing the closed circuit. It is the level of activity of γ motor neuron and its influence on the muscle spindle that sets the level of resting muscle tone. This lower motor neuron pathway is closely monitored and influenced by descending pathways from the cerebral cortex, basal ganglia, brainstem, and cerebellum. These descending pathways constitute a portion of the upper motor neuron. The maintenance of normal muscle tone requires the integrity of the entire central and peripheral nervous systems, from the cerebral cortex, cortical white matter pathways, basal ganglia, cerebellum, brainstem, spinal cord, peripheral nerve, neuromuscular junction, and muscle (see Table 38-6). Diseases that affect the function of the nervous system at any level may result in abnormal muscle tone (see Tables 38-6 and 38-7). Many neonates and infants with hypotonia have disorders of the brain. Most older children and adolescents with hypotonia have a disorder of the motor unit (anterior horn cell, peripheral nerve, neuromuscular junction, and muscle) (Fig. 38-4).
Passive Tone Passive tone can be assessed by evaluating the resistance to movement of the limbs through a range of motion at the joints. Evaluation of the shoulders, elbows, wrists, hips, knees, and ankles is especially helpful. The examiner senses a “looseness” of the limbs as the limbs are moved. In addition, grasping the midportion of the infant’s limb and passively flapping the extremity allow the examiner to evaluate the degree of limpness of the distal extremity. In the hypotonic infant, the hands and feet wave limply; in the normal infant, the ankle and wrist are maintained fairly rigidly in line with the rest of the extremity. Even in normal infants, there is a wide variation of muscle tone. Passive muscle tone varies and is particularly diminished after feeding and before sleep. There is profound hypotonia in all infants during sleep. Tone can also be affected by the position of the head. The child whose head is turned to one side may be manifesting an asymmetric tonic neck response, with increased extensor tone on the side of the body to which the head is turned and increased flexor tone on the contralateral side. This asymmetry of tone may be elicited even in the child who does not exhibit the typical “fencer’s” posture. Therefore, examination of an infant should always be conducted while the infant’s head is in the midline; the same is true for eliciting muscle stretch reflexes. Hypotonia can also be associated with heart failure, sepsis, acidosis, failure to thrive, and other systemicgeneralized serious conditions affecting the baby’s general health (see Table 38-1).
*This chapter is an updated and edited version of the chapter by Warren Cohen that appeared in the first edition.
651
Rare Lowe syndrome Zellweger syndrome Neonatal adrenal leukodystrophy Mucolipidosis type IV Tay-Sachs disease Gangliosidosis Mannosidosis
Uncommon Amino acid disorders Organic acid disorders Urea cycle disorders Scurvy Rickets Sotos syndrome Angelman syndrome Rett syndrome Smith-Lemli-Opitz syndrome
Common Sepsis Heart failure Acidosis Failure to thrive Hypoxia Renal failure Hypoglycemia Down syndrome Prader-Willi syndrome Noonan syndrome Fragile X syndrome
Systemic
Ehlers-Danlos syndrome Osteogenesis imperfecta Velocardiofacial syndrome
Stickler syndrome Marfan syndrome Achondroplasia
Connective Tissue
Miller-Dieker syndrome Walker-Warburg syndrome
Progressive encephalopathies Mitochondrial disease
Hypoxic-ischemic brain injury Brain malformation Intrauterine infection Postnatal brain injury
Cerebral
Arthrogryposis
Neonatal spinal cord transection Hypoxic-ischemic myelopathy Arteriovenous malformation
Myelodysplasia Spinal cord tumor Epidural abscess Transverse myelitis Trauma (transection or compression)
Spinal Cord
Table 38-1. Causes of Hypotonia and Weakness in Infancy and Childhood
Poliomyelitis Incontinentia pigmenti Fazio-Londe disease Infantile neuroaxonal dystrophy GM2 gangliosidosis Anterior spinal artery occlusion Arthrogryposis
Möbius syndrome
Spinal muscular atrophies
Anterior Horn Cell
Refsum disease Giant axonal neuropathy Metachromatic leukodystrophy Krabbe disease
Chronic inflammatory demyelinating polyneuropathy Hereditary motor and sensory neuropathy (Charcot-MarieTooth disease) Dejerine-Sottas disease Familial dysautonomia
Postinfectious polyneuropathy (Guillain-Barré syndrome) Toxic neuropathies Isoniazid Vincristine Nitrofurantoin Zidovudine
Peripheral Nerve
Toxic organophosphate poisoning Postneuromuscular blocking agents (vecuronium)
Botulism Infantile myasthenia Transient neonatal myasthenia
Neuromuscular Junction
Other muscular dystrophies Congenital myopathies Metabolic myopathies Mitochondrial myopathies Arthrogryposis
Duchenne muscular dystrophy Becker muscular dystrophy Myotonic dystrophy Inflammatory muscle disease (dermatomyositismyositis)
Muscle
Chapter 38 Hypotonia and Weakness Table 38-2. Nonparalytic Conditions: Hypotonia
without Significant Weakness 1. Disorders of the Central Nervous System a. Nonspecific mental deficiency b. Birth trauma, intracranial hemorrhage, intrapartum asphyxia, and hypoxia c. Hypotonic cerebral palsy d. Metabolic disorders: lipidoses (leukodystrophies); mucopolysaccharidoses; aminoacidurias; congenital disorders of glycosylation*; Leigh and Zellweger syndromes e. Chromosomal abnormalities Down syndrome 2. Connective Tissue Disorders Congenital laxity of ligaments Ehlers-Danlos and Marfan syndromes Osteogenesis imperfecta; arachnodactyly 3. Prader-Willi Syndrome 4. Metabolic; Nutritional; Endocrine Organic acidemias; hypercalcemia; rickets; celiac disease; hypothyroidism; renal tubular acidosis Modified from Dubowitz V: Muscle Disorders in Childhood, 2nd ed. London, WB Saunders, 1995, p 459. *Carbohydrate-deficient glycoproteins.
Table 38-3. Acute Generalized Weakness
Infectious Disorders 1. Acute infectious myositis 2. Acute inflammatory polyradiculoneuropathy (Guillain-Barré syndrome) 3. Enterovirus and West Nile virus infections Metabolic Disorders 1. Acute intermittent porphyria 2. Hereditary tyrosinemia
653
Table 38-4. Progressive Proximal Weakness
Spinal Cord Disorders Juvenile Spinal Muscular Atrophies 1. Autosomal recessive 2. Autosomal dominant 3. GM2 gangliosidosis (hexosaminidase A deficiency) Myasthenic Syndromes 1. Familial limb-girdle 2. Myasthenia gravis 3. Slow channel syndrome Myopathies 1. Muscular dystrophies a. Duchenne and Becker dystrophies b. Facioscapulohumeral syndrome c. Limb-girdle dystrophy 2. Inflammatory myopathies a. Dermatomyositis b. Polymyositis c. Inclusion body myositis 3. Metabolic myopathies a. Acid maltase deficiency b. Carnitine deficiency c. Debrancher enzyme deficiency d. Lipid storage myopathies e. Mitochondrial myopathies f. Myophosphorylase deficiency 4. Endocrine myopathies a. Adrenal cortex b. Parathyroid c. Thyroid Modified from Fenichel GM: Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, WB Saunders, 1993, p 171.
is pulled across the chest toward the opposite shoulder and the position of the elbow is noted. The presence of joint hyperextensibility is confirmed if the elbow passes the midline; this is suggestive of hypotonia.
Neuromuscular Blockade 1. Botulism 2. Tick paralysis
Postural Reflexes
Periodic Paralysis 1. Familial hyperkalemic 2. Familial hypokalemic 3. Familial normokalemic
The traction response is the most useful and most sensitive of the postural reflexes in infants. With the infant lying supine, the infant’s hands are grasped, and the infant is pulled up to a sitting position (Fig. 38-6). Once the sitting posture is attained, the head is held erect in the midline. During the maneuver, the examiner notes the infant’s attempt to counter the traction by flexion of the arms. In an infant younger than 3 months, the plantar grasp should also be evident. In addition, there should be flexion at the elbow, knee, and ankle in response to the maneuver. The degree to which the head and neck pull up along with the trunk depends on the child’s age (see Fig. 38-6). In infants younger than 33 weeks’ gestation, there is no traction response. From 33 weeks to term, the infant has head lag but responds to the traction maneuver by flexing the neck flexors in an attempt to lift the head. The full-term infant exhibits a traction response with minimal head lag, and when the sitting posture is attained, the head may be held erect momentarily and then fall forward. By age 3 months, there should be no head lag, and the head should be aligned with the plane of the back as the child is pulled to sitting. The absence of flexion of the limbs in response to the examiner’s pull and the presence of head lag inappropriate for age suggests hypotonia.
Poisoning 1. Opiates 2. Barbiturates 3. Other sedatives 4. Magnesium Modified from Fenichel GM: Clinical Pediatric Neurology: A Signs and Symptoms Approach. Philadelphia, WB Saunders, 1993, p 187.
Joint Extensibility The extent to which the joints may be extensible provides an indirect clue to the presence of hypotonia. Examination of mobility at the elbows, wrists, hips, and knees is helpful. The hypotonic infant may assume unusual postures in the presence of joint hyperextensibility. The “scarf sign” is a particularly useful sign of hyperextensibility in the young infant. With the infant in a semireclining position, the hand
Traction Response
Section Six Neurosensory Disorders
654 Table 38-5. Progressive Distal Weakness
Spinal Cord Disorders Motor Neuron Diseases 1. Juvenile amyotrophic lateral sclerosis 2. Spinal muscular atrophies a. Genetic forms b. Nonfamilial Asian Neuropathies 1. Hereditary motor sensory neuropathies (HMSN) a. HMSN I: Charcot-Marie-Tooth b. HMSN II: neuronal Charcot-Marie-Tooth c. HMSN III: Dejerine-Sottas d. HMSN IV: Refsum 2. Other genetic neuropathies a. Familial amyloid neuropathy b. Giant axonal neuropathy c. Pyruvate dehydrogenase deficiency d. Sulfatide lipidoses: metachromatic leukodystrophy e. Other leukodystrophies 3. Neuropathies with systemic diseases a. Drug induced b. Systemic vasculitis c. Toxins d. Uremia 4. Idiopathic neuropathy a. Chronic axonal neuropathy b. Chronic demyelinating neuropathy Myopathies 1. Hereditary distal myopathies 2. Myotonic dystrophy Scapulo(humeral)peroneal Syndrome 1. Bethlem myopathy 2. Emery-Dreifuss syndrome 3. Scapulohumeral syndrome with dementia 4. Scapuloperoneal neuronopathy Modified from Fenichel GM: Clinical Pediatric Neurology: A Signs and Symptoms Approach, 2nd ed. Philadelphia, WB Saunders, 1993, p 181.
Axillary Suspension
The response to axillary suspension allows assessment of generalized and shoulder girdle tone. The infant is held under the arms, lifted, and suspended from the axillae without the thorax’s being grasped. In infants with normal tone and strength, the shoulder girdle muscles exert enough strength to allow the infant to be suspended without slipping through the examiner’s grasp. In addition, the infant’s head is held midline and the legs are held with some flexion at the hips, knees, and ankles. The hypotonic infant droops with legs extended and head falling forward, and the absence of resistance of the muscles of the shoulder girdle allows the infant to slip through the grasp of the examiner as the baby’s arms fling upward. Ventral Suspension
The response to ventral suspension allows assessment of tone of the trunk, neck, and extremities (see Fig. 38-6). The examiner holds the infant, who is lying prone. The infant is supported only by the examiner’s hand on the abdomen. A normal infant holds the head erect and the back straight and holds the extremities with some flexion at the elbows, hips, knees, and ankles. A full-term neonate makes intermittent attempts to hold the head straight, maintains the back
straight, and can flex the limbs. The hypotonic infant droops in the examiner’s palm, as if in the shape of an inverted U, with the head and legs dangling limply. DIAGNOSTIC APPROACH A careful perinatal history is obtained to identify possible features suggestive of perinatal hypoxic-ischemic brain injury. The infant who has a neurologic dysfunction attributable to perinatal asphyxia should have demonstrated evidence of an acute encephalopathy during the neonatal period (disturbance of consciousness, poor feeding, seizures, autonomic dysfunction). A computed tomographic study or magnetic resonance imaging (MRI) of the head is helpful to identify evidence of brain malformation, intrauterine infection, hypoxic brain injury, intracranial hemorrhage, or hydrocephalus. If the history suggests seizures, an electroencephalogram should be obtained. An ophthalmologic evaluation may detect evidence of ocular malformation (cataracts, microphthalmia, optic hypoplasia), evidence of intrauterine infection (chorioretinitis), or retinal/macular abnormality (retinitis pigmentosa, cherry-red spot) (see Chapter 43). In some cases, requesting a hearing evaluation or brainstem auditory evoked response may be appropriate. A lumbar puncture is necessary only if acute or chronic (intrauterine) meningitis is suspected. Figure 38-1 summarizes the approach to the hypotonic newborn. After a thorough history and careful physical examination, it should be determined whether the infant has signs of encephalopathy. A computed tomographic scan or MRI of the head is obtained to detect any anatomic abnormalities. If the scan does not reveal an abnormality and if the neonate exhibits increased reflexes and tone over time, a diagnosis of static encephalopathy can be made. If hypotonia persists, anterior horn cell disease, congenital myopathy, or neuromuscular junction disease should be considered (see Table 38-1, Table 38-6, and Fig. 38-4). If the baby is not encephalopathic, the practitioner should determine whether a systemic disease (Prader-Willi syndrome or Down syndrome) is present. Is the motor-sensory level consistent with myelodysplasia or spinal cord injury? In addition, causes of arthrogryposis multiplex congenita must be considered (Table 38-9). If the baby is markedly weak, the examiner should check to see whether the mother is also weak or whether she displays myotonia. If either is true, then transplacental-derived transient neonatal myasthenia gravis or myotonic dystrophy, respectively, is a possibility (Table 38-10). If neither is the case, then myopathy (Table 38-11), congenital myasthenia, infant botulism (Table 38-12), or anterior horn cell disease must be considered (see Tables 38-4 and 38-5). Common Disorders Hypoxic-Ischemic Encephalopathy
Hypoxic-ischemic encephalopathy is a general term that describes a child with sustained hypoxic and ischemic injury (most commonly in the perinatal period) that results in varying degrees of mental and motor developmental impairment. The typical child with severe hypoxic-ischemic encephalopathy is markedly hypotonic during the neonatal period and demonstrates other manifestations of encephalopathy (seizures, poor suck, poor feeding, impaired alertness, hypotonia, or hypertonia). Seizures are present in 50% of the patients with moderate to severe encephalopathy. Neonates with hypoxic-ischemic injury may also be jittery. Over the course of weeks to several months, signs of hyperreflexia and hypertonia begin to evolve, generally in a rostral-caudal progression. In some infants, hypotonia persists and is the prominent motor sign. The term hypotonic cerebral palsy is often used to describe this group. In most of
Normal Back pain Bowel or bladder dysfunction
GBS, Guillain-Barré syndrome; SMA, spinal muscular atrophy; ± present or absent.
Normal Seizures Focal lesions Regression Developmental delay
Creatine phosphokinase Other
Less prominent Absent below lesion Below lesion
Less prominent Normal
Generalized; may be hemiplegic
↓ Acutely; ↑ ↓ ↓ Acutely; ↑ Normal Absent ±
Normal to ↑ Normal ↑ (Spasticity) ↓ Absent Present
Location
Deep tendon reflexes Strength Tone Level of consciousness Fasciculations Primitive reflexes, including Babinski Atrophy Sensation
Spinal Cord
Brain
Upper Motor Unit
Table 38-6. Distinguishing Features in Motor Weakness
Normal Facial involvement late
Symmetric for SMA; asymmetric for poliomyelitis
Present Normal
↓ To absent ↓ ↓ (Flaccid) Normal Present Absent
Anterior Horn Cell
Symmetric for GBS; asymmetric for mononeuritis; usually distal May be elevated Abnormal nerve conduction velocity Nerve biopsy
Present ±
↓ To absent (lost early) ↓ ↓ Normal Rare Absent
Peripheral Nerve
Normal Response to tensilon (myasthenia) Constipation, dilated pupils (botulism)
Symmetric
Absent Normal
Normal ↓ ↓ Normal Absent Absent
Neuromuscular Junction
Lower Motor Unit
↑ Tender muscles (myositis) Gower sign (dystrophies)
Symmetric; usually proximal
Present; pseudohypertrophy Normal
Normal to ↓ ↓ ↓ Normal Absent Absent
Muscle
Chapter 38 Hypotonia and Weakness
655
Initially
Brain Malformation
Spinal Cord Transection
Transverse Myelitis
Poliomyelitis
Spinal Muscular Atrophy
Spinal Cord Tumor
CT, computed tomography; EMG, electromyography; MRI, magnetic resonance imaging; MR, mental retardation; NCV, nerve conduction velocity.
Chronic progressive weakness
Proximal weakness Distal weakness Abnormal CT/MRI Abnormal NCV Abnormal EMG Acute onset weakness
Dysmorphism, malformation Seizures, MR, lethargy Motor/sensory level Hypotonia Hypertonia Reflexes increased Reflexes decreased
Hypoxic Ischemic Encephalopathy
Table 38-7. Common Causes of Hypotonia and Weakness
GuillainBarré
Myasthenia Gravis
Botulism
Inflammatory, metabolic myopathies
Decreased or normal
Myopathy
656 Section Six Neurosensory Disorders
Chapter 38 Hypotonia and Weakness
657
Hypotonic Newborn
History and exam... evaluate seizures, alertness, autonomic sx's
Yes
Signs of encephalopathy
No
Obtain head CT or MRI scan, observe course
CT/MRI abnl
Brain malformation Intrauterine infection Storage disease Intracranial hemorrhage
CT/MRI +/- abnl, increased reflexes, increased tone evolve
Static encephalopathy
Hypotonia without encephalopathy
CT/MRI nl, persistent hypotonia
Nonspecific generalized mild weakness
Motor/sensory level
Obtain, CPK, EMG, muscle biopsy
Sepsis CHF
Spinal cord transection
Anterior horn cell disease
CNS malformation mild HIE
Marked weakness
CK, EMG, muscle biopsy
Is mother weak? Yes
Neuromuscular junction disorder
Congenital myopathy
Myelodysplasia
Myasthenia or myotonic dystrophy
Myopathy
Connective tissue disorder
Tensilon test positive
Genetic testing for MyoD, maternal, EMG
Congenital myasthesia
Prader-Willi, Down syndromes
Myasthenia gravis
Myotonic dystrophy
Anterior horn cell disease
Figure 38-1. Approach to the hypotonic newborn. abnl, abnormal; CHF, congestive heart failure; CNS, central nervous system; CPK (CK), creatine phosphokinase; CT, computed tomography; EMG, electromyography; HIE, hypoxic-ischemic encephalopathy; MRI, magnetic resonance imaging; MyoD, myotonic dystrophy; nl, normal; sx, signs.
the infants, however, signs of spasticity or dyskinetic movements develop, and these children represent the more common cases of spastic cerebral palsy and dyskinetic cerebral palsy. The diagnosis is established by a nonprogressive but often evolving clinical course, with supportive evidence provided by the perinatal history, fetal heart rate monitoring, acid-base status of the fetus, Apgar scores, and pathologic conditions of placenta. Important intervention issues include physical therapy, referral for early services, special education, nutritional counseling, prevention of contractures, and adaptive equipment. Brain Malformations
Brain malformation can arise as a result of a chromosomal disorder, as a component of a multiple malformation syndrome, or as an isolated abnormality. When associated with chromosomal disorder or multiple malformation syndromes, the other associated features are the primary clues to diagnosis. In isolated brain malformation, the primary features are microcephaly (in most cases) and cognitive and motor developmental impairment. The MRI scan can detect abnormalities of development of the hemispheric structures (agenesis of the corpus callosum, holoprosencephaly), abnormalities of cortical cellular migration (lissencephaly, pachygyria), and cerebral heterotopias as well as brainstem and cerebellar malformations.
Uncommon Disorders Progressive Encephalopathies of Infancy
Progressive encephalopathies of infancy account for a small number of children with persistent hypotonia (see Chapter 32). These disorders are recognizable by a progressive deterioration of neurologic function and by diagnostically specific clues. The infant’s development is normal for some time and then plateaus; this is followed by developmental regression, with loss of previously acquired skills (see Chapter 32). Hypotonia is a feature of many of these disorders, at least at some point during the course of the illness (Tay-Sachs disease), and some disorders feature hypotonia as the result of the combination of central nervous system injury and an associated polyneuropathy (Krabbe and metachromatic leukodystrophies). Progressive disorders that may be associated with hypotonia include neonatal adrenoleukodystrophy, mannosidosis, fucosidosis, Gaucher disease types 2 and 3, GM1 gangliosidosis, infantile neuroaxonal dystrophy, infantile Refsum disease, Krabbe leukodystrophy, metachromatic leukodystrophy, mucolipidosis type IV, and Tay-Sachs disease. The diagnosis of these disorders is based on recognition of clinically suggestive clues and on results of specialized biochemical and molecular genetic testing (see Chapter 32). If such a disorder is suspected, the infant should be referred to appropriate genetic and neurologic specialists.
Section Six Neurosensory Disorders
658
Natural course of weakness
Static or progressive weakness
Intermittent weakness
Obtain EMG, CK
CK nl/mild abnl, EMG myopathic
CK markedly elevated, EMG myopathic
Muscle biopsy dystrophic, absent dystrophin
Muscle biopsy dystrophic, deficient dystrophin
Duchenne muscular dystrophy
Becker muscular dystrophy
CK nl/mild abnl, EMG myotonic
Muscle biopsy inflammatory
Muscle biopsy myopathic, dystrophin normal
Polymyositis
Evaluate distribution of weakness
Generalized weakness
Exercise intolerance, cramps
Periodic paralysis
Carnitine palmitoyl transferase deficiency
Mitochondrial myopathies
Myoadenylate deaminase deficiency
Dermatomyositis
Limb-girdle dystrophy, congenital myopathy
Yes
Defects of carbohydrate utilization
Myotonic dystrophy, paramyotonia, myotonia congenita
Are the hips, shoulders primarily involved?
No
Facioscapular dystrophy, oculopharyngeal dystrophy
Figure 38-2. Diagnostic approach to the child with muscle disease. abnl, abnormal; CK, creatine kinase; EMG, electromyography; nl, normal.
Mitochondrial Diseases
Mitochondrial diseases often affect both the brain and muscle and clinically manifest hypotonia, probably as a combination of both cerebral dysfunction and myopathy (Tables 38-13 and 38-14). The diagnosis is based on recognition of clinical symptoms, presence of lactic acidosis, presence of ragged red fibers on muscle histologic examination, and mitochondrial abnormalities identifiable on a muscle electron microscopic examination. The diagnosis of many mitochondrial diseases is possible by specific mitochondrial DNA testing. Other inborn errors of metabolism may produce hypotonia by central mechanisms (organic acidurias, hyperammonemia) or by interfering with muscle metabolism (Table 38-15). Brain Malformation Syndromes Miller-Dieker Syndrome. A cortical malformation, lissencephaly, produces severe developmental impairment and hypotonia early in life, and hypertonia develops later. The facial changes include bitemporal hollowing, up-turned nares, thin vermilion boarder, and small jaw. Visible deletion of chromosome band 17p13.3 is seen in about half the affected patients. Walker-Warburg Syndrome. The combination of brain
malformation (polymicrogyria, cerebellar malformation) and an
associated congenital muscular dystrophy produces marked hypotonia in infancy.
THE HYPOTONIC OLDER CHILD CLINICAL EVALUATION Posture and Strength Observation of the child’s spontaneous posture may suggest the presence of weakness. Muscle strength can be observed as the child performs functional tasks, including pulling to sit spontaneously from a prone position, arising to stand from a sitting or lying position (Gower sign) (Fig. 38-7), standing on one leg independently, hopping, walking, running, and climbing stairs. The wheelbarrow maneuver can be used to functionally assess strength in the upper extremities. In the child older than 5 years, manual muscle testing can be performed if the child is cooperative (see Table 38-8). The examiner evaluates each muscle group independently, comparing the child’s muscle strength in resistance to the examiner’s. The child with muscle weakness has difficulty performing motor tasks and may exhibit unusual postures (lordosis) or might manifest the Gower maneuver (see Fig. 38-7) or toe-walking and, on manual muscle testing, may be easily overcome by the examiner’s strength.
Chapter 38 Hypotonia and Weakness
659
Acute weakness, no seizures, no lethargy
Is there loss of sensation?
Yes
No Decreased/nl Motor unit disease
Are the reflexes increased or decreased? Increased
Yes
Are reflexes absent?
Sensory level, paraparesis, bowel and bladder involvement
No Weakness asymmetric, systemic illness, CSF pleocytosis
Poliomyelitis (anterior horn)
Muscle or neuromuscular junction disease
Yes
Distal sensory loss, symmetric weakness, facial weakness
Postinfectious polyneuropathy (Guillain-Barré), tick paralysis
Is there ocular or bulbar involvement? No Proximal weakness, elevated CK
Inflammatory myopathy
Spinal cord MRI:
Neuromuscular junction disorder:
Botulism
Myasthenia gravis
Organophosphate poisoning
Spinal cord tumor
Epidural abscess
Transverse myelitis
Figure 38-3. Diagnostic approach to the child with acute weakness. CSF, cerebrospinal fluid; CK, creatine phosphokinase; MRI, magnetic resonance imaging; nl, normal.
Passive Tone Passive muscle tone is more consistent during the waking hours in the child than in the infant. The major joints should be moved through a range of motion and the extent of resistance noted. Flapping the distal extremities provides a useful clue. Lifting the lower extremity briskly at the knee while the patient lies supine is a useful test of muscle tone. In the normal child, the foot briefly drags along the examination table, then rises with the leg. In the hypertonic
child, the leg remains extended stiffly at the knee. In the hypotonic child, the lower leg hangs limply and the foot drags as the knee is raised. Joint Extensibility The hypotonic child demonstrates hyperextensibility of joints, especially at the elbows, wrists, knees, and ankles. Examination of the small muscles of the fingers may also be helpful.
Section Six Neurosensory Disorders
660
A
Figure 38-4. Disorders of the lower motor neuron: anatomical approach. (From Dubowitz V: Muscle Disorders in Childhood, 2nd ed. London, WB Saunders, 1995, p 2.)
DIAGNOSTIC APPROACH The diagnosis of a particular neurologic disorder depends on the location of the lesion (i.e., which part of the nervous system is impaired or abnormal), the patient’s age, and whether the condition is progressive or static (see Tables 38-1 and 38-6). Figure 38-2 outlines an algorithm for determining the cause of muscle weakness in a child (see also Tables 38-2 to 38-5). ANATOMIC LOCALIZATION The initial approach is to identify the location of dysfunction along the axis of the nervous system. Disorders of the cerebral cortex commonly cause hypotonia in infants and children. Some progressive neurologic disorders affect both the brain and peripheral nerves (metachromatic leukodystrophy, a lipid storage disorder and some mitochondrial disorders). Other progressive disorders may affect both brain and muscle (Walker-Warburg syndrome, neonatal myotonic dystrophy, and some mitochondrial disorders). Sometimes disturbance of function at one site conveys a predilection for injury to another site in the nervous system. Children with
Table 38-8. Grading Muscle Strength
0: No contraction 1: Minimal contraction only 2: Moves in horizontal plane but not against gravity 3: Moves against gravity but not against resistance 4: Moves against gravity and minimal resistance 5: Moves against gravity and full resistance
B
Figure 38-5. Werdnig-Hoffmann disease: characteristic postures. Sixweek-old (A) and 1-year-old (B) infants with severe weakness and hypotonia from birth. Note the frog-leg posture of the lower limbs and internal rotation (“jug-handle”) (A) or external rotation (B) at shoulders. Intercostal recession is especially evident in B, and facial expressions are normal. (From Volpe J J [ed]: Neurology of the Newborn, 3rd ed. Philadelphia, WB Saunders, 1995, p 609.)
congenital muscle weakness (congenital myopathy) are likely to have had severe respiratory impairment at birth that resulted in secondary anoxic injury to the brain. Because hypotonia is nonspecific with regard to localizing the site of nervous system dysfunction, the evaluation of the child with hypotonia must begin with a search for other clues that might identify the location of the abnormality. IS THE PROBLEM A SYSTEMIC DISORDER? Systemic disorders (see Table 38-1) are a common cause of generalized hypotonia in infants and even in toddlers and children. Hypotonia is commonly seen in association with sepsis and other infections, heart failure, failure to thrive, hypercalcemia, renal failure, hypothyroidism, acidosis, hypoxia, hyperammonemia, hypoglycemia, rickets, scurvy, amino and organic acid disorders, severe malnutrition, and other chronic disorders. This observation warrants a careful search for a systemic or metabolic abnormality in children with hypotonia, particularly (but not exclusively) when the onset of hypotonia is acute (see Table 38-3 and Fig. 38-3). Most of these disorders cause hypotonia by causing a disturbance of cerebral cortex function. Frequently overlooked causes of hypotonia are those that are not traditionally considered neurologic disorders. Connective tissue disorders often produce a clinical picture similar to those of neurologic causes of hypotonia in infancy and early childhood, with associated delay of developmental milestones (velocardiofacial syndrome, achondroplasia, Marfan syndrome, Ehlers-Danlos syndrome). In several congenital disorders, hypotonia is a regular feature as a result of a combination of abnormalities of neurologic, muscle, and connective tissue function, including Sotos syndrome, Prader-Willi syndrome, Angelman syndrome, Noonan syndrome, Rett syndrome, and Smith-Lemli-Opitz syndrome.
Chapter 38 Hypotonia and Weakness
661
Table 38-9. Major Causes of Arthrogryposis Multiplex
Congenita Site of Major Pathologic Findings
Cerebrum
A Anterior horn cell
Peripheral nerve or root Neuromuscular junction Muscle
B Figure 38-6. Werdnig-Hoffmann disease: clinical manifestations of weakness of limb and axial musculature in a 6-week-old infant with severe weakness and hypotonia from birth. Note the marked weakness of the limbs and trunk on ventral suspension (A) and of the neck (B) on pull to sit. (From Volpe J J [ed]: Neurology of the Newborn, 3rd ed. Philadelphia, WB Saunders, 1995, p 609.)
Primary disorder of joint and/or connective tissue Intrauterine mechanical obstruction
Disorder
Microcephaly; migrational disorders: lissencephalypachygyria (e.g., Zellweger syndrome), polymicrogyria, agenesis of corpus callosum; fetal alcohol syndrome; cytomegalovirus infection; leptomeningeal angiomatosis; encephaloclastic processes: porencephalies, hydranencephaly, multicystic encephalomalacia; hydrocephalus Developmental agenesis/hypoplasia/ dysgenesis (amyoplasia congenita); Werdnig-Hoffmann disease; X-linked spinal muscle atrophy; Möbius syndrome; cervical spinal atrophy; lumbar spinal atrophy; lumbosacral meningomyelocele; sacral agenesis; other Hypomyelinative polyneuropathy; axonal (?) polyneuropathy; neurofibromatosis Infant of myasthenic mother; congenital myasthenia; infant of mother with multiple sclerosis(?) Congenital muscular dystrophy; congenital myotonic dystrophy; myotubular myopathy; central core disease; nemaline myopathy; congenital polymyositis, congenital fiber type disproportion; glycogen storage myopathy (muscle phosphorylase deficiency, phosphofructokinase deficiency) Marfan syndrome; other disorders of connective tissue; intrauterine periarticular inflammation Uterine abnormality; amniotic bands; oligohydramnios; twin pregnancy; extrauterine pregnancy
Diagnostic Considerations Any child with hypotonia and weakness should be evaluated for a systemic disorder. Laboratory evaluation, such as electrolyte measurements, renal function tests, thyroid function tests, and acid-base balance assessment, should be considered for common metabolic disorders. Laboratory evaluation should also be considered for uncommon metabolic disorders in children with chronic hypotonia, especially those with other neurologic findings and those with recurrent bouts of lethargy, pronounced hypotonia, vomiting, or acidosis. Appropriate metabolic screening tests include plasma and urine amino acid quantification, urine organic acid quantification, and measurements of blood ammonia, blood lactate, and pyruvate. Cytogenic studies should be done for any hypotonic child who additionally demonstrates microcephaly, growth retardation, congenital malformations, dysmorphism, global developmental delay, or features of specific disorders (Down or Prader-Willi syndrome). Connective tissue disorders should be considered, especially if joint hyperextensibility and hypotonia are disproportionate to the extent of weakness and in the absence of other neurologic abnormalities or microcephaly (see Table 38-2). The diagnosis of these
From Volpe JJ (ed): Neurology of the Newborn, 3rd ed. Philadelphia, WB Saunders, 1995, p 600.
disorders is generally based on clinical criteria, but molecular genetic testing is becoming increasingly available. If unusual neurologic or dysmorphic features are present, specific disorders, such as Rett syndrome, Angelman syndrome, Prader-Willi syndrome, Noonan syndrome, Sotos syndrome, and fragile X syndrome, must be considered. Common Disorders Down Syndrome
The child with Down syndrome generally has recognizable features, including microcephaly, up-slanted palpebral fissures, epicanthal folds, a flat nasal bridge, a protuberant tongue, excess posterior
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chromosome 15q11-q13 of paternal origin, and 20% to 25% have maternal disomy. Because the clinical findings are nonspecific during the early months, such testing should be performed in any neonate or infant with hypotonia of unknown cause. Important intervention issues include genetic counseling, referral for early services, special education, nutritional counseling, behavior management, and monitoring for medical complications of the disorder, including glucose intolerance and complications of morbid obesity.
Table 38-10. Clinical Features of Congenital Myotonic
Dystrophy % of Cases Exhibiting Feature
Clinical Feature
Reduced fetal movements Polyhydramnios Premature birth (50%) have febrile convulsions; 13% have acute symptomatic seizures other than febrile convulsions; 8% have single, unprovoked seizures of unknown cause; and 25% have chronic epilepsy. The incidence of acute symptomatic seizures is highest in the first year of life; the most common causes of these predominantly neonatal seizures are infection and metabolic insults. After age 4 years, head injury is the most common cause of acute symptomatic seizures, and infection is the next most common. The incidence of recurrent unprovoked seizures among children younger than 15 years has been estimated to be between 45 to 85 per 100,000 in developed countries. It is highest in younger children; in those younger than 1 year, it is about 100 per 100,000. The prevalence of active epilepsy—patients taking antiepileptic drugs (AED)—is between 4.3 and 9.3 per 1000, or about 0.5% to 1% of the population. Between 60% and 80% of children with epilepsy have no identifiable etiologic factors for the disease. Population-based studies report the following presumed causes for 23% of children with symptomatic epilepsy: developmental (epilepsy in association with neurologic abnormalities present since birth) in 13%; infection in 673
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674 Table 39-1. Classification of Seizures
Partial Seizures Simple partial seizures With motor signs With somatosensory or special sensory symptoms With autonomic symptoms or signs With psychic symptoms Complex partial seizures Simple partial onset followed by impairment of consciousness, with or without automatisms With impairment of consciousness at the onset, with or without automatisms Partial seizures, secondarily generalized seizures Simple partial, complex partial, or simple to complex partial before generalizing; the evolution may be to generalized tonic-clonic, tonic, or clonic seizures Generalized Seizures Absence seizures Simple, complicated, atypical Myoclonic seizures Clonic seizures Tonic-clonic seizures Tonic seizures Atonic seizures Unclassified Epileptic Seizures From: Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for Revised and Clinical Electroencephalographic Classification of Epileptic Seizures. Epilepsia 1981;22:489-501.
An aura is the portion of a seizure that is experienced before loss of consciousness. The aura that precedes a complex partial seizure is itself a simple partial seizure. An aura may be suspected if there is a change in behavior before seizures, such as interrupting an activity to seek out parents or complaining of an epigastric discomfort. Automatisms are semipurposeful movements that usually occur with impairment of consciousness either during or after an epileptic seizure. They may be a perseveration of an activity in progress at ictal onset or novel semipurposeful movements arising during the seizure. They are most often a mixture of masticatory, oral, and lingual movements and simple fragmentary limb movements, such as fidgeting with a held object or pulling at clothing. In infants, oroalimentary automatisms are more likely than gestural automatisms and must be distinguished from the normal behavior of infants. GENERALIZED SEIZURES Generalized seizures are defined as seizures in which the first clinical changes indicate initial involvement of both hemispheres. Motor involvement, if present, is bilateral, as are the initial EEG changes. Consciousness is impaired in most generalized seizures but not in all; for instance, brief myoclonic seizures and some atonic seizures may not be associated with any impairment of consciousness. Absence seizures (“petit mal”) begin with sudden interruption of activity and with staring; they are usually brief and end abruptly without postictal confusion. Simple absence seizures consist of only motionlessness and a blank stare. Absence seizures are more typically accompanied by added motor features and may be referred to as complicated absence seizures. Clonic motor activity may occur, most often involving only the eyelids and facial muscles, but it may be manifested as generalized myoclonic jerks of the trunk and limbs. Changes in muscle tone are common; increased tone is usually maximal in the axial musculature and may be predominantly flexor or extensor, symmetric or asymmetric. Alternatively, there may be a
loss of muscle tone associated with the seizure, so that the head droops, objects are dropped, or the person slumps; falling is unusual. Automatisms may be seen in 40% to 50% of absence seizures and are more common in absence seizures of long duration. Lip smacking, swallowing, fumbling or searching hand movements, or ambulation can appear during the seizure, or preictal activities may be continued in a slow, automatic manner. Paroxysmal alterations in autonomic function may also accompany absence seizures, including pupillary dilation, pallor, flushing, sweating, salivation, piloerection, or a combination of these. Atypical absence seizures are described as absence seizures with a less abrupt beginning and end, with more pronounced changes in muscle tone, and of longer duration. Table 39-2 is a comparison of the clinical features of absence seizures, complex partial seizures, and episodic daydreaming. Tonic-clonic seizures are perhaps the most dramatic of the epileptic seizures. The tonic phase begins with sudden sustained contraction of facial, axial, and limb muscle groups, and there may be an initial involuntary stridorous cry or a moan secondary to contraction of the diaphragm and chest muscles against a partially closed glottis. The tonic contraction is maintained for seconds to tens of seconds, during which time the child falls if standing, is apneic and may become cyanotic, may bite the tongue, and may pass urine. The clonic phase of the seizure begins when the tonic contraction is repeatedly interrupted by momentary relaxation of the muscular contraction. This gives the appearance of generalized jerking as the contraction resumes after each relaxation. At the end of the clonic phase, the body relaxes and the patient is unconscious with deep respiration. If roused, the patient is confused, may complain of muscle soreness, and usually wishes to sleep. The tonic-clonic sequence and the unconscious postictal state are very important historical points in the differential diagnosis of psychogenic convulsive events and epileptic tonic-clonic seizures. Myoclonic jerks are sudden, brief, shocklike contractions of muscles. They may involve the whole body or a portion of the axial musculature such as face and trunk, or they may be limited to the limbs. They can be isolated or repetitive, irregular or rhythmic. Myoclonus may arise from cortical, brainstem, and spinal cord neuronal groups. Some forms of myoclonus of brainstem or spinal origin occurring without other seizure types are not regarded as epileptic myoclonus but thought of as movement disorders. Generalized clonic seizures may occur without a preceding tonic phase, and the postictal phase is usually shorter than for tonic-clonic seizures. Generalized tonic seizures begin in the same way as tonic-clonic seizures. The tonic contraction subsides without the intervening relaxation-recontraction clonic phase. The extent of muscle involvement may vary from patient to patient and from seizure to seizure in a single patient. A massive generalized contraction produces facial grimacing, neck and trunk flexion or extension, abduction of the arms, and flexion of the hips. Subtle tonic seizures may produce only facial grimacing and slight neck and trunk flexion. Tonic seizures may be accompanied by pronounced autonomic activity with diaphoresis, flushing, pallor, and tachycardia even when the muscular contraction is slight. Atonic seizures are characterized by a sudden decrease or loss of postural muscle tone. The extent of muscle involvement may vary; an atonic seizure may be limited to a sudden head drop with slack jaw or may result in a fall because of loss of axial and limb muscle tone. The falls are referred to as “drop attacks,” and because they are unprotected, they often result in injury. Status epilepticus exists when epileptic seizures are prolonged or are frequently repeated without recovery between the seizures. The time most often defined is 30 minutes or longer, but seizures continuing for more than 5 to 10 minutes warrant immediate attention. Status epilepticus is most commonly characterized as convulsive or nonconvulsive status epilepticus. Convulsive status epilepticus may involve repetitive or prolonged generalized tonic-clonic, myoclonic, or tonic seizures. Nonconvulsive status epilepticus may involve
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Table 39-2. Differential Diagnosis of Episodic Unresponsiveness without Convulsions Clinical
Absence Seizures
Complex Partial Seizures
Frequency
Multiple daily
Rarely more than 1-2 per day
Duration
Often 30 s
Aura Abrupt interruption of child’s activity
Not present Yes: e.g., speech arrest midsentence, pause while eating, playing or fighting Common, often with upward eye movement Common Occur in longer absences, usually mild Unresponsive None
Average duration >60 s, rarely PHT, 8-15 min 31-75 18-73
*Great variation, shorter if exposed to enzyme-inducing drugs (e.g., phenobarbital) and within first 2-3 week of life. †
Dosage is in PHT equivalents per kilogram.
‡
Can be given every 15 minutes to a maximum of 2 mg.
§
Up to two doses only.
IM, intramuscularly; IV, intravenously; PHT, phenytoin; PO, per os (orally); PR, per rectum.
Maintenance Dosage (mg/kg/day)
Therapeutic Range (mg/L)
3-5 IV: 8-10 PO: 18-20 18-20
10-30 5-20 5-20
3 NA
0.3-0.7 NA
Chapter 39 Paroxysmal Disorders potassium channel genes, KCNQ2 on chromosome 20 and KCNQ3 on chromosome 8, have been found in some kindreds (see Table 39-4). Pyridoxine-Dependent Seizures
This is a rare autosomal recessive disorder in which seizures usually appear within the first 3 months of life, often within hours of birth but, in rare cases, as late as 2 to 5 years of age. The EEG may show focal, multifocal and generalized epileptiform activity. The seizures, myoclonic, generalized tonic-clonic and partial, and EEG discharges disappear over hours in response to intravenous 50 to 100 mg of pyridoxine. The children require long-term pyridoxine, 50 to 100 mg/day. The outcome may nonetheless be poor, with developmental delay despite early treatment.
685 INFANCY
The paroxysmal disorders of infancy (8 weeks to 2 years) are shown in Table 39-12. Paroxysmal Nonepileptic Disorders Infantile Syncope Cyanotic Infant Syncope (Breath-Holding Spells).
Cyanotic infant syncope consists of episodes of loss of consciousness followed by tonic stiffening in crying infants (see Chapter 6). These episodes have also been called breath-holding spells, anoxic
Symptomatic Focal Epilepsy Table 39-12. Paroxysmal Disorders in Infants
Malformations of Cortical Development. Disorders of cell
Nonepileptiform Disorders Infantile syncope* Cyanotic breath-holding spells Pallid syncope Shivering attacks Paroxysmal torticollis Extrapyramidal drug reactions, dystonia Gastroesophageal reflux with dystonia† Rumination† Stereotypic movements, autism, Rett syndrome, coexisting deafness and blindness† Withholding, constipation† Masturbation Spasmus nutans Opsoclonus Benign paroxysmal vertigo Myoclonus Nonepileptic; anxiety, excitement, acute metabolic encephalopathy Benign myoclonus of early infancy Hyperexplexia† Alternating hemiplegia of childhood Sleep disorders* Jactatio capitis, head banging
migration within the CNS may result in profound anatomic abnormalities and dysfunction or a spectrum of lesser abnormalities, ranging from focal areas of cortical dysgenesis and clinical deficits to subcortical collections of neurons (heterotopia) seen only under the microscope. Migrational abnormalities are rare but are commonly associated with seizures. Lissencephaly, or agyria, is a profound abnormality characterized by a smooth brain without development of the normal gyral pattern and sulci; there are often large heterotopia in the white matter, and neuroimaging studies may reveal the appearance of a “double cortex.” Hemimegalencephaly is characterized by gross enlargement of one hemisphere with no normal cortical development within that hemisphere and by often recognizable MRI scan abnormalities in the normal-sized hemisphere. More restricted abnormalities may occur in the form of a limited area of gyral enlargement and distortion called pachygyria. Schizencephaly refers to unilateral or bilateral clefts in the cerebral hemispheres, usually with abnormal arrangement (polymicrogyria) of the cortical gray matter lining the clefts. Porencephaly refers to fluid-filled cavities within the brain. Porencephalic cysts communicate with both the subarachnoid space and the ventricular system and are lined not by cortical gray matter but rather by gliotic tissue, because they result from loss of tissue as a consequence of insults, typically infarction, during development.
Acute Symptomatic Seizures, Occasional Seizures Febrile convulsions* Meningitis, encephalitis* Head injury, child abuse Poisoning Intercurrent medical illness, renal, liver disease, cardiac left-to-right shunt and embolism Metabolic disease, rickets
Early-Onset Generalized Epileptic Syndromes with Encephalopathy
Early myoclonic encephalopathy appears in neonates before 2 to 3 months of age, usually within the first 2 weeks of life. Myoclonus appears at the onset but may be fragmentary. Partial motor seizures, massive myoclonus, or infantile spasms may also occur. The EEG does not show hypsarrhythmia; rather, it shows a suppression-burst pattern that may later evolve into a hypsarrhythmic pattern. There is a failure or arrest of psychomotor development and a high rate of mortality before 12 months of age. A number of patients have had nonketotic hyperglycemia or congenital malformations of the nervous system. Familial cases with an identifiable inborn error of metabolism (glycine encephalopathy, D-glycericacidemia, propionic acidemia, methylmalonic acidemia) have also been reported. Early epileptic encephalopathic with suppression-burst EEG pattern (Ohtahara syndrome) has an onset during the same period. The affected child experiences intractable tonic seizures or epileptic spasms, and the EEG shows a suppression-burst pattern. Affected children have a severe encephalopathy, and the prognosis for remission from seizures or for normal development is very poor. Many of these patients have malformations of cortical development. There appear to be neonates in whom the EEG features and clinical course of these two syndromes overlap; these syndromes may evolve into West syndrome and the Lennox-Gastaut syndrome.
Epileptic Syndromes Symptomatic focal epilepsy† West syndrome Early myoclonic encephalopathy‡ Early infantile encephalopathic epilepsy‡ Malformations of cortical development‡ Neurocutaneous disorders (see Tables 39-1 and 39-3) Tuberous sclerosis Sturge-Weber syndrome Incontinentia pigmenti Epidermal nevus syndrome Severe myoclonic epilepsy in infancy *Common. †
See childhood section for discussion.
‡
See neonatal section for discussion.
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seizures, and convulsive syncope, but cyanotic infant syncope may be a better term because the loss of consciousness appears to be the result of transient impairment of cerebral perfusion. The subsequent tonic posturing in the typical attack is not epileptic but is thought to have the same brainstem origin as decerebrate or decorticate posturing. In rare cases, typical infant syncope may evolve into a true but short generalized tonic-clonic seizure or, in rare cases, status epilepticus, presumably triggered by the anoxia. Cyanotic infant syncope is common, seen in 4.6% of a large cohort of children monitored from birth, and can be mistaken for tonic-clonic seizures. A thorough history is usually sufficient for diagnosing this condition. The peak incidence is between 6 and 18 months of age, but it may occur in neonates or in children as old as 6 years of age. The typical clinical picture is an infant who is frightened, frustrated, or surprised; begins to cry vigorously; and then becomes apneic and cyanotic before becoming unconscious, stiff, or limp. The crucial diagnostic point is the history of an external event precipitating the episode. The striking features that are so easily confused with an epileptic seizure are the tonic posture or the clonic movements that may occur after the child has lost consciousness. The child regains consciousness rapidly, after being positioned horizontally, without a prolonged postictal state, although there may be a tendency to sleep. The differential diagnosis is noted in Table 39-13. Although the spells appear to be unpleasant for the child, they do not result in late sequelae and do not necessitate intensive investigation. The child should be evaluated for anemia; treatment of iron deficiency anemia reduces the frequency of syncopal events. Treatment with carbamazepine, phenytoin, or valproate may decrease the frequency or severity of postsyncopal convulsions in the rare child with epileptic seizures triggered by the anoxic event.
Pallid Infant Syncope. Pallid infant syncope occurs in response
to transient cardiac asystole in children with a hypersensitive cardioinhibitory reflex. This form is less common but more alarming. There is minimal crying, perhaps only a gasp, and no obvious apnea before the loss of consciousness. Again, there is a precipitating event; the child appears to lose consciousness after minimal injury or fright, collapses limply, and then may have posturing and clonic movements before regaining consciousness (see Table 39-13). Pallid infant syncope, if frequent and troublesome or if followed by prolonged generalized tonic-clonic convulsions, can be treated with atropine, which blocks the vagus nerve–mediated asystole. Most affected children require no medical treatment.
Sleep Disorders
Also referred to as head banging or rocking, jactatio capitis nocturna consists of rhythmic to-and-fro movements of the head or rocking of the body. It occurs typically at the transition from wakefulness to sleep, early in the evening or after arousal during the night. This behavior is quite common, occurring in up to 15% of children; it begins in infancy or early childhood but may persist up to 10 years of age. The child is not awake during the episode and does not remember the events, which usually last less than 15 minutes. Clonazepam at bedtime may be helpful if the episodes are prolonged, threaten to injure the child, or appear to be interfering with normal sleep patterns. In most cases, it is sufficient to ensure that the bed area is padded to prevent injury.
Table 39-13. Differential Diagnosis of Infantile Syncope Clinical
Infantile Syncope
Pallid Syncope
Age range Precipitating factors Occurrence in sleep Sequence of events
1-6 yr; peak, 6-18 mo Present (e.g., minor trauma, frustration, fright) Never
1-6 yr Present (e.g., minor trauma, frustration, fright) Never
Postictal symptoms
Usually minimal; infant may be lethargic and irritable
Usually minimal; quick return to normal
Interictal EEG
Normal
Normal
Ictal EEG
Reflects global cerebral hypoxia, diffuse rhythmic slowing → suppression → slowing with return of consciousness
Pathophysiology
Respiratory arrest without asystole
Reflects global cerebral hypoxia; diffuse, rhythmic slowing → suppression → slowing with return of consciousness Vagal bradycardia or temporary asystole
Crying → exhale; apnea → Upset, usually not crying → cyanosis, loss of conscious- sudden pallor → limp fall ness; opisthotonos → with fainting → tonic relaxation, resumption of posture, or clonic jerks breathing may occur
CNS, central nervous system; EEG, electroencephalogram.
Tonic-Clonic Seizures
Infantile Spasms
All ages Usually none
4-12 mo None
Common
At transition from awake to sleep and sleep to awake Sudden sustained flexion or extension of proximal limbs and trunk; duration, 2-20 s; seizures usually occur multiple times daily
Sudden loss of consciousness → increased tone, followed by synchronous jerking of body and limbs → unconsciousness; duration, 1-2 min Usually marked; Rapid return to unconsciousness preictal state initially, then confusion and lethargy Frequently abnormal Abnormal background with epileptiform and epileptiform discharges discharges EEG seizure High-amplitude patterns; postictal slow transient diffuse suppression, waves → diffuse then slowing suppression
Primary CNS event
Primary CNS event, agerelated epileptic seizure
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Shivering Attacks
Benign Paroxysmal Vertigo
Shivering or shuddering attacks are brief episodes characterized by sudden flexion of the head and trunk associated with a rapid tremulous contraction of the musculature. The appearance is exactly that of a sudden brief shudder experienced normally when exposed to cold. In this condition, however, the shuddering occurs repeatedly. Some infants experience more than 100 brief shudders per day. There may be clustering, with intervals of several weeks free of the episodes. The child may assume a characteristic posture with flexion of head, trunk, and elbows and adduction of elbows and knees. The attacks have been described in children between the ages of 4 months and 10 years, although most often the onset seems to occur in infancy and early childhood. The phenomenon is nonepileptic and benign, eventually disappearing. Some children and their relatives have been reported to have an essential tremor. The shuddering is faster and of lower amplitude than myoclonus and is paroxysmal, not sustained, as occurs with a tremor.
Benign paroxysmal vertigo may be confused with seizures, because attacks develop suddenly, are accompanied by ataxia, and may cause the infant to fall. There is pallor, distress, and assumption of a motionless, often supine, position but no loss of consciousness; older children can recall the event. There may be vomiting; nystagmus should be visible during the episode. Attacks last seconds to minutes and vary in frequency, sometimes occurring daily. Older children can identify symptoms of nausea and vertigo and are less likely to be thought to be experiencing seizures. The children are normal between attacks. The condition is closely related to migraine, with many shared symptoms and the later development of more typical migrainous headache. Treatment for repeated attacks may include dimenhydrinate.
Paroxysmal Torticollis
Torticollis is an abnormal posturing of the head and neck, with the head flexed toward the shoulder and the neck rotated with the chin turned toward the opposite shoulder. The posturing is paroxysmal, although variable in duration, lasting minutes or days, and there is no loss of consciousness. Some children have associated pallor, agitation, and vomiting, and the disorder has been suspected to result from labyrinthine dysfunction, like benign paroxysmal vertigo of childhood. The disorder is self-limited and remits in early childhood. There is an association with migraine in patients later in life and among their relatives. There are various causes of torticollis (see Chapter 52). In older children, torticollis may occur as a focal dystonia persisting to adulthood. Familial cases have been described, and in some, the torticollis may be the earliest manifestation of a more generalized dystonia. Sustained abnormal posturing should prompt appropriate radiologic investigations to exclude inflammatory or neoplastic disorders of the upper cervical spinal cord, posterior fossa, cervical spine, or soft tissues of the neck. In very rare cases, gastroesophageal reflux manifests with dystonic posturing of the neck and upper trunk. Adverse extrapyramidal reactions to phenothiazines and related drugs may produce dystonic posturing of the neck and trunk. Masturbation
Episodes of genital self-stimulation may occur in young children. Infant girls may assume stereotyped posturing with tightening of the thighs or applied pressure to the suprapubic or pubic area, not associated with manual stimulation of the vulva or rhythmic movements. The episodes vary in duration from minutes to hours and are often accompanied by irregular breathing, facial flushing, and diaphoresis. Spasmus Nutans
Spasmus nutans is a rare disorder of unknown origin characterized by nystagmoid eye movements, head nodding, and torticollis. Head nodding may develop before the nystagmus and can be horizontal, vertical, or mixed. Both the head movements and the nystagmus may be paroxysmal, allowing confusion with seizures. There is no loss of consciousness during an episode. Small-amplitude rapid eye movements are typical; they tend to be asymmetric between the eyes and may even be monocular. The eye movements vary in prominence with different directions of gaze (see Chapter 43). This is a self-limited disorder with onset between 4 and 18 months of age and not persisting after age 3 years, although nystagmus alone may persist in some children. Investigations should include imaging of the brain, optic nerves and chiasma, because some cases have been associated with CNS tumors.
Benign Myoclonus of Early Infancy
This uncommon syndrome may resemble the cryptogenic form of infantile spasms at onset, with bilateral myoclonic jerks developing in a previously normal infant. However, this is a benign, probably nonepileptic condition occurring in infants 3 to 8 months of age and disappearing after a period of weeks or months. The pattern of myoclonus may differentiate it from infantile spasms, including predominant involvement of the head, neck, and upper limbs with adversive head movements or tremors without involving the lower limbs. The EEG is normal. Myoclonic movements are not accompanied by an EEG seizure pattern. These abnormal movements may necessitate monitoring to establish the nonepileptic diagnosis. There is no arrest of normal development or regression as is seen in West syndrome. Most important, the myoclonus remits, not persisting after 2 years of age, and there is increased risk for other seizure patterns after its cessation. Alternating Hemiplegia of Childhood
Alternating hemiplegia of childhood is a rare syndrome of episodic hemiplegia that usually manifests in infancy with the following diagnostic criteria: 1. onset before age 18 months, often before age 6 months 2. recurrent episodes of fluctuating hemiparesis or hemiplegia, affecting both sides of the body and disappearing during sleep 3. other paroxysmal phenomena: tonic seizures, dystonic posturing, choreoathetosis, nystagmus and other paroxysmal oculomotor disturbances, and autonomic dysfunction, occurring during or between hemiplegic episodes 4. progressive cognitive and neurologic deficits The pathophysiologic mechanism remains unknown, although there are reports of mitochondrial dysfunction in some cases and an autosomal dominant pattern of inheritance in others. The differential diagnosis includes paroxysmal choreoathetosis and dystonia syndromes, familial hemiplegic migraine, transient ischemic attacks associated with cerebral vascular abnormalities such as moyamoya disease or cardiac emboli, mitochondrial disorders, hyperviscosity, sickle cell anemia crises, inherited disorders of metabolism (pyruvate dehydrogenase deficiency and Leigh disease), and epileptic seizures with postictal paralysis (see Chapter 41). Symptomatic treatment is available with flunarizine, a calcium channel blocker. Acute Symptomatic Seizures and Occasional Seizures Febrile Convulsions
Febrile convulsions are common and are defined as seizures occurring between the ages of 6 months and 5 years in association with a fever in the absence of intracranial infection or other identifiable
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cause. Patients with a history of previous afebrile seizures are not included in the affected population. The temperature elevation is variable. The highest incidence of febrile convulsions occurs between 1 and 2 years of age, and 85% of febrile convulsions occur before the age of 4 years. The incidence is between 2% and 5%; it is slightly more common in boys. The seizures are usually brief with bilateral clonic or tonic-clonic motor involvement without any postictal paralysis or a prolonged postictal state of confusion or drowsiness. The seizures generally occur well within the first 24 hours of a febrile illness, not necessarily when the fever is highest; they may be the first indication of illness. Complicated or severe febrile convulsions are defined as those lasting longer than 15 minutes, recurring during a single febrile illness, having unilateral or focal features, or followed by postictal paralysis. Seizures occurring late in a febrile illness should raise suspicions of encephalitis, brain abscess, or meningitis. Abnormal behavior associated with a febrile delirium and even violent shivering may be mistaken for seizure activity. Evaluation. The initial investigation must include a search for the
cause of the febrile illness. For this diagnosis, it is essential that primary CNS infection be ruled out as the cause of both the fever and the seizures. It is suggested that children younger than 12 months of age should routinely have a lumbar puncture when presenting with a febrile seizure; many clinicians would not perform a lumbar puncture in an otherwise healthy child with an uncomplicated febrile seizure over the age of 2 years. A lumbar puncture must be performed if there is any suspicion of intracranial infection and when features of the seizure or postictal state suggest a focal or lateralized seizure (see Chapter 52). In a child with focal seizures, fever, and signs of encephalitis, herpes simplex must be suspected. Computed tomography or MRI and EEG may be part of the workup if an underlying CNS infection is suspected or a preexisting neurologic deficit has been revealed by the history. Treatment. Treatment of a child still in convulsion on arrival at the
hospital should include prompt attention to protection of the airway and circulation. Giving acetaminophen rectally should lower the fever. If the convulsion does not cease promptly with lowering of the fever, rectal diazepam should be administered. Some children may require hospital admission. The family should be advised that future fevers with temperatures above 38° C (100.4° F) be treated with regular acetaminophen or ibuprofen. There is no increased rate of mortality from febrile convulsions, and the mental and neurologic development can be expected to be normal after a simple febrile convulsion. However, approximately 30% of febrile convulsions recur in future febrile illness, and the parents should be warned of this. Recurrence is most likely in the first 6 to 12 months after the initial febrile convulsion. Other factors that increase the chance of recurrence are onset at a young age, preexisting neurologic abnormalities, and family history of epilepsy or febrile convulsions. Most authorities would advise no treatment for almost all children with febrile convulsions. Rare exceptions include children presenting with prolonged (>15 minutes) seizures and children younger than 12 months old with multiple recurrences. For prolonged seizures, rectal diazepam could be considered as an abortive therapy. For children with frequent recurrences, one option is rectal or oral diazepam during febrile illnesses. If these intermittent therapies are ineffective or impractical, chronic phenobarbital or valproate could be considered for the rare child with prolonged or very frequent febrile convulsions. Informing and reassuring parents of the benign nature and usual course of febrile convulsions are very important and may be of greater value than any medication. Prognosis. There appears to be an increased risk of epilepsy among children with febrile convulsions. Overall, the risk is approximately
3%. Risk factors increasing the likelihood of future epilepsy include existence of a prior neurologic abnormality, prolonged convulsions (>30 minutes), focal or lateralized features of the seizure, and repeated convulsions within 24 hours. The incidence of epilepsy increases from 4% of those without risk factors to 49% of those with three risk factors. Risk factors for epilepsy with generalized seizures are more than three febrile seizures and epilepsy in a first-degree relative, which suggests that febrile convulsions in these individuals may be a manifestation of an increased predisposition to epilepsy. For epilepsy with partial seizures, the risk factors are prolonged convulsions, focal features of the seizure, and repeated seizures within 24 hours, which suggest either a causative role for febrile convulsions in partial epilepsy or a preexisting brain lesion. The number of recurrences of febrile seizures has not been shown to be a risk factor for later epilepsy. There is no evidence that AED treatment of febrile seizures affects the risk for later development of afebrile seizures. Epileptic Syndromes West Syndrome
West syndrome, or severe encephalopathic epilepsy in infants, is characterized by infantile spasms, the hypsarrhythmic EEG pattern, and developmental delay. It is a severe form of epilepsy, usually with evidence of diffuse cerebral dysfunction and a poor prognosis in most cases. The incidence is about 1 per 4000 to 6000 infants, with onset between 3 and 12 months of age; peak onset is 4 to 8 months. The spasm is a brief bilateral tonic contraction of muscles of the trunk, neck, and limbs, usually symmetric. The extent of muscle involvement varies from a powerful contraction that “jackknifes” the body to minimal contraction of truncal muscles that causes only stiffening. The classic spasm, “salaam attack,” begins with a jerklike contraction of trunk and limb musculature, which is maintained for a few seconds. Spasms may involve truncal flexion, extension, or both. Eye movements are commonly associated with the spasm either as deviation or as repetitive nystagmoid jerks. Apnea is common but tachypnea is uncommon. Children may cry or even appear to giggle at the end of the spasm. The seizures occur daily, frequently with hundreds being recorded per 24-hour period, often clustered together. Seizures may increase during the transitions from sleep to wakefulness and wakefulness to sleep. Electroencephalographic Features. The hypsarrhythmic
EEG pattern is a high-amplitude, chaotic slowing of generalized distribution without interhemispheric synchronization and with multifocal sharp waves throughout. Hypsarrhythmia is more frequent in younger infants and early in the course of the disorder, and it is more common to find some modified variant of it. Differential Diagnosis. Differential diagnosis for the seizures themselves can include colic, exaggerated Moro reflexes, or normal myoclonic jerks on falling asleep or waking. Two myoclonic syndromes occur in this age group and must be distinguished from infantile spasms: (1) benign myoclonus of early infancy (see preceding “Infancy” section) and (2) benign myoclonic epilepsy. Benign myoclonic epilepsy is a rare syndrome described in previously normal infants with onset between 4 months and 3 years. The infant has brief repetitive myoclonic jerks that involve the head and upper limbs and rarely the lower limbs; they occur daily in drowsiness and wakefulness. The ictal EEG shows 3-Hz spike-andwave or polyspike activity during the events. The background EEG rhythms are normal. There are no other seizure types, and the infant does not have behavioral or cognitive disturbances. The long-term prognosis is favorable for development and remission of seizures after response to treatment with an AED. Some affected patients have had tonic-clonic seizures in adolescence.
Chapter 39 Paroxysmal Disorders An EEG pattern of suppression-burst activity heralds a poor prognosis, and some groups have proposed that infants with a consistent EEG pattern of this nature and a much earlier onset of seizures may have distinct epileptic syndromes separable from the majority of patients with West syndrome. These related syndromes, early infantile epileptic encephalopathy and early myoclonic encephalopathy, are discussed in the preceding “Infancy” section.
Table 39-14. Paroxysmal Disorders of Childhood
Nonepileptiform Disorders Breath-holding spells*† Syncope‡ Migraine and migraine equivalents, recurrent abdominal pain, cyclic vomiting* Tic* Spasmodic torticollis† Drug reactions, dystonia Paroxysmal choreoathetosis Gastroesophageal reflux Benign paroxysmal vertigo† Myoclonus, nonepileptic; anxiety, excitement, acute metabolic encephalopathy† Hyperexplexia Masturbation† Withholding, constipation* Daydreaming, staring spells* Stereotypic movements, autism, coexistent deafness and blindness Munchausen syndrome by proxy Hyperventilation‡ Psychogenic seizures‡ Transient global amnesia‡ Sleep* Head banging, jactatio capitis† Pavor nocturnus Somnambulism, somniloquy
Evaluation. Investigation of patients with infantile spasms is directed at determining the cause and then classifying the condition into cryptogenic and symptomatic groups. The most common etiologic factor found is perinatal hypoxic-ischemic insult. Other important associations include intrauterine infection, prematurity, intracranial hemorrhage, malformations of cortical development, tuberous sclerosis, head injury, CNS infection, and inborn errors of metabolism. Approximately 10% to 15% of patients have no identifiable underlying cause and a history of normal development before the onset of their illness; this subset is referred to as cryptogenic, or idiopathic, West syndrome. This subset of patients is likely to have a much better long-term outcome: 38% are normal or mildly impaired, in comparison with only 5% in the symptomatic patients. About 50% of infants go on to have other seizure types when spasms cease. Persistence of the epilepsy in most of the patients is associated with loss of the spasms and development of other seizure types, such as tonic seizures, simple partial seizures, and tonic-clonic seizures. Treatment. Treatment with corticosteroids aborts the spasms in a
significant number of infants. Regimens vary, including initial doses of adrenocorticotropic hormone or prednisone. The spasms should cease and the EEG patterns improve if the child has responded. After 1 to 2 weeks at maximum dosages, the corticosteroid is gradually decreased until it is discontinued altogether after 2 to 3 months. Vigabatrin may be effective for infantile spasms, and it has been shown to be particularly effective in the treatment of infantile spasms with tuberous sclerosis. Topiramate and lamotrigine are being evaluated for possible efficacy. Valproate, nitrazepam, and clonazepam may also be helpful. The combination of valproate and lamotrigine is often more efficacious than either medication used alone.
Acute Symptomatic Seizures, Occasional Seizures Febrile convulsions* Brain tumor Meningitis, encephalitis Head injury, child abuse Poisoning Intercurrent medical illness, renal, liver disease, cardiac right-to-left shunt, and embolism Metabolic disease, rickets Epileptic Syndromes Benign partial epilepsies* Symptomatic focal epilepsy* Epilepsia partialis continua Rasmussen encephalitis Hemiconvulsion hemiplegia syndrome Childhood absence epilepsy* Epilepsy with myoclonic absences Lennox-Gastaut syndrome Myoclonic astatic epilepsy Landau-Kleffner syndrome Epilepsy with continuous spike-and-wave patterns during slow-wave sleep
Severe Myoclonic Epilepsy in Infancy
Severe myoclonic epilepsy in infancy is a rare cryptogenic generalized epilepsy appearing in the first year of life. The syndrome differs from the myoclonic syndromes already described (early myoclonic encephalopathy and early infantile encephalopathic epilepsy) by its later onset and the EEG findings. A mutation of a voltage-gated sodium channel gene is seen in 30% of cases (see Table 39-4). The child may present with febrile or afebrile seizures, usually with normal psychomotor development preceding the onset of seizures, and often with a family history of epilepsy. The seizures are generalized or unilateral clonic seizures; myoclonic seizures appear later (and may not be a major feature of the disorder despite the name), between 8 months and 4 years of age; and partial seizures and atypical absences may occur. The interictal EEG may be normal initially and only later show fast, generalized spike-and-wave epileptiform discharges and focal abnormalities. The seizures are usually refractory to AEDs, and psychomotor development eventually becomes retarded. Ataxia and signs of pyramidal tract dysfunction may become apparent. CHILDHOOD The paroxysmal disorders of childhood (2 to 12 years) are given in Table 39-14.
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*Common. †
See infant section for discussion.
‡
See adolescent section for discussion.
Paroxysmal Nonepileptic Disorders Migraine and Migraine Equivalents
Migraine is a common disorder, and some episodes may be confused with seizures because of their paroxysmal nature and association with neurologic deficits or altered consciousness (see Chapter 37). In cyclic vomiting, recurrent attacks of nausea, vomiting, and abdominal pain occur on a daily or weekly basis. There is no
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clouding of consciousness. Typically, there are symptom-free intervals lasting weeks to months. Migraine may develop later, or there may be a strong family history of migraine, and there appears to be some overlap of the cyclic vomiting with migraine. Tic Disorders
Tics are common. They are sudden, brief, purposeless involuntary movements or utterances that occur repetitively (see Chapter 35). Tics may be thought to be myoclonic seizures, and, indeed, some tics may have a rapid myoclonic character. Myoclonus cannot be suppressed by the patient, may have an ictal EEG correlate, and may be associated with other seizure types. Table 39-15 outlines some of the clinical features of episodic abnormal movements that may appear in children. Sleep Disorders Night Terrors and Confusional Arousals. Night terrors are a
common phenomenon in children and are most frequent in boys aged 5 to 7 years. Up to 15% of children younger than 7 years have experienced some form of these episodes. The attacks are characterized by sudden arousal from sleep, often screaming in terror, and then crying with agitation and tachycardia. There may be vigorous and potentially injurious motor activity in older children, such as running
or hitting the bed or wall. The striking feature of these episodes is that the child is inconsolable but seemingly awake. The episodes arise out of slow-wave non–rapid eye movement sleep, usually occurring 1 to 2 hours after bedtime, and are not responses to dream imagery (i.e., not nightmares). Episodes last several minutes. Prior sleep deprivation, febrile illness, emotional stress, and some medications (sedatives/hypnotics, neuroleptics, stimulants, antihistamines) may be precipitants. In contrast to the experience of nightmares, children are amnestic for the events and their distress in night terrors. Confusional arousals are less dramatic attacks with similar origin from slow-wave sleep and are more typical in younger children. The affected child stirs and begins crying and whimpering inconsolably. These arousals may be prolonged in infants, lasting up to 30 to 40 minutes. There is no specific treatment for these events; parents should be educated about the nature of these arousals and reassured that they are self-limited. Although efforts to calm the child may seem to prolong the attacks, it is probably best if a parent sits with the child, if only to prevent injury. Frequent disruptive attacks or those with potentially injurious motor activity may be decreased by short-term treatment with low-dose tricyclic antidepressants or benzodiazepines. Somnambulism. Somnambulism, or sleepwalking, is common in
childhood: Approximately 15% of children have walked in their sleep, especially in the 2- to 3-year-old age group, and 2.5% are habitual
Table 39-15. Abnormal Involuntary Movements Movement
Tics
Tremor
Chorea Athetosis
Dystonia
Myoclonus Ballismus Asterixis Dyskinesia
Characteristics
Associations
Brief involuntary movements (motor tics) or sounds (phonic or vocal tics), occurring against a background of normal motor activity Tics may be simple, sudden brief movements such as shrugging a shoulder, blinking, or grimacing; or complex, more coordinated movement that might appear purposeful, such as hitting or touching Snorting, sniffing, or throat clearing are examples of simple phonic tics and short utterances, echolalia, or coprolalia are complex phonic tics Movements caused by rhythmically alternating contractions of a muscle group and its antagonists The movements may involve proximal and axial muscles Classified as resting, postural, or action tremors according to the response to these maneuvers Random brief limb movements of variable duration, these can be incorporated into voluntary movements by the patient
Idiopathic tic disorders Tourette syndrome
Slow writhing movements of the extremities, often distal extremities The movements are random Often involuntary movements of this type have some features of chorea and are termed choreoathetoid Sustained muscle co-contraction of agonist and antagonist muscle groups, frequently causing twisting and repetitive movements or abnormal postures The velocity of the movements varies, usually being sustained at the height of the involuntary contraction for a second or longer The duration also varies in different syndromes; in spasmodic torticollis, there may be rhythmic jerks or spasms into the abnormal posture Subclassified by extent (focal, segmental, multifocal and generalized) and relationship to movement (action and rest) Rapid brief muscle jerks with an irregular or occasionally rhythmic quality Can be epileptic or nonepileptic in origin Wild, large-amplitude, irregular limb movements Repetitive movements caused by sudden, brief, irregular lapses in posture of an extremity. Sometimes used as a general term to describe abnormal involuntary movements
SLE, systemic lupus erythematosus.
Physiologic tremor, essential tremor
SLE Wilson disease Postinfectious Kernicterus
Idiopathic (inherited) syndromes Postlesional syndromes
Encephalopathies Idiopathic and symptomatic epilepsies Postlesional Metabolic encephalopathies
Chapter 39 Paroxysmal Disorders sleepwalkers, having episodes at least once a month. The age at onset peaks between 4 and 10 and between 8 and 15 years. There is a family history of sleepwalking and other parasomnias for 60% to 80% of patients. These episodes of apparent unresponsiveness and “automatisms” could be mistaken for complex partial seizures or a postictal state.
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childhood than in infancy, but the list of other potential causes of seizures, including brain tumor, intracranial infection, and poisoning, is very similar. In addition, some metabolic and neurodegenerative disorders manifest in childhood, not in infancy (Table 39-16). Epileptic Syndromes
Hyperekplexia Benign Partial Epilepsies of Childhood
A startle response is normally seen in children and adults in response to sudden, unexpected stimuli. The typical response consists of a facial grimace, eye blink and brief head nod, shoulder elevation, abduction of the arms with elbow flexion, truncal flexion, and knee flexion. Startle is exaggerated with anxiety, fatigue, and sleep deprivation. Hyperekplexia is characterized by an excessive startle response interfering with daily living, usually causing patients to fall stiffly in the posture of the startle response and sustaining injury, with preserved consciousness. A history of infantile stiffness of the trunk and limbs and nocturnal myoclonus is present in many affected patients. There appears to be an infantile expression of the disorder, with severe hypertonia occurring with handling; the hypertonia may be so severe as to cause apnea, bradycardia, and even sudden death. Generalized seizures have been reported in some cases; mental retardation and delayed motor development appear to be common. The background EEG is usually normal. There may be some improvement with clonazepam or valproate therapy. Linkage analysis has mapped a gene for this condition to chromosome 5q33-35, and mutations in the GLRA1 gene, encoding the α1 subunit of the glycine receptor, have been found in families with an autosomal dominant or recessive inheritance pattern. In some epileptic syndromes, such as the Lennox-Gastaut syndrome, generalized seizures may be precipitated by sudden unexpected stimuli. This phenomenon has been termed startle-induced epileptic seizures or startle epilepsy. Startle-induced seizures can normally be differentiated from nonepileptic startle responses by the presence of other seizure types and EEG abnormalities. Self-Stimulatory Behavior
Repetitive purposeless movements may be performed by physically and intellectually handicapped children and by autistic children. Combined with unresponsiveness, these behaviors may be mistaken for automatisms in complex partial seizures. The important features that distinguish such behavior from epileptic activity are the setting in which it occurs, the variable content and duration of the “attacks,” and the complete failure of the episodes to interrupt more stimulating activities. However, it may be very difficult to determine the nature of the episodes by interview; video and EEG monitoring may be required. Factitious Disorder (Munchausen Syndrome) by Proxy
Factitious disorder is a consistent simulation of illness that leads to unnecessary investigations and treatments. When parents pursue such deception and cause their children to be investigated and treated, the situation is referred to as factitious disorder (or Munchausen syndrome) by proxy. Presentations with a history of paroxysmal loss of consciousness or seizures are common. The syndrome is described in children under 6 years of age; the mother is often the perpetrator (see Chapters 35 and 36). Seizures refractory to carefully prescribed AEDs must always prompt a review of the diagnosis, and the clinician must also be careful to consider fabricated presentations. Acute Symptomatic Seizures and Occasional Seizures Febrile convulsions remain one of the most common causes of occasional seizures in early childhood. Head injury is more common in
Partial seizures and focal EEG discharges usually suggest the presence of a localized cerebral lesion. There is a group of idiopathic partial epilepsies beginning in children without abnormalities on neurologic examination or neuroimaging studies and frequently with a family history for epilepsy. The benign partial epilepsies of childhood (BPECs) are characterized by partial seizures and focal epileptiform discharges, both with age-dependent spontaneous recovery, in the absence of anatomic lesions. Clinically, the seizures begin between 18 months and 12 years of age, most often at 8 to 10 years; there is no neurologic deficit or developmental delay. The seizures are brief and stereotyped in an individual, although they vary among patients. The seizures do not have a prolonged postictal deficit, are usually infrequent, and respond well to AED treatment. The focal epileptiform discharges occur with normal background rhythms. The sharp waves or spikes have a characteristic structure and are often very frequent, increasing during sleep. Rare generalized epileptiform discharges may occur, but if they are prominent, the diagnosis of BPEC should be questioned. The most well-defined form of BPEC is benign epilepsy with centrotemporal spikes and seizures, often referred to as benign rolandic epilepsy. Brief hemifacial motor seizures with anarthria and drooling are typical. Consciousness is typically preserved, although this may not be true with longer seizures. A somatosensory aura involving the tongue, cheek, or gums may precede the motor seizure. Many seizures occur at night as tonic-clonic seizures, presumably secondary generalized with unwitnessed partial onset. Onset is between 3 and 13 years, with a peak onset at 9 to 10 years; there is a male-to-female predominance of approximately 3:2. Management depends on seizure frequency; if the typical EEG discharges have been found in a child without seizures or after a first seizure, there is usually no indication to treat with AEDs. If seizures are infrequent and nocturnal, the option of no treatment should be discussed. AED treatment should be considered for patients experiencing more frequent seizures, troublesome seizures during the day, or seizures associated with any morbidity such as postictal headaches or lethargy. The seizures are usually controlled easily with a variety of AEDs, including carbamazepine or gabapentin. The seizures of BPEC resolve spontaneously before 16 years of age, and so all treated patients should have AEDs withdrawn at least by that time. The EEG may be helpful in deciding when to withdraw treatment. Patients older than 14 years who are seizure-free for 1 to 2 years with normal EEGs should withdraw from treatment; the clinician should strongly consider a trial of withdrawal in patients 10 to 14 years old who are seizure-free and have a normal EEG. Younger patients with active EEGs are likely to have recurrence of seizures with AED withdrawal. Benign childhood epilepsy with occipital paroxysms forms a subset of idiopathic partial epilepsies of childhood. There are two types of this subset: one with early onset (peak onset at 3 to 5 years), nocturnal seizures with tonic eye deviation, and vomiting and another with later onset (peak onset at 7 to 9 years) characterized by seizures beginning with visual symptoms, which is consistent with an occipital origin. Hemiclonic seizures or the automatisms of temporal lobe complex seizures often follow, according to whether the seizure spreads to suprasylvian or infrasylvian regions. A severe headache may follow the visual auras and a diagnosis of childhood migraine is often considered. The EEG typically shows highamplitude sharp waves or spike-and-wave complexes recurring at
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Table 39-16. Inherited Disorders of Metabolism and Neurodegenerative Diseases Associated with Seizures in Childhood and
Adolescence Name
Clinical Features and Laboratory Findings
Investigations
Syndrome of Progressive Myoclonus Epilepsy Multiple specific disorders cause the clinical syndrome of PME Prominent myoclonus; irregular repetitive, spontaneous or with action, stimulus sensitive Associated seizures types; usually tonic-clonic but also tonic, absence, and partial seizures Progressive neurologic deterioration, with prominent ataxia and other motor signs developing later Progressive dementia, varying in degree between the specific disorders Most cases are caused by the following five disorders: Unverricht-Lundborg Onset, ages 8-15 years; myoclonus and GTC seizures, cerebellar ataxia, slowly progressive but mild cognitive decline; patients have long survival in comparison to other disorders in this group Myoclonus epilepsy and Onset, ages 5-12 years (range, 3-62 years); myoclonus, ragged red fibers (MERRF) GTC seizures, progressive ataxia, dementia Other features include deafness, optic atrophy, neuropathy, myopathy, pyramidal signs, dysarthria and nystagmus There may be clinical overlap with other mitochondrial encephalomyopathies: mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and Kearns-Sayre syndrome Lafora body disease Onset, ages 10-19 years; generalized clonic, GTC seizures and partial seizures with visual auras; myoclonus develops later and becomes very disabling; severe dementia; death within 5 years of disease onset Lafora bodies (intracellular amyloid inclusions) are found in skin, muscle, neurons, and hepatocytes Neuronal ceroid lipofuscinosis Late infantile form (JanskyBielschowsky)
Juvenile form (BattenSpielmeyer-Vogt)
Adult onset (Kufs)
Sialidosis Type 1
Type 2
Onset, ages 2-4 years; severe epilepsy, myoclonic, GTC, atonic, atypical absence seizures (not tonic, vs. Lennox-Gastaut syndrome), progressive severe dementia, ataxia, pyramidal and extrapyramidal signs, visual loss later, usually death in adolescence Ophthalmologic examination necessary; EEG; marked photic sensitivity to 1-Hz stimulation, electroretinogram (ERG) and visual evoked potential (VEP) abnormalities Onset, ages 4-10 years; usually manifests with decreased visual acuity secondary to retinal degeneration, psychomotor delay, cerebellar and extrapyramidal signs, later onset of seizures, and GTC and myoclonus Progressive severe dementia accompanies the other neurological signs Death in early adulthood ERG and VEP abnormalities Onset, ages 11-50 years; dementia, psychiatric symptoms, cerebellar signs, and extrapyramidal signs are most prominent; seizures often tonic; visual disturbances are less common; fundi are normal; on EEG, marked photic sensitivity to 1-Hz stimulation Onset, ages 8-20 years; decreased visual acuity and macular cherry-red spot; action- and stimulus-induced myoclonus; cerebellar ataxia; no dementia or decreased length of survival A peripheral neuropathy may be present Onset, ages 10-30 years; described in Japanese patients
Chromosome 21q22; cystatin B mutations Clinical diagnosis, must exclude other causes of PME syndrome Serum and CSF lactate and pyruvate measurements Muscle biopsy; light microscopy, electron microscopy (EM), biochemical analysis of oxidative metabolism, and DNA studies
Biopsy of skin must include eccrine sweat glands (i.e., axilla) to exclude Lafora bodies Chromosome 6q24; gene EPM2A produces laforin
Skin, conjunctival, or rectal mucosal biopsy; skin biopsy is the most practical and least morbid Lipopigment accumulation in lysosomes, best seen in eccrine secretory cells; the inclusions have a characteristic structure on EM that differs between the different subtypes of neuronal ceroid lipofuscinosis EEG, ERG, and VEP testing Same as for late infantile form
Urine specimen, blood sample for cultured leukocytes, and skin biopsy to obtain cultured fibroblasts for enzyme analysis Same as for type 1
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Table 39-16. Inherited Disorders of Metabolism and Neurodegenerative Diseases Associated with Seizures in Childhood and
Adolescence—cont’d Name
Clinical Features and Laboratory Findings
Investigations
Dysmorphic features and PME syndrome Elevated excretion of urinary sialylated oligosaccharides, enzyme analysis shows deficiency of α-N-acetylneuraminidase (type 1), additional deficiency of β-galactosidase (type 2) Less common causes of PME syndrome in this age group: Juvenile neuronopathic Gaucher disease; PME, supranuclear palsy, and splenomegaly; no dementia; pancytopenia on CBC, leukocytes show low β-glucocerebrosidase activity Dentatorubral-pallidoluysian atrophy, seen in Japanese patients; PME is one manifestation Neuroaxonal dystrophy; may appear as PME; also, chorea, lower motor neuron signs; axon steroids in neurons, may be seen in autonomic nerve endings around eccrine secretory coils Late-onset GM2 gangliosidosis; sensitivity to acoustic stimulus; myoclonus, severe dementia, dystonia, pyramidal signs; cherry-red spot may be seen at macula Hallervorden-Spatz disease Action myoclonus–renal failure syndrome, described in FrenchCanadians; tremor, PME, and, later, proteinuria and renal failure; no dementia Other Rare Disorders with Seizures in Childhood and Adolescence Juvenile Huntington disease Onset, age >3 years; developmental delay; dystonia; GTC, atypical absence, myoclonic seizures; parkinsonian features may be present Alpers syndrome Progressive neurologic degeneration of childhood A clinical syndrome; now suspected to be a mitochondrial encephalopathy Normal at birth, then failure to thrive with developmental delay, myoclonic jerks, seizures, episodes of status epilepticus, hypotonia, and visual loss followed by spastic quadriparesis Epilepsy partialis continua may be present The spectrum of clinical features includes deafness, ataxia, chorea and liver disease Rett syndrome Onset, ages 1-2 years; in girls only; delay or regression in motor development, loss of language, ataxia, “handringing” mannerism Seizures occur later; myoclonic, partial, and generalized tonic-clonic Episodes of apnea, ataxic breathing, and hyperventilation; pyramidal signs Maple syrup urine disease Less severe forms may manifest late, even in adulthood, with episodic symptoms of encephalopathy and ataxia and possibly seizures Porphyria Onset, late adolescence, after puberty; 15% of affected patients have seizures during an acute attack of porphyria
CBC, leukocytes for enzyme analysis Clinical diagnosis in life Peripheral nerve biopsy, skin biopsy Hexosaminidase A activity Clinical diagnosis in life Clinical diagnosis, renal function
Muscle biopsy
Muscle biopsy for mitochondrial enzyme analysis and histologic study, although cause is unknown, genetic testing
Urine and serum amino acids Urinary porphyrins
CBC, complete blood cell count; CSF, cerebrospinal fluid; EEG, electroencephalogram; GTC, generalized tonic-clonic; PME, progressive myoclonus epilepsy.
1 to 0.5 Hz posteriorly, usually maximal in the occipital regions. The discharges are present when the eyes are closed and should disappear with eye opening. There is some controversy about the specificity of the electroclinical features and whether these cases are true variants of benign childhood epilepsy. The conditions are relatively uncommon, and the same EEG pattern may be seen with symptomatic occipital epilepsy. Acquired Epileptic Aphasia and Continuous Spike-and-Wave Patterns in Slow-Wave Sleep
These two conditions are age-related epileptic encephalopathies with disturbances in language and cognition occurring in association with persistent focal or bilaterally synchronous epileptiform activity and
seizures without an underlying structural lesion. In each, the epileptiform activity is thought to disturb synaptogenesis and connectivity in the maturing brain. Although they are rare, some authorities consider them part of the spectrum of benign childhood epilepsy. Epileptic aphasia, or the Landau-Kleffner syndrome, begins in a previously normal child (peak age at onset, 5 to 7 years) with the regression of language. There is a severe auditory agnosia, speech may disappear, the child often appears to be deaf, and there is usually a marked deterioration in behavior. Childhood psychosis and the autistic spectrum disorders are often considered in the differential diagnosis. Seizures occur but are not frequent and cannot explain the language deficits. The EEG in sleep shows almost continuous bilateral epileptiform discharges maximal over the temporal regions. The seizures are partial and easily controlled with medication, but
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the language regression and the EEG discharges do not remit with conventional AEDs. Treatment with corticosteroids does improve the condition in many children, but more than half have persistent language and learning deficits despite the eventual disappearance of the EEG abnormalities. In continuous spike-and-wave patterns in slow sleep, there is a more diffuse cognitive dysfunction, and more than 85% of the sleep EEG record is occupied by bilaterally synchronous epileptiform discharges. The disorder typically manifests at 5 to 7 years of age, and there is a broader spectrum of seizure types, including absences, atonic seizures, and complex partial seizures, which may be frequent in some patients.
against tonic-clonic seizures. Therefore, valproate is the drug of choice if both seizure types are present. If either ethosuximide or valproate proves ineffective after an adequate trial at maximum tolerated doses, a trial of the other should be commenced. Combination ethosuximide and valproate therapy has been effective in some patients with absence seizures not controlled by either drug alone. Clonazepam may also be effective, but it is associated with sedative and behavioral side effects. Alternatives may include lamotrigine, topiramate, or zonisamide, although few data about their efficacy in this setting are available. Epilepsia Partialis Continua and Rasmussen Encephalitis
Symptomatic Focal (Localization-Related) Epilepsy
The most common seizure type in symptomatic focal epilepsy in children is the complex partial seizure. Complex partial seizures may arise from temporal, frontal, parietal, or occipital lobes but most often from the temporal lobe. The causes of focal epilepsy in childhood are diverse and include birth asphyxia, later anoxic episodes, head injury, neoplasms, infection, malformations of cortical development, the cerebral lesions of neurocutaneous syndromes, vascular malformations, and cerebral infarction. Mesial temporal sclerosis is the most common finding in temporal lobes resected to treat refractory focal epilepsy in adults. The incidence of mesial temporal sclerosis in childhood nonidiopathic focal epilepsy has not yet been determined. MRI is a crucial diagnostic procedure and can reveal a variety of structural abnormalities. Symptomatic focal epilepsy commonly evolves as a medically refractory disorder; however, in some patients, it can be amenable to surgical resection. The investigation of children for epilepsy surgery is a highly specialized process that follows documentation of medical intractability. Concordant evidence of a single epileptogenic region within the brain must be found with ictal video and EEG monitoring, both structural neuroimaging (MRI) and functional neuroimaging (single photon emission computed tomography and positron emission tomography) and neuropsychologic evaluation. If a focus can be demonstrated, it must be shown that resection of that area will not cause loss of sensorimotor or cognitive function. In the case of temporal foci, the risk of postoperative memory dysfunction must be addressed. In seizures with foci from extratemporal sites, it may be necessary to map cortical sensorimotor and language function by cortical stimulation to determine the limits of a surgical resection. Childhood Absence Epilepsy
Childhood absence epilepsy is an idiopathic generalized epilepsy beginning in previously normal children between 3 and 12 years of age, with peak incidence at 6 to 7 years of age; girls are more frequently affected. It accounts for only about 8% to 10% of schoolaged children with epilepsy. There is a family history of epilepsy in approximately 15% to 25% of patients. The absence seizures are simple or, more often, complicated with mild automatisms or other motor features. Absence seizures are very frequent, occurring daily, but they respond well to therapy. The EEG is normal apart from runs of 3-Hz spike-and-wave complexes; clinical seizures are associated with discharges lasting more than 2 to 3 seconds. The discharges and clinical seizures can be produced by hyperventilation. Prognosis is generally favorable, with remission in approximately 80% of cases by late adolescence. Generalized tonic-clonic seizures occur in 40% to 50% of patients with childhood absence epilepsy. They typically develop years after the onset of absences and may appear after remission from the absence seizures. Usually, the tonic-clonic seizures are infrequent and medically controllable. Treatment with ethosuximide or valproate controls absence seizures in most patients. However, ethosuximide offers no protection against tonic-clonic seizures, whereas valproate is also effective
Epilepsia partialis continua describes continuous partial motor seizures usually manifesting as repetitive clonic jerks of the face, upper limb, lower limb, or larger portion of one half of the body that continue in this localized manner for hours to days or months. These focal seizures, with occasional secondary generalization, are caused by circumscribed rolandic or perirolandic cortical processes that include vascular lesions, focal cortical dysplasia, neoplasms, and unidentified focal areas of atrophy. The focal seizures in this condition are generally impossible to control with AEDs, and surgical management with a limited cortical resection may be necessary. The risk of motor and sensory deficits limits possible resections, and careful mapping of the site of seizure onset and its relationship to functional cortex is required. Mitochondrial encephalomyopathies (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) and an inherited disorder of metabolism (nonketotic hyperglycinemia) have also been reported to cause epilepsia partialis continua. Rasmussen encephalitis is a clinically defined syndrome of predominantly lateralized cerebral dysfunction, with onset of seizures between 2 and 10 years of age. A variety of seizure types can occur, including focal motor seizures and complex partial seizures with secondary generalization, myoclonus, and epilepsia partialis continua; they are refractory to management with AEDs. The disorder is characterized by a progressive hemiparesis, language disturbances if the dominant hemisphere is affected, and intellectual decline. Progressive hemispheric atrophy, maximal in the central, temporal, and frontal regions, can be documented with neuroimaging studies. Pathologic specimens show nonspecific changes suggestive of encephalitis, although no etiologic agent has been identified. Worsening of the neurologic deficits can be expected over time, although the seizures may lessen and even “burn out.” Functional hemispherectomy, performed early in the course of the disease before complete hemiparesis, should control seizures, arrest the motor deterioration, and in most cases lead to stabilization or even improvement in language and intellectual function. However, significant morbidity and mortality rates are associated with the surgery, and the child is left with a paretic upper limb, although he or she can walk unaided. Lennox-Gastaut Syndrome
The Lennox-Gastaut syndrome is characterized by generalized seizures and epileptiform discharges with delayed mental development and behavioral problems beginning between the ages of 1 and 8 years. The patients have a mixed seizure disorder with multiple seizure types; the typical seizures are axial tonic seizures, atypical absences, and atonic seizures, although patients may also have tonicclonic, myoclonic, and complex partial seizures. The seizures are not easily controlled and are usually frequent, often several occurring per day. Episodes of status epilepticus are common, and nonconvulsive stupor with continuous spike-and-wave discharges or a stuporous state with repeated tonic seizures is typical. The waking EEG has abnormally slow background activity, and the EEG correlates of sleep may also be poorly organized. The epileptiform abnormalities
Chapter 39 Paroxysmal Disorders consist of slow (10 Hz) in sleep. AEDs are always indicated but rarely able to control seizures completely. More often, some reduction in frequency and severity of seizures may be obtained. Monotherapy should be attempted with substitution of another agent if the initial drug proves ineffective. However, because of multiple seizure types, patients commonly need combinations of AEDs. Valproate should be used as a first-line agent for patients with atonic, tonic, and myoclonic seizures and may be helpful with tonic-clonic seizures. Patients with refractory tonic-clonic seizures or partial seizures as well as generalized seizures may benefit from the addition of lamotrigine. Combinations of AEDs must be monitored carefully for drug toxicity and unwanted interactions. Carbamazepine has been reported to exacerbate atypical absence seizures in some patients. Phenytoin can be an effective drug in controlling generalized tonic-clonic and tonic seizures. Barbiturates may be effective, although they are often poorly tolerated, and drugrelated drowsiness may exacerbate tonic seizures in some patients. Other alternatives include clonazepam, topiramate, and levetiracetam. Felbamate has been reported to improve control of the debilitating tonic or atonic “drop attacks” in patients with this syndrome. An issue perhaps peculiar to this notoriously refractory seizure disorder is the need to consider what level of seizure activity can be tolerated. For instance, the best control achieved may be infrequent daytime tonic seizures in the setting of daily absence seizures and frequent nocturnal tonic seizures. AED toxicity may be particularly noxious in these patients, leading to increased numbers of falls, worsening behavior, lethargy, and exacerbation of seizures. A major source of morbidity and an important management issue is repeated falls associated with tonic and atonic seizures. Appropriate restriction in daily activities and the wearing of helmets with face protection are often required. Division of the anterior portion of the corpus callosum has been successful in controlling the falls associated with tonic or atonic seizures, but not all patients benefit, and seizure control is not complete. Myoclonic Astatic Epilepsy
Although sometimes seen as a variant of the Lennox-Gastaut syndrome, myoclonic astatic epilepsy has been described as a distinct entity. Patients have a mixed seizure disorder with myoclonus, atypical absences, and tonic-clonic seizures but not tonic seizures. The term astatic refers to loss of station or posture with abrupt falling during myoclonic seizures. The peak age at onset is between 2 and 5 years, and the range is from 7 months to 6 years. Approximately one third of patients have a family history of epilepsy. In comparison with the interictal EEG in Lennox-Gastaut syndrome, that in myoclonic astatic epilepsy shows faster generalized spike-and-wave and polyspike-and-wave epileptiform discharges. The absence of tonic and partial seizures and the EEG findings distinguish this syndrome from Lennox-Gastaut syndrome. The course is variable, but a proportion of patients have a favorable one. A certain small group of children with an apparently unfavorable, even catastrophic-looking initial clinical presentation may respond well to valproate therapy and have spontaneous remission of seizures. Panayiotopoulos Syndrome
This common and benign syndrome affects children between 3 and 6 years of age. The seizures may be prolonged and mimic nonepileptic conditions. The seizures have an autonomic component and often manifest with associated emesis, pallor, hypersalivation, and flaccidity. The EEG demonstrates occipital or extraoccipital spikes. Seizures occur during nocturnal sleep or daytime naps. Children may appear confused and may develop focal or generalized motor seizures. The outcome is good, with remission occurring in 2 years. Treatment with AEDs is not always needed.
695 ADOLESCENCE
The paroxysmal disorders of adolescence (12 to 18 years) are shown in Table 39-17. Paroxysmal Nonepileptiform Disorders Syncope
Loss of consciousness with falling is the salient feature of syncope (see Chapter 42 and Table 39-18). Psychogenic Seizures
Nonepileptic paroxysmal abnormal behaviors (psychogenic seizures) may be a manifestation of psychiatric illness or emotionally based. Psychiatric disease, particularly panic attacks, may be mistaken for epilepsy.
Table 39-17. Paroxysmal Disorders of Adolescence
Nonepileptiform Disorders More Common Syncope Migraine Psychogenic seizures Dissociative states, conversion disorders Panic attacks, hyperventilation Daydreaming Sleep Nocturnal myoclonus, hypnic jerks Narcolepsy Somnambulism Somniloquy Less Common Episodic rage Malingering Paroxysmal choreoathetosis Tremor Tic Drug reactions, dystonia Transient global amnesia Acute Symptomatic Seizures, Occasional Seizures More Common Drug abuse Head injury Meningitis and encephalitis Less Common Brain tumor Intercurrent medical illness, endocrine disorder, systemic neoplasia Epileptic Syndromes More Common Symptomatic localization-related epilepsy Juvenile myoclonic epilepsy Less Common Juvenile absence epilepsy Epilepsy with generalized tonic clonic seizures on awakening Epilepsia partialis continua (Kojewnikow syndrome) Rasmussen encephalitis Progressive myoclonic epilepsy (see Table 39-16)
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Table 39-18. Differential Diagnosis of Syncope Clinical
Precipitating factors Prodrome Occurrence in sleep Evolution
Skin Incontinence Self-injury Degree of postictal confusion Family history Interictal EEG
Syncope
Tonic-Clonic Seizures
Almost always: patient is standing; environment is warm; fright; pain Lightheaded, dizzy, queasy; vision dims; loss of color, “grey out”; sweating May be averted by head down or recumbency Never Limp faint → fall → motionless unconsciousness, often with pallor, clammy skin; there may be a tonic phase with generalized stiffening
Usually none, although sleep deprivation or awakening may be contributory Aura or sense of déjà vu or jamais vu may be present
Pale and cool Rare Rare Minimal
Common Sudden loss of consciousness → increased tone and massive truncal flexion or extension, followed by synchronous jerking of body and limbs with rubor or cyanosis and sweating → unconsciousness Flushed, cyanosed, warm Occasional Common (biting tongue) Marked
Often positive for syncope Usually normal
May be positive for seizures Frequently abnormal, epileptiform discharges
Panic attacks may begin without the patient’s being able to identify an external precipitant, and then the sense of dread or fear may be mistaken for a psychic aura. Many of the symptoms experienced, including palpitations, paresthesia, formication, lightheadedness, and carpopedal spasm, result from hyperventilation and tachycardia. There may be some apparent disturbance of consciousness. Historically, the sequence of events is important, especially the hyperventilation and associated symptoms. The patient may be asked to hyperventilate in the office to see whether symptoms are reproduced; hyperventilation must continue for 3 to 5 minutes with good effort for a negative result to be useful. Rage attacks may occur and be confused with epileptic seizures. Often seen in intellectually impaired patients, they represent intense frustration in the presence of an inability to vent the frustration in other ways or to communicate it. Rage attacks may also occur in children with normal intelligence or in those taking anabolic steroids. Psychogenic seizures are common. Among adults, 20% of patients referred with refractory seizures are found to have psychogenic seizures; in children, the number is smaller. Psychogenic seizures may appear as a manifestation of a conversion disorder. Psychogenic seizures or hysterical seizures probably occur in a dissociative state. Typically, they are characterized by marked motor activity such as pelvic thrusting, arching of the back, thrashing of the limbs, and even self-injury. The episodes may have a gradual onset with build-up of motor activity, and they usually last longer than epileptic seizures (Table 39-19). Other forms that the psychogenic seizure may take include a gradual slump to a motionless supine position with unresponsiveness and eyes closed, often with some flickering of the eyelids, referred to by some people as a “swoon.” Deliberate simulation of an epileptic attack may occur in some patients with epilepsy in an effort to manipulate their environment or circumstances, and in this case the differential diagnosis may include school refusal.
but not after a psychogenic seizure. The test specimen must be compared with a baseline serum prolactin level collected at the same time of day, not within 24 hours of one of the episodes. Marked elevation of serum creatinine kinase level can be seen for 2 to 3 days after a tonic-clonic convulsion but generally not after a psychogenic seizure. However, elevation of creatinine kinase level reflects muscle damage, and a vigorous psychogenic episode with injury is also followed by elevation of creatinine kinase level. Treatment. Treatment of psychogenic seizures must include an
identification of underlying psychosocial and psychiatric problems by psychiatric personnel. Major mood disorders and severe environmental stress, especially sexual abuse, are common among children and adolescents with psychogenic seizures and should be considered in every case. Presentation of the nonepileptic diagnosis to the patient after monitoring of a typical spell must be positive (“These attacks are not epileptic and will not necessitate chronic medication or further neurologic investigation”) and truthful (“We don’t know exactly what is causing them, but emotional factors are clearly playing a major role”). The prognosis of psychogenic seizures in the pediatric population is much better than in adults, with 80% of patients seizure-free at 3-year follow-up. Acute Symptomatic Seizures and Occasional Seizures The causes of acute symptomatic seizures in adolescence include those described in the preceding neonatal and childhood sections except for febrile convulsions. Head injury may be more common among adolescents, because participation in contact sports and motor vehicle accidents occur in the middle to late teen years. Street drug abuse can be associated with seizures.
Evaluation. The interictal EEG is repeatedly normal in patients
with psychogenic seizures. For definitive diagnosis, it may be necessary to record a clinical episode with continuous video and EEG monitoring. Serum prolactin or creatinine kinase levels may also be helpful in the differential diagnosis of psychogenic seizures and epilepsy. Elevation of serum prolactin level can be seen within 30 minutes after a tonic-clonic or a temporal or frontal complex partial seizure
Epileptic Syndromes Juvenile Myoclonic Epilepsy
Juvenile myoclonic epilepsy has an onset between 12 and 18 years of age. The hallmark of the disorder is early-morning myoclonus involving axial and upper limb muscles, usually with sparing of
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Table 39-19. Differential Diagnosis of Psychogenic Seizures Clinical Factors
Psychogenic Seizures
Age at onset Duration of seizures Evolution Quality of convulsive movements Stereotypical attacks Examination during the seizure Self-injury Incontinence During sleep Changes in seizure frequency with medication Interictal EEG Ictal EEG Pitfalls in diagnosis
Epileptic Seizures
Usually older than 8-10 years Predominates in girls; 15%-30% of patients are boys May be very prolonged May have a very gradual onset and ending Thrashing, asynchronous limb movements, often with partial responsiveness Typically variable May resist examination, combative Rare Rare No; may occur nocturnally but while patient is awake Rare Repeatedly normal No EEG seizure patterns; normal rhythms while patient is unresponsive 1. Psychological factors may not be immediately apparent 2. Misleading information may be given by parents (as in Munchausen syndrome by proxy)
Any gender, no sex predominance Usually seconds to minutes Usually more abrupt onset Usually rhythmical and synchronous with loss of consciousness Typically stereotyped Usually unresponsive and amnestic for ictal events Common in GTC seizures Common in GTC seizures Common Usual Often abnormal EEG seizure patterns 1. Asynchronous vigorous automatisms are found in frontal lobe seizures 2. Bilateral limb movements and posturing without loss of consciousness occurs in supplementary motor seizures 3. EEG seizure patterns may be absent during some seizures (e.g., auras, SMA)
EEG, electroencephalogram; GTC, generalized tonic clonic; SMA, supplementary motor area.
facial muscles. Episodes typically occur on awakening. Tonic-clonic seizures occur in the majority of patients. The history of early-morning myoclonic jerks may not be volunteered and should be asked of all patients presenting with generalized tonic-clonic seizures. The patients may not have identified the myoclonus and instead describe nervousness, shakiness, or clumsiness for the first 1 to 2 hours of a morning. Fatigue, sleep deprivation, stress, and alcohol exacerbate the seizures. The tonic-clonic seizures typically begin with a clustering of repeated myoclonic jerks. Absence seizures occur in 15% to 40% of patients. Neurologic examination findings and IQ are normal. The interictal EEG shows spike-and-wave complexes at 3.5 to 6 Hz. Linkage analysis of patients and their family members has suggested that the disorder is linked to chromosome 21. Valproate is the preferred AED. Lamotrigine is an effective agent and is often used because of concern about the possible side effects of valproate (weight gain and potential hormonal disturbance). Alternatives may include topiramate and zonisamide, although extensive data concerning their efficacy in this setting are not available. The seizures are well controlled in 80% to 90% of patients, but lifelong treatment is required, because relapse is common even after prolonged seizure-free intervals. It is estimated that more than 90% of patients suffer relapse within the first 6 to 12 months after cessation of AEDs. Juvenile Absence Epilepsy
In comparison with childhood absence epilepsy, juvenile absence epilepsy has a later onset, at about the time of puberty, and the seizures are less frequent (less than daily). Neurologic examination findings and IQ are normal. The EEG shows generalized spike-andwave discharges, usually at rates faster than 3 Hz. Tonic-clonic seizures may occur, usually on awakening, more frequently than in childhood absence epilepsy. The treatment is the same as that for childhood absence epilepsy, but the prognosis for complete remission on therapy is less favorable.
Epilepsy with Generalized Tonic-Clonic Seizures on Awakening
This idiopathic generalized epilepsy involves generalized tonicclonic seizures occurring more than 90% of the time within 2 hours of awakening or in an early-evening period of relaxation. Sleep deprivation and disruption are often potent precipitants of seizures. The age at onset of the seizures is usually between 10 and 20 years; a family history of epilepsy occurs in approximately 10% to 13% of cases. Myoclonic and absence seizures may also be present, and the distinction between juvenile myoclonic epilepsy and juvenile absence epilepsy is not clear. The EEG may show generalized spike-and-wave complexes or polyspikes. Treatment starts with valproate, although barbiturates may be very effective. Lamotrigine is also used because of concern about the side effects of valproate. Topiramate and zonisamide may also be helpful. The prognosis for complete control of seizures on therapy is very good: 65% to 79% of patients have experienced remission with therapy. Avoidance of precipitating factors that disrupt sleep patterns is important. The relapse rate if AEDs are stopped is high (83%).
PRINCIPLES OF ANTIEPILEPTIC DRUG USE The goal of AED therapy is to use a single agent in adequate dosages to completely control seizures. If seizures recur, the dosage of an AED should be gradually increased to achieve the maximum tolerated dose for the patient without causing symptoms of drug toxicity. Therapeutic ranges are derived from population studies in which the serum levels of patients with seizures controlled by an AED were compared with those of patients experiencing side effects. The therapeutic levels should be used as a guide. They should not be interpreted as the “normal” levels; the “therapeutic” level is that which controls the individual’s seizures without causing symptoms of toxicity.
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If one agent does not control the seizures, another AED should be substituted and tried as monotherapy. An adequate trial of therapy entails the maximum tolerated dose of an AED for a period of time in which several of the patient’s seizures (or clusters of seizures) would usually occur or for at least 2 months, whichever is longer. This interval may be shortened in infants and children with very frequent seizures. Changes in AED dosages and regimens should be made gradually, and due regard must be given to time taken to reach steady-state serum concentrations on the new regimen (Tables 39-20 and 39-21).
If the child with epilepsy fails to achieve complete control of seizures on monotherapy with one of the first-line drugs, an alternative first-line drug should be substituted and, if unsuccessful, followed by a trial of monotherapy with one of the more recent AEDs. Drug changes can be made gradually on an outpatient basis; the existing AED can be reduced by 20%, and the new AED commenced at the usual starting dosage (see Table 39-20). Each week, the dosage of the new AED can be increased with a corresponding reduction in the previous AED until the new drug is at the desired maintenance dosage and the previous AED has been discontinued. The physician
Table 39-20. Antiepileptic Medication: Clinical Usage
Antiepileptic
Indication
Introduction of Medication
Maintenance Dosage (mg/kg/day)
Side Effects
Monitoring of Serum Levels
First-Line Drugs Carbamazepine
Partial seizures and secondarily GTCS
No loading dose
10-30 as t.i.d. For controlledrelease preparations, 20% increase in dosage as b.i.d.
Ethosuximide
Absence seizures, symptomatic generalized epilepsy with falls, negative myoclonus Partial seizures, primary generalized tonic-clonic seizures, absence seizures, myoclonus and as adjunct in LennoxGastaut syndrome Partial seizures and secondarily GTC seizures
Add 33% of maintenance dosage every 7 days
10-40 as t.i.d., with meals
0.5 mg/kg/day; increase by 1 mg/kg/day weekly, increase 2nd wk during concomitant use of valproate
5-15 as b.i.d. or t.i.d. as monotherapy; 1-5 q.d. or b.i.d. with concomitant use of valproate
Loading 10-20 mg/kg PO
5-10 as b.i.d.
Primary GTC seizures, myoclonus and absence seizures, partial seizures
Loading dose only for status epilepticus: 20 mg/kg
15-60 as b.i.d. or t.i.d.
Partial seizures Adjunct in LennoxGastaut syndrome Partial seizures and GTC seizures
Begin at night with 33% of maintenance dosage 6-8 mg/kg PO for 2 days, then maintenance dosage Begin with phenobarbital, increasing over 3 days, then add primidone
Lamotrigine
Phenytoin
Valproic acid
Drowsiness, vertigo, diplopia, hyponatremia (SIADH), dose-dependent neutropenia, rash in 4%-10% Rare: serious blood dyscrasia, hypersensitivity reaction Nausea, gastrointestinal discomfort, headache Rare: aplastic anemia
Yes
Rash, insomnia, headache, ataxia, drowsiness, diplopia Marked changes in half-life are dependent on comedication Rare: StevensJohnson syndrome Ataxia, diplopia, gingival hyperplasia, coarsening of facial features Chronic use: cerebellar atrophy Rare: hypersensitivity reaction Weight gain, hair loss, tremor at high dosage, ovarian cysts, hyperandrogenemia Rare: hepatotoxicity, pancreatitis, encephalopathy
May be useful with polytherapy
0.5-1 as b.i.d.
Sedation
No
3-4 as b.i.d.
Drowsiness, behavioral changes, hyperactivity
Yes
5-20 as b.i.d. or t.i.d.
Acute reaction: nausea, vomiting, vertigo Sedation
Yes
10-20 as b.i.d. or t.i.d.
Altered taste, parasthesia, initial drowsiness, crossreactivity with sulfonamide allergy Rare: renal calculi, precipitation of hepatic coma in liver failure
No
No
Yes
Yes
Second-Line Drugs Clobazam Phenobarbital Primidone
Partial seizures and secondarily GTC seizures
Third-Line Drugs Acetazolamide
Absence seizures May use as trial in refractory generalized epilepsy
33% of maintenance dosage for 1 week, then gradual increase over next weeks
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Table 39-20. Antiepileptic Medication: Clinical Usage—cont’d
Antiepileptic Clonazepam
Chlorazepate
Indication Infantile spasms, myoclonus, reflex epilepsy; Second-line therapy for absence seizures and partial seizures Adjunct for partial and secondarily GTC seizures
Maintenance Dosage (mg/kg/day)
Introduction of Medication
Side Effects
Monitoring of Serum Levels
0.01-0.03 mg/kg/day for 1 week, then increase by 0.250.5 mg/day each week
0.03-0.1 as b.i.d. or t.i.d.
Sedation, drooling; behavioral change: irritable, aggressive, hostile
No
0.3 mg/kg/day for 1 week, then increase by 0.4-3 mg/day each week
7.5-15 as b.i.d.
Sedation, ataxia, drooling
No
0.5-0.7 q8h when fever >38.5° C (see Table 39-5) 0.03-0.22 mg/kg, IV bolus (see Table 39-5) Can be given via buccal or intranasal route, also as infusion for status epilepticus: 0.15-0.2 mg/kg IV bolus, 1 μg/kg/min to start, then variable infusion, usually ≤18 μg/kg/min
Sedation, ataxia, vertigo IV use: respiratory depression and apnea, hypotension IV use: respiratory depression and apnea, hypotension IV use: sedation, respiratory depression, apnea, hypotension
No
Add 25% of maintenance dosage every 4 days Add 25% of maintenance dosage every 2 days Add 25% of maintenance dosage every week Add 25% of maintenance dosage every week
No
30-60 as t.i.d. or q.i.d.
Headache, insomnia, anorexia, nausea, and vomiting Rare: aplastic anemia, hepatitis Drowsiness, fatigue, ataxia, nonspecific dizziness
20-60 as b.i.d. in adults
Drowsiness, lethargy, headache
No
0.25-1 as b.i.d.
Sedation, impaired swallowing, drooling, ataxia
No
Add 25% of maintenance dosage every week 0.1 mg/kg/day; increase by 0.1 mg/kg/day every 1-2 weeks
20-50 as b.i.d. or t.i.d.
Rash less common and hyponatremia more common than with carbamazepine Drowsiness, poor concentration, irritability, tremor Gradual introduction lessens cognitive side effects Paresthesia, anorexia, drowsiness, poor concentration, word finding difficulties Gradual introduction lessens cognitive side effects Rare: renal calculi Drowsiness, fatigue, gastrointestinal upset, weight gain, peripheral visual field defects Depression and psychosis reported in adults Drowsiness, anorexia, nausea, headache, poor concentration, renal stones
Yes
Drugs for Special Circumstances Diazepam Lorazepam
Prophylactic rectal use for febrile convulsions Status epilepticus Status epilepticus
Midazolam
Status epilepticus
No No
More Recent Drugs Felbamate Gabapentin
Partial seizures, adjunct for symptomatic generalized epilepsy Adjunct for refractory partial seizures
45 as t.i.d.
Levetiracetam
Partial seizures
Nitrazepam
Oxcarbazepine
Infantile spasms Myoclonic seizures, reflex epilepsy Adjunct symptomatic generalized epilepsy Partial seizures
Tiagabine
Partial seizures
Topiramate
Partial seizures GTC seizures, absences, myoclonus, epileptic spasms. Lennox-Gastaut syndrome
1 mg/kg/day, increase by 1 mg/kg/day every 1-2 weeks
5-10 as b.i.d.
Vigabatrin
Partial seizures Tuberous sclerosis and West or Lennox-Gastaut syndromes
Add 25% of maintenance dosage every week
10-50 as b.i.d. or q.d. Higher doses for infantile spasms, up to 100-150
Zonisamide
Partial seizures GTC seizures, myoclonus, epileptic spasms
2-4 mg/kg/day; increase by 2 mg/kg/ day to maintenance dose
4-18 as q.d. or b.i.d.
0.4-1.25 as b.i.d. to q.i.d.
No
No
No
No
Yes
b.i.d., twice a day; GTC, generalized tonic-clonic; IV, intravenous; q.d., every day; q.i.d., four times a day; SIADH, syndrome of inappropriate antidiuretic hormone; t.i.d., three times a day.
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Table 39-21. Antiepileptic Medication: Pharmacokinetic Parameters Antiepileptic
1
% Protein Bound
Metabolism/Elimination
Half-life (Hours)
Therapeutic Range (mg/L)1
First-Line Drugs Carbamazepine Ethosuximide Lamotrigine Phenytoin Valproic acid
75 90 40-50 2 mm dilation means parasympathetic (third nerve) palsy. Extraocular movements: Absence acutely means deep drug poisoning, severe brainstem damage, polyneuropathy, or botulism. Dysconjugate deviation: At rest, this means an acute third, fourth, or sixth nerve palsy or internuclear ophthalmoplegia. Tonic conjugate deviation toward a paralytic arm and leg means forebrain seizures or a contralateral pontine destructive lesion; such deviation away from the paralytic arm and leg means forebrain gaze paralysis. Spontaneous eye movements: In comatose patients, nystagmus, bobbing, and independently moving eyes all mean brainstem damage. Oculocephalic (away from direction of head turning) or oculovestibular (toward cold caloric irrigation) responses: Absence of responses means drug overdose or severe brainstem disease; dysconjugate responses with equal pupils mean internuclear ophthalmoplegia; responses with unequal pupils mean third nerve disease.
5. Examine the motor systems. Strength Unilateral weakness or motionlessness of arm and leg means contralateral supraspinal upper motor neuron lesion, most often cerebral; if of arm, leg, and face, contralateral cerebral lesion. Occasionally. arm and leg weakness reflects contralateral brainstem lesion. Weakness or motionlessness of all four extremities implies metabolic disease; less likely is brainstem disease (tone and reflexes increased) or peripheral disease (tone and reflexes decreased). Attempt to elicit reflex posturing Arm flexed, leg extended: contralateral deep cerebral-thalamic lesion Arm and leg extended: thalamic or mesencephalic lesion Arms extended and legs flexed or flaccid: pontine lesion Legs flexed, arms flaccid: pontomedullary or spinal lesion Compare side-to-side reflexes and examine plantar responses. 6. Seek seizure activity or abnormal movements: (1) generalized, (2) focal, (3) multifocal, and (4) myoclonic. Control 1 immediately, 2 and 3 deliberately; if 4 is present, treat underlying disease. Acute tremor, asterixis, multifocal myoclonus: seek metabolic cause. 7. Inspect breathing. Regular hyperpnea: metabolic acidosis; pulmonary infarction; congestive failure or alveolar infiltration; sepsis; salicylism; hepatic coma Cyclically irregular (Cheyne-Stokes): low cardiac output plus bilateral cerebral or upper brainstem dysfunction Irregularly irregular gasping, slow or weak: lower. brainstem dysfunction (including hypoglycemia, drug effects); less often, peripheral ventilatory paralysis 8. Proceed with laboratory tests and emergency management as described in text.
Adapted from Plum F: Neurology/sustained impairments of consciousness. In Wyngaarden JB, Smith LH, Bennett JC (eds): Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 2057.
likely causes of coma, although there is considerable overlap (Table 40-9).
MANAGEMENT APPROACH The approach to the child with an alteration of consciousness can be divided into four parts: (1) stabilization, (2) rapid neurologic assessment, (3) reversal of immediately treatable toxic or metabolic causes, and (4) determination of level of CNS function and of the cause of the coma (Fig. 40-2). STABILIZATION ABCs The initial step is a rapid but meticulous evaluation of the patient’s airway, breathing, and circulation (ABCs), including determination
of vital signs. Obtunded, stuporous, or comatose patients usually require intubation unless their mental status is improving or can be readily reversed. Intubation may be necessary not only to secure an airway but also to treat hypoventilation, to protect the airway if a gag reflex is not present, and to facilitate hyperventilation therapy in a child with suspected intracranial hypertension. Manipulation of the neck, particularly extension, should be avoided when an airway is being stabilized or secured, unless a cervical spine injury can be ruled out. Attention is next directed toward an assessment of the circulation; this mandates evaluation of vital signs, presence and volume of peripheral pulses, and adequacy of end-organ perfusion. Blood pressure must be high enough to support perfusion of vital organs. Patients may be in shock with a normal blood pressure and may manifest tachycardia and, often, tachypnea. In early shock, except for septic shock, peripheral pulses are diminished in comparison with central pulses. As shock progresses and stroke volume decreases, the pulse pressure narrows, and the peripheral pulses become weak or “thready” and finally nonpalpable. Early septic
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Table 40-4. Pediatric Glasgow Coma Scale Activity
Eye opening
Verbal
Motor
Table 40-6. Staging of Reye Syndrome
Best Response
Score
Spontaneously To speech To pain None Oriented Words Vocal sounds Cries None Obeys commands Localizes pain Flexion to pain Extension to pain None
4 3 2 1 5 4 3 2 1 5 4 3 2 1
Normal Total Score Based on Age Birth-6 months 9 7-12 months 11 1-2 years 12 2-5 years 13 >5 years 14
Stage I
Stage II
Stage III Stage IV
Stage V
Lethargy, follows verbal commands, normal posture, purposeful response to pain, brisk pupillary light reflex, and normal oculocephalic reflex Combative or stuporous, inappropriate verbalizing, normal posture, purposeful or nonpurposeful response to pain, sluggish pupillary reaction, conjugate deviation on doll’s eye maneuver Comatose, decorticate posture, decorticate response to pain, sluggish pupillary reaction, conjugate deviation on doll’s eye maneuver Comatose, decerebrate posture and decerebrate response to pain, sluggish pupillary reflexes, and inconsistent or absent oculocephalic reflex Comatose, flaccid, no response to pain, no pupillary response, no oculocephalic reflex
From Tasker RC, Dean JM, Rogers MC: Reye syndrome and metabolic encephalopathies. In Rogers MC (ed): Rogers Textbook of Pediatric Intensive Care, 2nd ed. Baltimore, Williams & Wilkins, 1992, p 792.
Adapted from Simpson D, Reilly P: Pediatric coma scale. Lancet 1982;2:450.
Table 40-5. Reed Classification of Coma
Grade 0* Grade 1* Grade 2*
Grade 3† Grade 4†
Asleep Can be aroused Will answer questions Comatose Withdraws from painful stimuli Intact reflexes Comatose Does not withdraw from painful stimuli No respiratory, circulatory depression Intact reflexes Comatose Reflexes absent No respiratory, circulatory depression Comatose Reflexes absent Respiratory or circulatory problems
Adapted from Ellenhorn MJ, Barceloux DE: Medical Toxicology, Diagnosis and Treatment of Human Poisoning. New York, Elsevier Science, 1988, p 17. *Good prognosis. †
Very serious, may need measures to enhance elimination.
shock or “warm” shock is often characterized by a widened pulse pressure and bounding pulses. End-organ perfusion is best evaluated in the skin, kidneys, and brain. The skin should be checked for temperature, color, and capillary refill. Cool extremities, pallor, mottling, peripheral cyanosis, and capillary refill of more than 2 seconds indicate poor perfusion. As perfusion worsens, the coolness of the extremities extends proximally. Urine output may not be helpful in the initial evaluation of a patient, but it becomes an important marker to monitor during therapy. As renal perfusion improves, urine flow rate increases. The patient’s alteration in consciousness may be a consequence of shock. In early stages of shock, the patient is
typically lethargic or confused. Lethargy alternating with combativeness is often seen. Infants older than 1 to 2 months of age should normally focus on their parents’ faces. Failure to recognize parents is a sign of poor perfusion. Infants may also be irritable and have a weak cry. As shock progresses, changes in level of consciousness become more profound. The child may progress from responding to voice to responding to pain only and may subsequently become unresponsive. History During stabilization, a history of the patient must be obtained by another physician or nurse if available. Pertinent questions should focus on the recent history preceding the change in mental status, the medical history, and a family history, particularly of seizures or encephalopathy. Did the child sustain any traumatic injuries in the previous few days? Has the child been febrile, or are there other signs or symptoms of infection or systemic disease? A dietary history in infants presenting with a depressed level of consciousness is paramount and may raise suspicion of hypoglycemia (fasting or emesis) or hyponatremia (ingestion of free water). Exposure to drugs or toxins should be suspected in any patient with a sudden onset of unexplained symptoms (coma, seizures) or a gradual onset of symptoms preceded by a period of confusion or delirium. The caregivers should be asked directly about possible access to medications, illicit drugs, and environmental toxins. RAPID NEUROLOGIC ASSESSMENT After stabilization, the next phase in management is a rapid neurologic assessment (see Table 40-3), which should take no more than a few minutes. The primary goal is to determine whether there is a potentially rapidly progressive intracranial process that may be life-threatening, such as an expanding mass lesion (subdural or epidural hematoma), and whether patients are rapidly deteriorating. A secondary objective is to provide prognostic and triage information to other personnel who may be involved with the child in the future. This information permits comparisons of sequential examinations and is important in the patient who receives medications
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Figure 40-1. Rostral-caudal deterioration in coma. (From Tasker RC, Dean JM, Rosen MC: Reye syndrome and metabolic encephalopathies. In Rogers MC [ed]: Textbook of Pediatric Intensive Care, 2nd ed. Baltimore, Williams & Wilkins, 1992, p 778.)
(neuromuscular blockers, CNS depressants) in the emergency department that may obscure subsequent neurologic findings. The rapid assessment includes an evaluation for traumatic injuries, focal neurologic findings, brainstem dysfunction, and clinically significant intracranial hypertension. Traumatic Injuries Traumatic injuries can result in life-threatening illnesses at any age, including newborns. The head and neck should be carefully inspected and the skull palpated for evidence of trauma (Table 40-10).
Table 40-7. Classification of Hepatic Encephalopathy
Grade 0 Grade I Grade II Grade III Grade IV
Normal Altered spatial orientation, sleep patterns, and affect Drowsy but arousable, slurred speech, confusion, and asterixis Stuporous but responsive to painful stimuli Unresponsive, with decorticate or decerebrate posturing possible
From Rogers EL, Perman JA: Gastrointestinal and hepatic failure. In Rogers MC (ed): Textbook of Pediatric Intensive Care, 2nd ed. Baltimore, Williams & Wilkins, 1992, p 1151.
In infants, a bulging fontanelle represents raised intracranial pressure, which may have various causes. In the absence of a febrile illness, trauma, including that caused by shaken-baby syndrome (child abuse), should be suspected in any infant with a bulging fontanelle. Retinal hemorrhages are often present on funduscopic examination in children with the shaken-baby syndrome (see Chapter 36). Focal Neurologic Findings The presence of focal findings is determined by examination of a child’s pupils for asymmetry in size or reactivity and examination of the motor system for asymmetrical movement of the extremities or face. The motor response is part of the Glasgow Coma Scale. Brainstem Dysfunction Brainstem function is evaluated by observing the child’s respiratory pattern, assessing corneal reflexes, and testing oculocephalic (doll’s eye) or oculovestibular (cold caloric) reflexes. The oculocephalic reflex should not be checked unless a cervical spine injury has been ruled out. Significant brainstem dysfunction is rarely associated with a normal breathing pattern (Fig. 40-3). Cheyne-Stokes respiration is a pattern of breathing in which periods of hyperpnea alternate with shorter apneic phases, observed in the presence of bilateral hemispheric or diencephalic dysfunction. It may also precede transtentorial herniation. The hyperpneic periods have a characteristic smooth, crescendo-decrescendo pattern.
Hypoglycemia* Inborn errors of metabolism* Hyperammonemia Hepatic failure Renal diseases Uremic encephalopathy Hypertensive encephalopathy Dialysis encephalopathy (dysequilibrium syndrome) Hyperosmolar states Hypernatremia Hyperglycemia–diabetes mellitus* Hypoosmolar states Hyponatremia* Rapid decrease in osmolality in hyperosmolar states Endocrine disorders Adrenal insufficiency Hyperthyroidism and hypothyroidism Hypoparathyroidism Mineral abnormalities Hypercalcemia Hypocalcemia Hypermagnesemia Hypomagnesemia Hypophosphatemia Hypercapnia Hypoxia* Shock* Vitamin deficiency and dependency states Nicotinic acid Pantothenic acid Pyridoxine Thiamine Vitamin B12 Intussusception encephalopathy Methemoglobinemia Acidosis Alkalosis Porphyria Reye syndrome ? Hemorrhagic shock and encephalopathy syndrome Mitochondrial encephalopathies
Metabolic/Systemic Sympathomimetics Anticholinergics Phenothiazines PCP LSD Marijuana Cocaine Heavy metals (lead) Salicylates Organophosphates and carbamates Antihistamines Industrial solvents (inhaled) Alcohols Narcotics Sedative-hypnotics Barbiturates Carbon monoxide Tricyclic antidepressants Carbamazepine Cyanide Methaqualone
Toxic* Concussion* Cerebral contusion Epidural hematoma Subdural hematoma Brainstem Epidural contusion Diffuse axonal shear injury Cerebral edema* Intraparenchymal hemorrhage Intraventricular hemorrhage (neonate)* Obstructive hydrocephalus Posttraumatic seizure Fat embolism
Traumatic*
LSD, lysergic acid diethylamide; PCP, phenylcyclohexyl piperidine (phencyclidine HCl); ?, unknown etiology.
*Common.
Viral Aseptic meningitis* Encephalitis* ? Reye syndrome ? Hemorrhagic shock and encephalopathy syndrome Postinfectious encephalomyelitis Systemic infection with shock Bacterial Meningitis* Brain abscess Epidural empyema Subdural empyema Systemic infection with shock Toxic shock syndrome Fungal Fungal meningitis Fungal brain abscess Protozoan Meningitis Abscess Postimmunization encephalopathy
Infectious
Table 40-8. Etiologic Classification of Altered Mental Status in Children
Tumor Hydrocephalus Hydrocephalus with shunt malfunction Subdural hematoma Epidural hematoma Brain abscess Subdural empyema Epidural empyema Cerebral edema Intracranial hemorrhage Cerebrovascular accident
Anatomic Cardiac arrest Cardiac arrhythmia Severe shock Near-drowning Neonatal asphyxia* Hypoxemic respiratory failure Carbon monoxide poisoning Cyanide toxicity Anaphylaxis Asthma
HypoxicIschemic Postictal state* Status epilepticus* Absence status Complex partial seizure
Epileptic Embolism Spontaneous intraparenchymal hemorrhage Subarachnoid hemorrhage Vasculitis Lupus erythematosus Hypertensive encephalopathy Acute confusional migraine*
Vascular
Conversion disorders* Catatonic schizophrenia
Psychological
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Table 40-9. Common Causes of Altered Mental Status by Age Neonate
Infant
Hypoglycemia Birth asphyxia Congenital anomalies of the central nervous system Systemic infection with shock Cardiogenic shock Congenital infection Bacterial meningitis Inborn errors of metabolism Hypocalcemia Intraventricular hemorrhage Seizures Birth trauma
Meningitis Bacterial Viral Trauma Abuse/shaken-baby syndrome Asphyxia Apparent life-threatening event Intentional suffocation Systemic infection with shock Ingestion Inborn errors of metabolism Hypoglycemia Hyponatremia Hypernatremia Hypocalcemia Encephalitis Postimmunization encephalopathy Hemorrhagic shock and encephalopathy syndrome Intussusception encephalopathy Seizures
Central neurogenic hyperventilation is encountered with midbrain dysfunction; patients with this problem are tachypneic and hyperpneic. Apneustic breathing is associated with damage in the middle to lower pontine region. This pattern is characterized by a prolonged pause at full inspiration. Clusters of breaths separated by periods of apnea may be observed in patients with low pontine to upper medullary lesions, whereas medullary lesions result in ataxic or irregular breathing, slow regular breathing, or agonal respiration. Absent or asymmetrical corneal reflexes or abnormal oculocephalic or oculovestibular reflexes also suggest serious brainstem involvement.
Child
Meningitis Bacterial Viral Encephalitis Trauma Ingestion Reye syndrome Systemic infection with shock Seizure Near-drowning Hypoglycemia Intussusception encephalopathy Diabetic ketoacidosis
Adolescent
Meningitis Bacterial Viral Encephalitis Intentional ingestion Recreational drug/alcohol use Suicide gesture or attempt Often involves multiple agents Trauma Seizures Diabetic ketoacidosis Systemic infection with shock Toxic shock syndrome Reye syndrome Spontaneous intracranial hemorrhage Psychological
hyperventilated and given mannitol before the CT scan. Children with altered mental status and a suspected head injury but without focal findings or brainstem dysfunction should also undergo emergency CT scanning. If their Glasgow Coma Scale score is 8 or less, an airway should be secured before the scan. The absence of a history of trauma or physical findings suggestive of a rapidly progressive intracranial process does not preclude a traumatic or an anatomic cause of coma. A child may have a subarachnoid hemorrhage (ruptured aneurysm, arteriovenous malformation) or hydrocephalus without any of the aforementioned signs or symptoms of raised intracranial pressure.
Intracranial Hypertension
REVERSAL OF IMMEDIATELY TREATABLE TOXIC OR METABOLIC CAUSES
Indications of clinically significant intracranial hypertension are usually apparent during an assessment of pupillary responses, vital signs, and motor responses (Tables 40-11 and 40-12). A unilaterally fixed and dilated pupil in a patient who is not awake represents uncal herniation precipitated by an increase in intracranial pressure in the supratentorial space. Impending central herniation from increased pressure on the caudal brainstem may be preceded by the Cushing triad of hypertension, bradycardia, and irregularities of respiration. The three components are not necessarily all present together, however. Decerebrate or opisthotonic posturing should also be considered a sign of raised intracranial pressure in an unresponsive patient. A lateral rectus palsy (cranial nerve VI) may also be an early sign of intracranial hypertension. A history of headaches, persistent vomiting, or ataxia may also suggest raised intracranial pressure. A child with focal neurologic findings or brainstem dysfunction is considered to have a rapidly progressive intracranial lesion until proven otherwise. These children require an emergency head CT scan and an assessment for other life-threatening injuries if trauma is suspected. Vital signs should be monitored frequently. Intubation is performed before the CT scan if the Glasgow Coma Scale score is 8 or less or if signs of increased intracranial pressure are present. If raised intracranial pressure is suspected, the child should be
Hypoglycemia and narcotic intoxication are two rapidly reversible causes of coma. Hypoglycemia is a medical emergency that must be reversed because sustained hypoglycemia may result in permanent neurologic damage (see Chapter 61). When vascular access is achieved, blood can be obtained for laboratory studies, including a blood glucose level determination. However, once an intravenous catheter has been placed, all unresponsive children should receive 0.5 to 1.0 g/kg (2 to 4 mL/kg) of 25% dextrose unless a diagnosis other than hypoglycemia is apparent. If the child’s mental status improves or if there is laboratory confirmation of hypoglycemia, the dextrose bolus should be followed by a continuous infusion of glucose and electrolytes to prevent rebound hypoglycemia. Naloxone (0.1 mg/kg, maximum 2 mg; may repeat every 2 to 3 minutes if no response) is also administered to all children who have marked depression of consciousness without an obvious cause, particularly if hypoventilation is observed. Miosis is not a necessary finding because ingestion of multiple agents, including narcotics, may not result in small, constricted pupils. Large ingestions of narcotics may necessitate larger single doses of naloxone because of the competitive nature of its antagonistic effect, or they may necessitate multiple doses because its half-life is shorter than that of the narcotic ingested.
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Table 40-10. Signs of Head Trauma Possibly Associated
with Intracranial Disease
Stabilization
ABCs Vascular access
Rapid neurologic assessment
Focal neurologic findings Brainstem dysfunction Head trauma
General
No
Reverse immediately treatable toxic or metabolic causes
Yes • Secure airway • Maintain vital signs • Treat intracranial pressure • Assess for other evidence of trauma • CT scan
Response to glucose? No Yes Hypoglycemia Response to naloxone? Yes No
Intoxication
Clinical signs of CNS infection? No
Yes Lumbar puncture
Determine level of CNS function and etiology
Detailed physical examination and laboratory studies Abnormal
Intoxication Metabolic/systemic disorders Hypoxic-ischemic Epileptic
Normal
CT Scan Normal Intoxication Epileptic Psychologic
Abnormal Anatomic lesions Vascular
Figure 40-2. Management approach to coma. ABCs, airway, breathing, and circulation; CNS, central nervous system; CT, computed tomography.
Signs of Basilar Skull Fracture
Lacerations Hematomas Ecchymosis Swelling Palpable crepitations Step-off of skull
Hemotympanum CSF rhinorrhea CSF otorrhea “Raccoon eyes” Battle sign
CSF, cerebrospinal fluid.
Another reversible cause of coma is a benzodiazepine ingestion. Flumazenil, a specific competitive antagonist of benzodiazepines, should not be routinely administered to unresponsive children in the emergency department. There are no compelling data suggesting that flumazenil reverses respiratory depression. Administration of flumazenil to a patient who has ingested multiple agents can precipitate seizures, particularly if the concomitant ingestion can cause seizures (e.g., tricyclic antidepressants). The next question to be answered is whether there are clinical signs or symptoms of meningitis or encephalitis. Specifically, the child should be assessed for the presence of a bulging fontanelle, nuchal rigidity, and Kernig or Brudzinski signs (see Chapter 52). Prior administration of antibiotics does not affect meningeal irritation. Most (85%) children with meningitis have an alteration in mental status (53% lethargic, 22% stuporous, 10% comatose). Focal neurologic findings or seizures may be seen in children with meningitis. If meningitis is suspected, a lumbar puncture, including measurement of the opening pressure, should be performed unless the procedure is contraindicated (Table 40-13). If a contraindication exists, the child should be stabilized, receive empirical antimicrobial therapy, and undergo head CT scanning. The patient should undergo lumbar puncture as soon as it is no longer contraindicated. If a patient presents with sudden nuchal rigidity not preceded by a prodromal illness, a subarachnoid hemorrhage should be suspected and a CT scan performed before the lumbar puncture.
Figure 40-3. Abnormal respiratory patterns associated with pathologic lesions (shaded areas) at various levels of the brain. Tracings by chest-abdomen pneumography; inspiration reads up. A, Cheyne-Stokes respiration. B, Central neurogenic hyperventilation. C, Apneusis. D, Cluster breathing. E, Ataxic breathing. (Adapted from Plum F, Posner JB [eds]: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1982, p 34.)
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Table 40-11. Signs of Incipient Downward Herniation Central
Arousal Breathing Pupils Oculocephalic responses Motor signs
Uncal
Impaired early, before other signs Sighs, yawns, sometimes Cheyne-Stokes respirations First, small reactive (hypothalamus); then one or both approach midposition Initially sluggish, later tonic conjugate Early hemiparesis opposite to hemispheric lesion followed late by ipsilateral motor paresis and extensor plantar response
Impaired late, usually with other signs No early change Ipsilateral pupil dilates, followed by somatic third nerve paralysis Unilateral third nerve paralysis Motor signs late, sometimes ipsilateral to lesion
From Plum F: Neurology/sustained impairments of consciousness. In Wyngaarden JB, Smith LH, Bennett JC (eds): Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 2050.
LEVEL OF CENTRAL NERVOUS SYSTEM FUNCTION AND CAUSE The coma can be initially considered stable if (1) focal neurologic findings are not present, (2) there is no evidence of significant brainstem dysfunction, (3) intracranial pressure is not raised, (4) there is no evidence of head trauma or CNS infection, and (5) the child does not have a rapidly reversible toxic or metabolic cause. A detailed physical examination and laboratory evaluation can then be undertaken to determine the level of CNS function and the cause of the coma. Physical Examination Coma can be thought of as resulting from hemispheric or brainstem (including reticular activating formation) dysfunction. Dysfunction in either location may be produced by anatomic or nonstructural causes (referred to as metabolic causes in this discussion). The origin of coma (hemispheric versus brainstem) and its cause (metabolic versus structural) can be elucidated by evaluation of pupillary size and reactivity, eye movements, respiratory pattern, and motor responses. Pupillary light reflexes are generally preserved in metabolic encephalopathy, whereas their absence strongly suggests a structural lesion. The only exception to the latter is drug effect, particularly with potent anticholinergic compounds, such as glutethimide, atropine, or scopolamine, which produce fixed and dilated pupils. The balance between sympathetic and parasympathetic stimulation, which result in pupillary dilation and constriction, respectively, normally determines pupillary size and reactivity. A unilaterally dilated and fixed pupil is a sign of uncal herniation with entrapment of the oculomotor nerve. Parasympathetic fibers innervating the eye
accompany the oculomotor nerve. Sympathetic fibers originate from at least four hypothalamic nuclei so that diencephalic dysfunction results in small, reactive pupils. Hypothalamic damage often results in ipsilateral miosis associated with Horner syndrome (miosis, ptosis, and anhidrosis). Anhidrosis, in contrast to that observed with cervical lesions, involves the entire ipsilateral half of the body. This is an important clinical finding in that it may portend imminent transtentorial herniation. Injury to nuclei located in the midbrain disrupts both sympathetic and parasympathetic pathways, resulting in midsized, fixed pupils. Damage to the midbrain tectal regions also produces midposition or slightly large, fixed pupils. In contrast to nuclear damage, however, accommodation may be intact, so that pupillary size fluctuates spontaneously. Pontine lesions, principally hemorrhage, interfere with descending sympathetic fibers, causing symmetrically small pupils for which a magnifying glass may be needed to detect a light reflex. Lateral medullary lesions may also produce Horner syndrome, whereas central herniation results in fixed, dilated pupils. Figure 40-4 summarizes pupillary findings in comatose patients. Evaluation of eye movements is helpful in differentiating hemispheric from brainstem causes of coma. Frontal regions of the cerebral hemispheres are responsible for voluntary eye movements, the quick phase of nystagmus, and control over brainstem reflexes that determine eye movements. Bilateral hemispheric depression may result in roving eye movements if brainstem function is intact. Because stimulation of a frontal gaze center causes conjugate deviation of the eyes to the opposite side, tonic lateral deviation of the eyes implies a seizure emanating from the contralateral hemisphere. Eye deviation may also result from an ipsilateral hemispheric injury with unopposed stimulation from the undamaged hemisphere or from a contralateral pontine lesion. The degree of eye deviation is usually more dramatic with hemispheric damage than with brainstem damage.
Table 40-12. Characteristics of Supratentorial Lesions
Leading to Coma Initiating symptoms usually cerebral-focal: aphasia; focal seizures; contralateral hemiparesis, sensory change, or neglect; frontal lobe behavioral changes; headache Dysfunction moves rostral to caudal: e.g., focal motor → bilateral motor → altered level of arousal Abnormal signs usually confined to a single or adjacent anatomic level (not diffuse) Brainstem functions spared unless herniation develops From Plum F: Neurology/sustained impairments of consciousness. In Wyngaarden JB, Smith LH, Bennett JC (eds): Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 2050.
Table 40-13. Contraindications to Lumbar Puncture
Clinically important cardiorespiratory compromise in a neonate or young infant Signs of raised intracranial pressure (pupillary changes, ptosis, hypertension, bradycardia, posturing, cranial nerve VI palsy, retinal changes) Skin or soft tissue infection overlying area where lumbar puncture is to be performed Focal neurologic findings Suspected brain abscess (illness duration longer than expected for meningitis; focality)
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714 METABOLIC
Small reactive
DIENCEPHALIC Small reactive
TECTAL Large “fixed”, hippus
Figure 40-4. Pupils in comatose patients. (Adapted from Plum F, Posner JB [eds]: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1982, p 46.)
PONS Pinpoint
III NERVE (UNCAL) Dilated, fixed
MIDBRAIN Midposition, fixed
If the patient’s eyes are not moving, then reflex eye movements are tested by the oculocephalic and oculovestibular responses (Fig. 40-5). These maneuvers involve the same major neuronal pathways. Afferent fibers from the labyrinth, cerebellum, and cervical muscles reach the vestibular nuclei (cranial nerve VIII) in the medulla. Fibers from the vestibular nuclei then course to the ipsilateral abducens nuclei (cranial nerve VI). Fibers from the abducens nuclei then decussate in the midpons and ascend in the medial longitudinal fasciculus to reach the contralateral oculomotor nuclei (cranial nerve III). Positive reflexes indicate the absence of cortical input on an intact brainstem. The oculocephalic reflex is elicited by rotating the child’s head from side to side and observing the eye movements. If brainstem function is intact, the eyes deviate in a direction opposite to the head movement. Both left and right lateral rotation should be tested. This reflex should then be tested in a vertical plane by rapidly flexing and extending the neck. A positive response is upward gaze when the neck is flexed and downward deviation when the head is extended. Such maneuvers are contraindicated if cervical spine injury is suspected. The oculovestibular reflex is tested by instilling ice water into the ear canal. The ear canal must be visualized to ensure that there is no obstruction and that the tympanic membrane is intact. The head is then placed at a 30-degree angle from the horizontal so that the semicircular canal is vertical, and up to 120 mL of ice water is then injected slowly into the external ear canal over a few minutes through an angiocatheter. After a minimum of 5 minutes, the other ear may be tested; this interval allows time for the oculovestibular system to reequilibrate. A positive response in an awake patient is nystagmus with the slow component toward the irrigated ear and the fast component away from the stimulus. With bilateral hemispheric depression, the fast phase of nystagmus dissipates, and the eyes are tonically deviated toward the irrigated ear. Both the oculocephalic and oculovestibular reflexes are absent in patients with low brainstem lesions because neurotransmission between the vestibular and abducens nuclei is interrupted. In patients with damage to the medial
longitudinal fasciculus, the ipsilateral eye fails to adduct on irrigation of the contralateral ear canal. However, the opposite eye abducts normally. For example, with a lesion in the left medial longitudinal fasciculus, the right eye abducts, but the left eye does not, in response to irrigating the right ear canal. This reaction is caused by disruption of fibers between the abducens and the contralateral oculomotor nuclei (see Fig. 40-5). In addition to assessing ocular motility, the examiner should test the corneal reflex and determine the presence or absence of a blink. The absence of a blink in response to a loud noise or bright light implies dysfunction of the pontine reticular formation secondary to either metabolic or structural causes. Unilateral absence of a blink implies a facial nerve lesion. The afferent limb of the corneal reflex is carried by the trigeminal nerve (cranial nerve V). The normal effector response involves both upward deviation of the eye (oculomotor nerve) and closure of the eyelid (facial nerve). A normal reflex suggests that the integrity of pathways between the midbrain and the pons has not been violated. Examination of the motor system includes observation of body position, spontaneous movements, and response to noxious stimuli (Fig. 40-6). A normal body position usually denotes an intact brainstem, as do spontaneous, nonposturing movements. Hemiparesis or hemiplegia implies a structural lesion in the contralateral hemisphere or subcortical region or an ipsilateral spinal cord injury. The presence of hypertonia or hyperreflexia suggests previous corticospinal tract disease or an acute brainstem injury at the midbrain-pontine level. It can also be observed in patients with severe metabolic derangements, such as hepatic coma, hypoglycemia, anoxia, and uremia. Hypotonia implies bilateral hemispheric dysfunction or a medullary or spinal cord lesion. In patients with severe depression of brain function, motor function can be assessed only after the application of a noxious stimulus, such as a sternal rub or increasing subungual pressure to the fingernails or toenails. Ascending sensory pathways to the cerebral hemispheres are intact, and descending motor pathways are functioning to some degree if the response to a noxious stimulus includes verbalization or eye opening or a normal
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Figure 40-5. Ocular reflexes in unconscious patients. The upper section illustrates the oculocephalic (upper row) and oculovestibular (lower row) reflexes in an unconscious patient whose brainstem ocular pathways are intact. In the middle section of the drawing, the effects of bilateral medial longitudinal fasciculus (MLF) lesions on oculocephalic and oculovestibular reflexes are shown. The left portion of the drawings illustrates that oculocephalic and oculovestibular stimulation deviates the appropriate eye laterally and brings the eye, which would normally deviate medially, only to the midline, because the medial longitudinal fasciculus, with its connections between the abducens and oculomotor nuclei, is interrupted. The right portion is normal with MLF lesions. The lowest section of the drawing illustrates the effects of a low brainstem lesion. On the left, neither oculovestibular nor oculocephalic movements cause lateral deviation of the eyes, because the pathways are interrupted between the vestibular nucleus and the abducens area. Likewise, in the right portion of the drawings, neither oculovestibular nor oculocephalic stimulation causes vertical deviation of the eyes. (Adapted from Plum F, Posner JB [eds]: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1982, p 55.)
Figure 40-6. Motor responses to noxious stimuli. A, Localization of pain as patient attempts to remove stimulus. B, Decorticate posturing. C, Decerebrate posturing. D, Flaccid patient with no response. (Adapted from Plum F, Posner JB [eds]: The Diagnosis of Stupor and Coma, 3rd ed. Philadelphia, FA Davis, 1982, p 66.)
motor response, such as localization of the stimulus, withdrawal of the limb, or movement away from the stimulus. Decorticate posturing implies hemispheric dysfunction with an intact brainstem (see Fig. 40-6). Decerebrate posturing is more ominous (see Fig. 40-6). Opisthotonos with clenched teeth is a severe form of decerebration. This response usually suggests brainstem compression or a severe structural injury to the midbrain-pontine region. It can also occur in association with severe metabolic diseases, such as hepatic coma, anoxia, and hypoglycemia. Less commonly, decerebrate posture may represent delayed cortical demyelination after a hypoxic-ischemic injury. Pontomedullary or spinal cord damage is associated with a flaccid response to noxious stimulation. A patient’s breathing pattern is also helpful in localizing the area of CNS dysfunction. Hyperventilation can be observed not only in midbrain structural lesions but also in toxic-metabolic encephalopathies as a primary response to stimulation of the respiratory center (salicylate, theophylline, hepatic coma) or as a compensatory response to a metabolic acidosis. This pattern is also seen with raised intracranial hypertension, as may occur in a child with meningitis. Hypoventilation with a normal rhythm, particularly if associated with a symmetrically depressed motor examination, usually implies global CNS depression secondary to drug ingestion. A detailed physical examination should be performed next and may provide further clues to the cause of the coma (Table 40-14). Several laboratory or ancillary studies should be obtained in all patients, whereas ordering of other studies depends on clinical
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Table 40-14. Physical Examination and Diagnosis of Coma System
Skin
Sign
Dry Moist Pigment Nevi Petechiae Cyanosis Erythema Butterfly rash Desquamation Nail changes
Breath odor
Fruity Feculent Garlic
Scalp Eyes
Ears Nose Mouth Neck Thyroid Heart Abdomen Extremities
Almonds Wintergreen Ammoniacal Acrid (pearlike) Contusions Vasodilation Chemosis Periorbital ecchymosis Subhyaloid hemorrhage Vasospasm (retina) Hemorrhage Otitis media Cerebrospinal fluid rhinorrhea Scarred tongue Pigmentation Lead lines Rigid Enlarged Murmur Hepatomegaly Fracture Ecchymosis
Disorder
Dehydration, myxedema, adrenal insufficiency, anticholinergic poisoning Syncope Addison disease Tuberous sclerosis with seizures Bacteremia, subacute bacterial endocarditis, idiopathic thrombocytopenic purpura Hypoxia, congenital heart disease with cerebral embolism, methemoglobinemia Carbon monoxide, atropine, or mercury intoxication Lupus erythematosus, tuberous sclerosis Vitamin A intoxication, scarlatina Splinter hemorrhage–endocarditis Mycotic infection and hypoparathyroidism Periungual fibroma (tuberous sclerosis) Diabetic ketoacidosis; amyl nitrate, alcohol, isopropyl alcohol poisonings Hepatic encephalopathy Selenium toxicity, arsenic poisoning, organophosphate poisoning Cyanide poisoning Methyl salicylate poisoning Uremia Paraldehyde, chloral hydrate poisoning Trauma Sagittal sinus thrombosis Cavernous sinus thrombosis Blow-out orbital fracture Subarachnoid hemorrhage Hypertensive encephalopathy Basilar skull fracture Brain abscess, lateral sinus thrombosis Basilar skull fracture Seizure disorder Addison disease Plumbism (lead intoxication) Meningitis, pneumonia, subarachnoid hemorrhage, encephalitis Myxedema, thyrotoxicosis Subacute endocarditis, brain abscess Leukemia, hepatic failure, heart failure Trauma, fat embolism Trauma, hemorrhagic diathesis
Adapted from Tait VF, Dean JM, Hanley DF: Evaluation of the comatose child. In Rogers MC (ed): Textbook of Pediatric Intensive Care, 2nd ed. Baltimore, Williams & Wilkins, 1992, p 741.
suspicions formulated from the history and physical examination (Table 40-15). Patients with suspected anatomic causes of coma should undergo emergency head CT scanning, whereas those with a suspected CNS infection should undergo lumbar puncture. Other studies to consider are electrocardiography to rule out conduction abnormalities, seen with many drugs; liver function studies; blood ammonia determination; measurement of calcium, magnesium, and phosphorus; and serum osmolality measurement. An osmolal gap as well as an anion gap should be calculated. The osmolal gap is the difference between the measured and calculated serum osmolality (normal is 3 g/dL below admission level) Falling platelet count (65%) than are older children. Polycythemia has been estimated to be present in 1.5% of newborns. It is most commonly encountered in neonates who are born at high altitude, those who are small for gestational age, infants of diabetic mothers, or recipients in twin-twin transfusion syndrome; it may also be seen in neonatal hyperthyroidism or adrenogenital syndrome. Clinical signs of the elevated hematocrit are present in some but not all affected infants and include plethora, acrocyanosis, impaired renal function, poor feeding, apnea, tachypnea, hypoglycemia, and indirect hyperbilirubinemia. Neurologic symptoms include jitteriness, irritability, lethargy, seizures, and focal motor deficits. Most cases of polycythemia are idiopathic or secondary to acquired abnormalities of fetal oxygen delivery. Nonetheless, other polycythemias bearing autosomal dominant or recessive inheritance patterns have been described. These familial polycythemias are associated with mutant hemoglobins that create abnormalities of oxygen delivery. Polycythemia and its resultant hyperviscosity may contribute to stroke in neonates. Inadequate cerebral perfusion and cerebrovascular thrombosis cause cerebral ischemia. Although most of the systemic complications of polycythemia resolve with adequate treatment, neurologic signs frequently do not. Cerebral infarction resulting from polycythemia-related ischemia causes deficits that resolve either slowly or not at all. Neurologic sequelae may be present in up to 35% of neonates with symptomatic polycythemia. If signs of polycythemia are found in a neonate, further evaluation should be undertaken. Venous or arterial hematocrit, rather than capillary hematocrit, should be measured. If the family history and physical examination findings suggest a hereditary polycythemia, hemoglobin electrophoresis should be undertaken. Routine hemoglobin electrophoresis does not elucidate high oxygen-affinity hemoglobinopathies in all cases. If clinical suspicion is high, the heat instability test for unstable hemoglobins and oxygen dissociation assays can be utilized. Neuroimaging should be used to assess for cerebral infarction.
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Treatment of symptomatic patients consists of hematocrit reduction by a partial exchange transfusion until the hematocrit is reduced to 50% to 55%. The equation to calculate the amount of blood removed and the amount of normal saline infused is volume (milliliters) = (current hematocrit − 50) × weight in kilograms × 90 mL/current hematocrit Neonatal Cerebral Venous Thrombosis Thrombosis may occur in cerebral veins that conduct deoxygenated blood from the parenchyma to the dural sinus system. These sinuses—the sagittal, straight, transverse, cavernous, and petrous— then convey the blood to the jugular veins. Occlusion of flow anywhere in these venous conduits leads to ischemia, infarction, and even hemorrhage. Infection, dehydration, polycythemia, congenital heart disease, extracorporeal membrane oxygenation, and protein C deficiency and other hypercoagulable states such as factor V Leiden and methyltetrahydrofolate reductase mutations have all been implicated as causes of cerebral venous thrombosis in neonates. However, often no cause is found for this occlusion of the cerebral venous system in neonates. Most affected patients are full-term infants. Adjacent areas of brain parenchyma reveal neuropathologic changes typical of infarction. The only signs may be lethargy and focal seizures. The features of slowly developing focal motor deficits, headache, and cranial nerve dysfunction found in older children and adults with cerebral venous thrombosis is seldom observed. Neuroimaging reveals the venous stasis best if magnetic resonance phase imaging, which detects blood flow, or magnetic resonance venography is performed, as well as conventional T1- and T2weighted imaging. Treatment of underlying infection, metabolic disorder, or coagulopathy is necessary. However, if the cerebral venous thrombosis appears to be idiopathic, no anticoagulation is necessary. Follow-up information has been limited, but the neurologic prognosis appears good in the idiopathic cases. Intracranial Hemorrhage in the Neonate Intracranial hemorrhage occurs in neonates in one of four different neuroanatomic distributions: subdural (SDH), subarachnoid (SAH), intraparenchymal (IPH), or intraventricular (IVH). Whereas SDH occurs more commonly in full-term infants, the other three types of hemorrhage are more common in premature infants. Subdural Hemorrhage
SDH in neonates usually results from head trauma during birth. Thus, factors of labor and delivery promoting the application of increased force on the fetal head are liable to promote SDH. Cephalopelvic disproportion, rigidity of the bony pelvis, prolonged duration of labor, unusual presentations, or the need for prolonged manipulation or forceps application may each generate increased forces on the fetal head and cause SDH. As a result, shearing forces may create tears in the vein of Galen or tears of superficial cerebral veins. If forces are extreme, tears at the junction of falx and tentorium can generate large subdural blood collections in the relatively small posterior fossa, culminating in compression of the brainstem and cerebellar tonsillar herniation. The incidence of SDH has steadily declined recently as a result of improved obstetric practice. Clinical features of SDH depend on the location and size of the hemorrhage. Tentorial laceration (Fig. 41-1) can cause stupor or even coma. Pupillary and extraocular movement abnormalities are common. Dystonic postures such as retrocollis or opisthotonos are seen. Finally, abnormalities of respiratory pattern regulation such as apneustic or ataxic respirations are seen and signify imminent
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Figure 41-1. A and B, Generalized tonic seizures, lethargy progressing to coma, and irregular respiratory pattern were observed in a 1-day-old full-term infant. Cranial computed tomographic scan demonstrates a hyperdense region emanating from the falx and tentorium (arrows) caused by traumatic tear of tentorium, which resulted in hemorrhage from the straight sinus.
respiratory arrest. Less severe SDHs in the posterior fossa evolve more slowly and cause less severe brainstem dysfunction. Subdural collections of blood over the cerebral surfaces that result from tears of superficial cerebral veins may be asymptomatic. Minimal manifestation consists of irritability. With time the blood may liquefy and draw water into the area by osmotic forces, thus expanding the size of the lesion. If the collection is sufficiently large, seizures occur. Greater pressure may cause oculomotor dysfunction, accompanied by pupillary dilation and ablated pupillary light responses. SDH may escape diagnosis in the first few weeks of life and appear later as a chronic subdural effusion; in this situation, the clinician must suspect child abuse (see Chapter 36). Such an occurrence is marked by a rapidly enlarging head circumference and increased transillumination of the skull. There may also be a combination of acute and chronic SDH in cases of child abuse. Symptomatic SDH is often treated with subdural taps (through the anterior fontanel) to remove the blood and relieve the pressure. Subarachnoid Hemorrhage
Blood can occupy the subarachnoid space in one of two ways. First, blood may reach the subarachnoid space after hemorrhage has occurred in the cerebral parenchyma or in the periventricular region. Second, SAH may result from disruption of the superficial leptomeningeal arteries or of the fragile vessels bridging the subarachnoid space; disruption of either vascular structure leads to direct bleeding into the subarachnoid space, so-called primary SAH. Primary SAH commonly occurs after hypoxic-ischemic brain insults and after fetal head trauma. Mild SAH is clinically the most common type, occurring as an occult phenomenon with few if any manifestations. Greater amounts of blood collecting over the convexities may result in focal motor deficits and often benign seizures. Large SAH accumulating over the convexities has been associated not only with seizures but with infarction of underlying cerebral cortex. The presence of accompanying infarction is indicated by the occurrence of focal seizures. A history of difficult labor and delivery may be associated with large SAH. Cerebral infarction in the setting of SAH has been observed more commonly in full-term infants than in premature infants. When SAH is mild, the neurologic outcome can be good. Even in cases of SAH accompanied by an infrequent seizure or cerebral infarction, the prognosis is often favorable. Adverse consequences appear to be more dependent on the severity of any underlying intrapartum trauma or hypoxic-ischemic brain injury.
Intraparenchymal and Intraventricular Hemorrhage
IPH of the brain occurs in both full-term and preterm infants. Cerebral hemorrhage in the absence of IVH occurs most commonly in full-term infants. Hemorrhage into the parenchyma of the cerebral hemispheres can be caused by head trauma, vascular malformation, coagulopathy, thrombocytopenia, tumor, or infarction. A common cause of prenatal, intrapartum, and postnatal hemorrhage is alloimmune thrombocytopenia, caused by acquired antiplatelet antibodies when a mother becomes sensitized to paternal antigens on fetal platelets. Maternal immune thrombocytopenia may also affect the fetus, producing thrombocytopenia in utero. However, the incidence of neonatal cerebral hemorrhage is much lower in immune thrombocytopenia than in alloimmune thrombocytopenia. Vitamin K deficiency should be considered for breast-fed full-term neonates who present with intracranial hemorrhage. In the absence of recognized coagulation or anatomic abnormalities, cerebral hemispheric IPH has been attributed to hemorrhagic infarction. In premature infants, parenchymal hemorrhage most often occurs in conjunction with severe IVH. Hemorrhage from the friable, unsupported germinal matrix leads to accumulation of intraventricular blood and, often, ventricular distention. These events, in turn, cause impairment of blood flow in the medullary veins located in the periventricular white matter, preventing blood drainage into the greater cerebral venous system. Eventually, the periventricular venous congestion leads to ischemia and a resultant venous infarction. Developmental outcome in full-term infants with IPH depends on the location and extent of the underlying cause. The occurrence of posthemorrhagic hydrocephalus or of moderate to severe asphyxia is predictive of abnormal outcomes, including motor impairment or cognitive delay. In premature infants, the simultaneous occurrence of IVH with IPH carries high risk for major motor deficits and marked cognitive impairment. Evaluation of Stroke in Infants Head ultrasonography detects areas of increased echogenicity in the cerebral cortex. In especially severe cases of ischemia, increased echogenicity of injured subcortical structures such as the thalamus and basal ganglia can be appreciated. Ischemic cortical injury involving the territory of the middle cerebral artery (frontal and parietal lobe regions surrounding the central sulcus) is better revealed by ultrasonography than are other vascular territories. The principal advantages of cranial ultrasonography are its easy portability to the patient’s bedside and its lack of radiation exposure to the infant.
Chapter 41 Stroke in Childhood CT of the brain is useful, particularly for evaluation of full-term infants after a suspected cerebral insult. Diffuse injury appears as abnormal generalized attenuation throughout the cerebral parenchyma with loss of the distinction between gray and white matter; this abnormality may represent cerebral edema. Focal and multifocal brain injury is readily detected by cranial CT. MRI scans obtained within the first 4 days of life in full-term infants with signs of severe HIE reveal white matter abnormalities and indistinct gray matter–white matter junctions on T2-weighted images. DWI can identify areas of recent infarct even earlier than conventional T1- and T2-weighted images. Subsequent images can show chronic changes such as cerebral atrophy, paucity of white matter, delayed myelination, and ventriculomegaly. MRI has proved useful in documenting delay of myelination, a sequel to perinatal ischemic white matter injury not readily discerned with CT. This additional capability has provided a potential explanation for subtle motor deficits found in children who have ischemic brain injury in the perinatal period. As observed in MRI studies of adults, neonatal focal cerebral ischemic injuries may be identified early in their course. MRI also detects neonatal hypoxic-ischemic injuries of basal ganglia not well detected by either head ultrasonography or CT. Moreover, MRI with venography is the procedure of choice in the neonatal period for identification of venous thrombosis. Laboratory testing for the wide variety of etiologic factors underlying stroke should be conducted. The causes include infection, liver dysfunction, coagulopathy, prothrombotic states, organic and amino acid inborn errors of metabolism, urea cycle disorders, and mitochondrial abnormalities.
CHILDREN AGED 1 TO 13 YEARS When stroke occurs in children, focal symptoms are reported and corresponding localized deficits are noted on the neurologic examination, which correlate neuroanatomically with the involved region of the CNS. In older children able to cooperate, findings elicited are helpful in localizing the site of the cerebrovascular event. Lateralized weakness often signifies injury to the contralateral hemisphere, including the regions governing movement. Such motor impairment accompanied by cranial nerve dysfunction on the side of the head opposite to the side of extremity weakness suggests brainstem infarction at a location above the pyramidal decussation. Findings of the sensory examination also may be helpful. Preservation of primary sensory modalities provides assessment of spinothalamic axis (pain and temperature) and posterior column (proprioception) integrity. Loss of pain and temperature sensation on one side of the body, combined with motor weakness, and the presence of proprioceptive deficits on the other side indicate that the cerebrovascular event is in the spinal cord. If the same distribution of motor and sensory disturbances occurs but is accompanied by cranial nerve dysfunction, a brainstem site of injury is likely. Finally, impairment of cortically based sensations such as graphesthesia and stereognosis on one side of the body implies a contralateral hemispheric cause of the observed cortical sensory deficit. Analysis of language function in the older child may provide help in localizing the region of the cerebrovascular event. Unilateral lesions of the dominant hemisphere involving the frontal lobe immediately anterior to the motor strip supplying the face results in a characteristic speech disturbance. Broca (nonfluent) aphasia consists of the patient’s inability to utter or to write the words or phrases that he or she wishes to express. Although the patient knows the thoughts that he or she wishes to express, the volitional motor function for written or oral expression cannot be mustered. Infarction in the more posterior superior temporal lobe results in an aphasia of a different type: Wernicke aphasia, characterized by marked impairment of auditory comprehension. Comprehension of written matter may be impaired as well. Although the patient remains fluent in speech, language is peppered with unintelligible utterances that are meaningless
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(neologisms) or are similar but incorrect versions of the intended word (paraphasias). The larger the injury to this region, the more severe is the impairment of language. Speech in most right-handed people and in 50% of left-handed people is governed by the left hemisphere (so-called left hemispheric dominance). The remaining minority share right hemispheric dominance. The causes of stroke in 1- to 13-year-old children may be considered in two general groups: (1) ischemic stroke and (2) intracranial hemorrhage. The ischemic category comprises embolic, thrombotic, and hypotensive causes of stroke. The category of intracranial hemorrhage includes both IPH and SAH. Ischemic Stroke in Children Congenital Heart Disease
Congenital heart disease remains the most common diagnosable cause of stroke in childhood. Children with cyanotic congenital heart disease (right-to-left shunts or mixing lesions) face the greatest risk (see Chapter 10). An embolic stroke constitutes the most common cerebrovascular event. Cardiac defects involving right-to-left shunts allow emboli originating in peripheral venous circulation to bypass their filtration and removal by the pulmonary vascular bed. Thus, emboli entering the heart via venous return may be shunted to the peripheral arterial circulation, only to lodge in the cerebrovascular tree (Fig. 41-2). Patent foramen ovale contributes significantly to the occurrence of stroke in children and young adults. Echocardiographic evaluation of young patients who have had stroke reveals patent foramen ovale or evidence of right-to-left shunting in many. Transesophageal echocardiography conducted with Valsalva bubble studies for evidence of direct right-to-left flow is the most useful diagnostic test. Valvular defects can cause stroke. Mitral valve prolapse may contribute to the occurrence of embolic stroke in the young. Small emboli are dislodged from the abnormal valve leaflets. Mitral valve prolapse has been estimated to underlie 20% to 30% of strokes in patients younger than 30 years. Echocardiography in both
Figure 41-2. Cranial computed tomographic scan of a 3-month-old boy with trisomy 21 and tetralogy of Fallot who, after cardiac catheterization, had focal seizures involving the right side of the face and right arm. Region of hypodensity in left hemisphere (arrowheads) reflects infarction of the left middle cerebral artery territory, most likely caused by embolic occlusion of that vessel.
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two-dimensional and M modes proves most helpful in discerning the cardiac valvular abnormality. Rheumatic valvular disease (mitral, aortic), once a common cause of embolic stroke, has become an infrequent cause of childhood stroke. Infected valves in bacterial endocarditis pose considerable risk for the occurrence of embolic stroke (native, prosthetic, rheumatic, or congenitally abnormal valve). Infective mitral and aortic valvular vegetations may dislodge and travel distally to occlude cerebral arteries. The most common organisms found are streptococci and staphylococci (see Chapter 11). Even after vegetations have been successfully sterilized, they may embolize and cause stroke. Emboli from infected valvular vegetations may embolize, travel to the cerebral vasculature, and seed the adventitia of the cerebral vessel. The resultant infection and inflammation results in weakening of the vessel and development of a mycotic aneurysm. Aneurysms may lie dormant for some time before their rupture leads to SAH or IPH and resultant neurologic signs. Procoagulopathies
Several disorders of coagulation can lead to embolic or thrombotic stroke. Adverse consequences of antiphospholipid antibodies have been identified in all age groups. Children, adolescents, and young adults experience the cerebrovascular consequences of these antibodies most often. Antiphospholipid antibodies, including the lupus anticoagulant (LAC), are polyclonal antibodies found in serum that are able to bind to both neutral and negatively charged phospholipids (see Chapter 50). LAC and anticardiolipin antibodies were first associated with thrombotic or embolic cerebrovascular events in patients with systemic lupus erythematosus (SLE). Subsequently, patients suffering stroke with no evidence of underlying immune-mediated illness other than the LAC or anticardiolipin antibody were found. The antibody prolongs the partial thromboplastin time (PTT) in vitro but acts as a procoagulant in vivo. A common finding associated with coagulation testing among children with arterial ischemic stroke is the presence of anticardiolipin antibody. The presence of these antibodies in a patient who concurrently smokes cigarettes, has findings positive for antinuclear antibodies, or suffers from hyperlipidemia may impart a higher risk for stroke than if the patient carries the antibody alone. The antibody’s presence is indicated by a prolonged PTT and a falsely positive serum Venereal Disease Research Laboratory result. The antibody’s presence can be conclusively demonstrated functionally and immunologically. Although cerebral infarction and TIAs constitute the most frequently observed neurologic manifestations related to the presence of these antibodies, migraine headache, seizures, and monocular visual disturbances are also associated. Therapy for patients with antiphospholipid antibodies who have suffered stroke has not been fully substantiated by randomized prospective study. Nonetheless, low-dose anticoagulation has been advocated. Absence of specific serum proteins that act as inhibitors of coagulation may lead to stroke in children. Two of these proteins, protein S and protein C, have been associated with thrombotic or embolic cerebrovascular disease in the young. Protein C and its cofactor protein S act as anticoagulants and synergistically attenuate coagulation by deactivating the activated forms of factors V and VIII. Absence of (or resistance to) either of these proteins disrupts the balance of coagulation toward increased spontaneous clotting and can result in stroke. In addition, antithrombin III opposes the action of the activated forms of factors II, IX, X, XI, and XII through the irreversible formation of inactivating complexes with these factors. Deficiencies of proteins S and C as well as of antithrombin III may cause arterial thrombotic or embolic stroke or venous infarction. Although their deficiencies are often congenital, they may be acquired through liver disease or nephrotic syndrome. Factor V Leiden, prothrombin 20210A, and lipoprotein A are all important factors that may contribute to the pathogenesis of arterial ischemic stroke in children. Elevated lipoprotein A, protein C deficiency, and sickle cell anemia
Figure 41-3. Cranial T1-weighted magnetic resonance imaging scan of a 9-year-old boy treated with L-asparaginase for acute lymphoblastic leukemia, who experienced new headache, seizures, and lethargy. Bright signal in superior sagittal sinus (arrowheads) and in straight sinus (arrows) denotes L-asparaginase–induced cerebral venous thrombosis.
increase the risk of recurrent strokes. A screening battery of tests, including prothrombin time, PTT, and specific immunologic and functional testing for the proteins suspected of being deficient is essential for diagnosis. Treatment with anticoagulation therapy after stroke has been recommended. Cancer and its treatment may predispose children to cerebrovascular ischemic events. Promyelocytic leukemia and its treatment have been observed to provoke disseminated intravascular coagulation, leading to stroke. Lymphoreticular cancers more than solid tumors have been linked to thrombotic and embolic strokes. In addition, dural sinus and cerebral venous thrombosis have been found after therapy with L-asparaginase (Fig. 41-3). TIAs occurring after induction chemotherapy for acute lymphoblastic leukemia have been observed. Cranial radiation therapy may induce an occlusive vasculopathy, leading to focal cerebral ischemia. Autoimmune Disorders
Autoimmune disorders may cause neurologic disturbance and cerebrovascular involvement (Table 41-4). Symptoms of abrupt onset with accompanying deficits referable to the CNS have long been associated with SLE. A CNS vasculitis had been presumed to underlie the CNS manifestations of SLE; however, autopsy study of patients suffering from SLE revealed a virtual absence of cerebrovascular inflammation. Rather, small areas of infarction relate to proliferative changes in cerebral arterioles that lead to luminal occlusion. Large areas of infarction are more probably related to LAC-derived thromboembolism or to embolism from the sterile cardiac valve leaflet vegetations associated with SLE (Libman-Sacks endocarditis). Additional causes of CNS illness include thrombocytopenic hemorrhage, steroid-induced pseudotumor or psychosis, and CNS infection. True cerebral arterial vasculitis may be an isolated disease or seen in association with recognizable systemic autoimmune disorders. Isolated angiitis of the CNS may affect small, medium-sized, or large vessels. Multiple regions of infarction are often found on MRI. Neuropathologic evidence of polymorphonuclear leukocyte or monocyte infiltration leading to intimal proliferation and vessel wall necrosis is found. The inflammation affects blood flow and predisposes to thrombosis.
Chapter 41 Stroke in Childhood Table 41-4. Autoimmune Disorders Associated with
Central Nervous System (CNS) Involvement Disorder
CNS Manifestations
Systemic lupus erythematosus Mixed connective tissue disease Polyarteritis nodosum Wegener granulomatosis Takayasu arteritis Henoch-Schönlein purpura Primary CNS vasculitis
Migraine headache, seizures, stroke, cerebellar dysfunction, transverse myelopathy, aseptic meningitis, psychosis Seizures, stroke, cerebellar dysfunction, trigeminal neuropathy Migraine headache, stroke, subarachnoid hemorrhage, seizures Migraine headache, subarachnoid hemorrhage, stroke Seizure, stroke Headache, stroke, seizures, chorea Headache, stroke, seizure
Stroke may occur in the course of polyarteritis nodosa. Involvement of the CNS is found in 20% to 40% of such patients. Wegener granulomatosus, a necrotizing vasculitis of the upper pulmonary system, rarely affects the CNS; stroke is uncommon. When the CNS is affected, extension of sinus or nasal inflammation into the basilar skull frequently has occurred. Mixed connective tissue disease, which clinically overlaps with polymyositis, SLE, and progressive systemic sclerosis, can involve the CNS. Cranial neuropathy, most commonly trigeminal nerve dysfunction, has been the most frequently cited deficit. Stroke manifesting as sudden-onset hemiparesis and aphasia has been reported in children afflicted with mixed connective tissue disease. Takayasu arteritis, involving the aorta and its principal branches, has been associated with thrombotic stroke. Inflammation-induced luminal constriction leading to thrombosis is thought to cause cerebral ischemia in children. Angiographic improvement of vessels in the carotid tree is observed with immunosuppressive treatment. Necrotizing arteritis with inflammatory infiltrate has been found in both meningeal and cerebral vessels of children suffering from Henoch-Schönlein purpura. Both fixed and transient deficits may occur in this disorder. Treatment with steroids or other immunosuppressive agents proves most helpful in these disorders. Long-term anticoagulation has not been studied but should be considered with appropriate caution in acute situations. Inflammation of cerebral vessels may also occur in the course of bacterial meningitis. The subarachnoid arteries become immersed in exudate. The vessel wall is affected by the inflammatory process. If this condition allowed to proceed long enough, thrombophlebitis ensues. Vascular occlusion results, with consequent features of stroke. Antibiotics combined with steroids early in the course of treatment form the cornerstone of therapy. Metabolic Disorders Causing Stroke
Homocystinuria, a disorder of homocysteine metabolism, can cause thrombotic stroke in children. Abnormal homocysteine metabolism results from one of three inheritable enzymatic defects. The most striking phenotype results from deficiency of cystathionine synthetase, the enzyme that facilitates the catabolism of homocysteine to cystathionine. Accumulation of not only homocysteine but also methionine results. Children affected by this autosomal recessive disorder (Table 41-5) have marfanoid habitus, global developmental
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Table 41-5. Genetic Causes of Stroke
Thrombotic/Embolic Stroke Homocystinuria or elevated homocysteine levels Fabry disease Fibromuscular dysplasia Procoagulopathies* Sickle cell anemia Hemorrhage Factor VIII deficiency Factor IX deficiency Factor XI deficiency Familial intracranial aneurysm Sickle cell disease Familial cavernous angioma Glanzmann thrombasthenia X-linked thrombocytopenia Unknown Mechanism Familial porencephaly Organic acidemia Mitochondrial disorders Rare Monogenic Disorders APP, CST3, BRI genes (autosomal dominant amyloid angiopathies) NOTCH3 gene (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) KRITI gene (cavernous angiomas) *Protein C, protein S, and antithrombin III deficiencies and factor V Leiden or prothrombin 20210A mutations.
delay, lens dislocation, and thromboembolism. Thromboemboli may travel to cerebrovascular beds, causing stroke. Serum hyperhomocystinuria injures the vascular endothelium. The denuded vessel wall then becomes a site for thrombosis. The resulting thrombus may remain at its site of origin or it may embolize to a distal locus. Therefore, stroke may have thrombotic or embolic characteristics. Both arterial and venous infarctions may result. Treatment is dietary and aimed at reducing levels of homocysteine in serum. Pyridoxine administration and methionine restriction are effective in 30% to 40% of treated patients. Some patients without homocystinuria but with elevated homocysteine levels may be at risk for vascular morbid conditions, including stroke. Sulfite oxidase deficiency, another autosomal recessive disorder, results in the accumulation of serum sulfite. The associated phenotype may result from deficiency of either the enzyme or its associated and essential pterin-containing molybdenum cofactor. Mental retardation, seizures, lens displacement, and acute hemiplegia result. The mechanism of the strokelike episodes has not been fully elucidated. It is possible that ischemic mechanisms are not involved and that direct metabolic neurotoxicity accounts for the sudden onset of deficits resembling those of stroke. Sulfites and S-sulfocysteine accumulate in urine. Dietary attempts to reduce sulfite accumulation have been unsuccessful. Fabry disease, a lipid storage disease attributable to ceramide trihexosidase deficiency, results in accumulation of the sphingolipid trihexoside in the kidneys, vascular endothelium, and corneas. Symptoms become apparent in childhood or adolescence. Angiokeratomas and painful paresthesia often constitute the first symptoms. Renal failure follows. However, because of endothelial accumulation of sphingolipid in vessel walls, cerebrovascular occlusion results in stroke. Recurrent stroke is common in this rare X-linked disorder. Supportive care, as well as recombinant enzyme therapy, and treatment designed to improve renal function and minimize pain are instituted.
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The manifestations of mitochondrial disorders include recurrent and sometimes catastrophic stroke. The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) manifests in childhood and results from a mutation of mitochondrial DNA. The most common biochemical finding is a deficiency of complex I of the electron transport chain. An elevated serum or cerebrospinal fluid lactate level serves as its chemical signature, and molecular confirmation of the diagnosis can be secured from blood. Although some features of MELAS are shared by other mitochondrial syndromes, hemiparesis of abrupt onset is fairly specific for this syndrome. Excruciating headache resembling migraine may precede the strokelike episodes. Seizures and sensorineural hearing loss are almost always present at some point in the course of the illness. Neuropathologic study of brains from patients with MELAS has shown cystic cavities and necrosis of cortex with relative sparing of white matter. Other metabolic disorders have been associated with stroke in childhood. Urea cycle defects, especially ornithine transcarbamoylase deficiency manifesting in girls, can cause stroke. Deficiency of arginase, another important enzyme of the urea cycle, has been observed in association with hemiparesis and diparesis of subacute onset. Finally, familial lipoprotein disorders, especially those featuring a dearth of high-density lipoprotein or an abundance of triglycerides, have been associated with stroke in children. In most cases, a family history of hyperlipidemia is found. Moyamoya Disease
Moyamoya disease commonly affects children younger than 15 years and manifests with TIAs or sudden-onset fixed motor deficits. Progressive narrowing and occlusion of the intracranial portion of the internal carotid arteries are characteristic. Endothelial proliferation, fibrosis, and intimal thickening characterize the vascular disease. Resultant proliferation of collateral vessels from the basilar skull circulation creates an intricate latticework of compensatory blood flow. The appearance on angiography is characteristic and
consists of a fine vascular network located at the base of the brain. Moyamoya means “hazy” or “puff of smoke” (Fig. 41-4). Children usually present with acute hemiplegia as a result of uncompensated occlusion of the internal carotid artery. Because the anatomic abnormality is often bilateral, the hemiplegia may alternate. Disturbance of fine motor function has been observed. Chorea has been reported in association with moyamoya syndrome. Although the vascular abnormality may be congenital, moyamoya syndrome can occur as a sequel to a primary disorder causing internal carotid artery occlusion. It has been found in children with sickle cell disease, neurofibromatosis, tuberculous meningitis, and fibromuscular dysplasia. Evidence suggesting a hereditary origin in some cases has been reported in Japan. Optimal treatment has not been determined. Evidence of inflammation has not been found. Calcium channel blockers have been reported to increase collateral vessel diameter, improve perfusion, and ameliorate neurologic symptoms. Several surgical procedures (extracranial-intracranial or dural-intracranial bypass) designed to reestablish effective perfusion of endangered brain have been performed. Sickle Cell Disease
Acute hemiplegia may be found in children with sickle cell disease (see Chapter 48). Cerebral infarction occurs in approximately 6% of patients. It may be an isolated event, or it may occur in the setting of a sickle crisis. Neurologic signs include hemiparesis, aphasia, and visual disturbances. Cerebral infarction may also be clinically silent. Neuroimaging studies, particularly MRI, reveal that stroke occurs in watershed distributions between two cerebrovascular territories, affecting both the gray and white matter of the cortex. The proposed pathophysiologic mechanisms encompass both sickling in large vessels, leading to thrombotic hypoperfusion, and diminished flow in small cerebral vessels as a result of the decreased compliance of sickled erythrocytes. Cerebral vessels reveal endothelial proliferation, disruption of the elastic lamina, and stenosis. Cerebral hyperemia
Figure 41-4. Sudden onset of right hemiparesis in a 6-year-old boy. A, Cerebral angiogram shows left internal carotid artery (arrows) leading to a highly arborized, telangiectatic network of vessels (arrowheads) typical of moyamoya disease. The typical middle cerebral artery vascular tree is absent. B, Cranial coronal magnetic resonance imaging scan of the same patient shows region of low signal in the middle cerebral artery territory and denotes infarction (curved arrows). Flow voids in the basal ganglia (straight arrows) are radiographic manifestations of the basilar collateral circulation typical of this vascular anomaly.
Chapter 41 Stroke in Childhood thought to be caused by vasodilation has been suggested as a mechanism contributing to the occurrence of watershed infarctions in sickle cell patients. Recurrences are common. Exchange transfusion diminishes the observed hyperemia and reduces the occurrence of stroke in these patients. Children who have suffered large strokes demonstrate correspondingly multifaceted deficits of cognitive function. Those in whom focal strokes have occurred show more subtle neuropsychologic deficits. Children with sickle cell disease who have silent infarctions may demonstrate school dysfunction as the only manifestation of neurologic involvement of the disease. These children can demonstrate twice the rate of school difficulties found in children with sickle cell disease without infarctions. SAH also occurs among children with sickle cell disease. The frequency of SAH is less than that of infarction, occurring in fewer than 2%. Whereas ruptured cerebral aneurysm is frequently found in adults with sickle cell disease who have SAH, it is absent in affected children with SAH. The clinical findings of SAH differ from those of infarction in patients with sickle cell disease. Severe headache, vomiting, and alteration in mental state characterize SAH in children with sickle cell disease. Meningeal signs and focal neurologic deficits may be found on examination. Angiography should be performed on all patients to detect any surgically correctable vascular lesion underlying the hemorrhage. Medical therapy consisting of transfusion therapy has been suggested. Intracranial Hemorrhage Coagulopathies
Although some coagulation disturbances may predispose a patient to ischemic stroke (hypercoagulable states), others may promote intracranial bleeding (see Chapter 50). The hemophilias (A and B) are X-linked disorders that may result in intracranial bleeding. Bleeding may occur in either intraparenchymal or subarachnoid locations. Hemophilia A arises from factor VIII deficiency. Patients with this disorder may experience intracranial bleeding in association with head trauma. Unfortunately, spontaneous intracranial bleeding not associated with head trauma also occurs. The risk of spontaneous bleeding rises with the severity of factor VIII deficiency. Hemophilia B derives from a deficiency of factor IX. Intracranial bleeding is seen less frequently among these patients than among patients with hemophilia A. Hemophilia B is encountered much less frequently than hemophilia A, and this difference may account for the less frequent observation of intracranial bleeding.
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Clinical symptoms depend on the intracranial location of the hemorrhage. If the bleeding occurs in the subarachnoid space, symptoms of severe headache, nuchal rigidity, and meningismus are found. Mental status is frequently altered. If bleeding occurs within brain parenchyma, focal features, including hemiparesis, may be found. Thrombocytopenia
Severe thrombocytopenia rarely leads to cerebral hemorrhage, especially if the cause is idiopathic (immune) thrombocytopenic purpura. Thrombocytopenia caused by bone marrow failure (drug-induced suppression, aplastic anemia, malignancy) may pose a greater risk. Significant risk of intracranial hemorrhage is thought not to occur until the platelet count is less than 20,000/mm3. Small petechial hemorrhages into white matter are thought to be more common than are large parenchymal hemorrhages. Causes of thrombocytopenia include idiopathic immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, infection, and malignancy (replacement of bone marrow or drug-induced suppression). The features of these underlying causes dominate the clinical picture (see Chapter 50). Vascular Malformations
Arteriovenous malformation (AVM) of the brain is the most common cause of intracranial hemorrhage in preadolescent children. The malformation represents a developmental anomaly that manifests with hemorrhage much more frequently in children than in adults. The AVM consists of dilated vascular channels, some of which reveal the highly muscularized walls of arterioles. Gliotic neural tissue resides in and among the vascular branches of the malformation. It is more common in boys. The most frequent presenting events associated with AVM in children are seizures and hemorrhage. Most AVMs reside in the cerebral hemispheres; 10% arise in the posterior fossa. The clinical features of AVM hemorrhage consist of those found in IPH. Focal features depend on the area of brain in which the bleeding has occurred. A higher mortality rate has been observed in children than in adults harboring hemorrhagic AVMs. The risk of hemorrhage from an unruptured AVM is approximately 3% per year. Initially, treatment of AVMs consisted of anticonvulsant therapy for secondary seizures. Surgery was reserved for AVMs that bled at presentation. The introduction of MRI has led to better localization of the malformation (Fig. 41-5). In addition, percutaneous selective
Figure 41-5. Cranial magnetic resonance imaging scan of a 6-year-old girl with recurrent headache. A, Axial view demonstrates flow voids deep in the left hemisphere near the lateral ventricle (arrowheads), consistent with arteriovenous malformation. B, Coronal view through parietal lobes also demonstrates numerous flow voids (arrowheads) indicative of arteriovenous malformation.
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Section Six Neurosensory Disorders
embolization of portions of the AVM or of the entire AVM has permitted the resection of AVMs thought previously to be inoperable. AVMs residing in critical regions of the CNS not amenable to surgery have been treated with stereotactic radiosurgery. Promising results have been obtained. Radiation damage to the CNS has complicated the recovery of approximately 3% of patients receiving this therapy. Intracranial aneurysms constitute the most common cause of intracranial bleeding in all patients younger than 20 years and are more frequent in boys. In contrast to aneurysms in adults, the most common site of aneurysmal bleeding in children is along the intracranial portion of the internal carotid artery. The vertebral and basilar arteries are other common sites of intracranial aneurysm in children. In addition, intracranial aneurysms discovered in children tend to be larger than those found in adults. Although most aneurysms constitute vascular developmental anomalies, other causes exist, including mycotic aneurysms associated with bacterial endocarditis (Fig. 41-6). Acquired cerebral artery aneurysms have
been reported in children infected with the human immunodeficiency virus. Intracranial aneurysms are found with increased frequency among patients suffering from polycystic renal disease, those with aortic coarctation, and those with Ehlers-Danlos syndrome, in comparison with the general pediatric population. Intracranial aneurysms have been noted to exist in close association with AVMs in some pediatric cases. All affected patients should be studied with angiography after aneurysmal bleeding. Patients should be closely observed for development of hydrocephalus and increased intracranial pressure. Aneurysmal bleeding resulting in significant SAH can precipitate cerebral vasospasm. Vasospasm, in turn, can cause a secondary cerebral infarction. Vasospasm occurs most commonly 7 to 10 days after the aneurysmal bleeding. Prophylaxis is the most effective treatment for vasospasm. Maintenance of blood pressure through intravascular volume expansion has been shown to reduce the incidence of posthemorrhagic vasospasm. Early enthusiasm for treatment with calcium channel blockers has attenuated.
Figure 41-6. Mycotic cerebral aneurysm hemorrhage. A, Cranial computed tomographic scan reveals hyperdense area in left temporal lobe (arrowheads) representing intraparenchymal hemorrhage. B, Cerebral angiography in lateral view shows lobulated structural abnormality representing the mycotic aneurysm, most probably residing in the middle cerebral artery tree (arrows). C, Anteroposterior angiographic view confirms the location of the aneurysm in the middle cerebral artery (straight arrows) located laterally rather than the more medial anterior cerebral artery (curved arrows). The internal carotid artery (open arrows) gives rise to both the anterior and the middle cerebral arteries.
Chapter 41 Stroke in Childhood The syndrome of posterior fossa brain malformations, facial hemangiomas, arterial anomalies, coarctation of the aorta, and cardiac and eye defects (PHACE) is a constellation of disorders (see Table 41-2). CNS malformations affect the posterior fossa and include Dandy-Walker malformation, arachnoid cysts, cerebellar hypoplasia, and enlarged cisterna magna. Vascular anomalies include brachiocephalic artery and aortic arch anomalies (coarctation of aorta), cerebrovascular arterial hypoplasia, aneurysms, stenosis and aberrancies, and progressive occlusive arterial disease leading to stroke. Evaluation of Stroke in Children Neuroimaging provides the foundation of evaluation. Intracranial blood is rapidly seen with CT. The early stages of ischemic stroke, however, are detected with difficulty. MRI provides evidence of ischemia in the early stages of stroke. Magnetic resonance angiography has provided reliable information about the blood flow in and the structure of large intracranial vessels. Small intracranial vessels are poorly seen on magnetic resonance angiography, however, and invasive contrast angiography remains the neuroradiologic procedure of choice for full elucidation of the cerebral vasculature. Laboratory studies helpful in the evaluation of the child who has suffered stroke are determined by the patient’s clinical features. Table 41-6 provides a synopsis of the tests most commonly employed. ADOLESCENTS The causes of adolescent stroke include those discussed for preadolescent children. Determination of stroke mechanism—embolic, thrombotic, or hemorrhagic—remains important. Nonetheless, stroke among adolescents may also be caused by other entities not commonly found in neonates or preadolescent children. Fibromuscular Dysplasia Fibromuscular dysplasia involves arteries throughout the body. First described in renal arteries, the pathologic features of fibromuscular dysplasia have been found in carotid, vertebral, and intracranial arteries. Fibromuscular dysplasia involves irregularly spaced focal zones of fibrous and muscular hyperplasia of the media, disruption of the elastic lamina, and eventration of the media. The constricted regions of vascular fibrosis alternate with regions of luminal dilation to create the characteristic beaded appearance on angiography. Fibromuscular dysplasia is more common in young girls and has been found in adolescents; with carotid involvement, a bruit may be auscultated in the neck. If renal arteries are affected, hypertension may be present. Neurologic symptoms signifying cerebrovascular involvement most commonly consist of TIAs and mild strokes. A thrombotic mechanism is presumed but has never been proven. No treatment for symptomatic patients is established, although arterial dilation with metal dilators or transluminal angioplasty has been recommended. Sexual Activity, Oral Contraception, and the Puerperium Sexual intercourse generates marked increases in systemic blood pressure. Sustained hypertension elevates the risk of hypertensive intracranial hemorrhage. The risk for such a hemorrhage is heightened by the existence of an intracranial aneurysm or arteriovenous hemorrhage. Oral contraceptives have been associated with stroke in young women. In some series, the combination of migraine headache and concurrent oral contraceptive use has been cited as a risk factor for stroke.
739
Table 41-6. Neuroradiologic, Laboratory, and
Cardiovascular Assessment of Stroke in Children Neuroradiologic Assessment Rapid detection of intracranial blood Cranial CT Cranial MRI (also detects extravascular blood but is not as rapidly obtained as cranial CT images) Detection of brain parenchymal changes related to stroke Cranial MRI, including diffusion weighted imaging Cranial CT (reveals changes later in course than MRI) Detection of abnormal vascular structure Percutaneous cerebral angiogram (provides the most complete and accurate demonstration of extracranial and intracranial vasculature) Cranial MRA Laboratory Assessment Disturbance of RBC, WBC, or platelet number Hematocrit Platelet count WBC count with differential Disturbance of coagulation PT, PTT Antithrombin III level Protein C level, protein S level; resistance to protein C assay Lupus anticoagulant detection, anticardiolipin antibody, antiphospholipid antibody Metabolic disturbances Serum electrolytes, glucose Serum amino acids Urine organic acids Serum/CSF lactate and pyruvate Urine toxic screen Disturbance of hemoglobin Hemoglobin concentration Hemoglobin electrophoresis Inflammatory disturbances ESR ANA, RF CSF studies: glucose, protein, cell counts, special stains, cultures Lipid and lipoprotein disturbances Serum triglycerides Serum cholesterol; if high, obtain fasting HDL Cardiovascular Assessment ECG Standard and transesophageal echocardiogram ANA, antinuclear antibodies; CSF, cerebrospinal fluid; CT, computed tomography; ECG, electrocardiography; ESR, erythrocyte sedimentation rate; HDL, high-density lipoproteins; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell; RF, rheumatoid factor; WBC, white blood cell.
Pregnancy and the postpartum state have been considered periods of hypercoagulability. In addition, venous stasis increases. These two factors are believed to promote the occurrence of cerebral venous thrombosis and resultant cerebral venous infarction in pregnant patients and in patients immediately after parturition. Frequently, the initial manifestation is headache. Seizures, either focal or generalized, are common. Acute hemiparesis is the most common focal feature on neurologic examination. Papilledema can appear as intracranial pressure rises caused by resultant venous outflow obstruction in the head. The appearance of these signs or symptoms in a gravid or postpartum adolescent should raise suspicion about the existence of underlying cerebral venous thrombosis.
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Diagnosis is made with cranial neuroimaging; MRI provides the best noninvasive assessment. If seizures occur, anticonvulsant treatment should be initiated. Once the diagnosis is confirmed, anticoagulants should be administered. Cocaine Use SAH can result from cocaine use. The probability of this occurrence is higher in cocaine users with occult intracranial aneurysms or arteriovenous malformations. Irrespective of the method of cocaine administration, SAH may occur. Cocaine produces tachycardia, hypertension, and vasoconstriction. The resultant sudden rise in systemic blood pressure is thought to precipitate SAH. Ischemic lesions have also been found. Nonetheless, intracranial hemorrhage appears to occur more commonly than ischemic infarction. Treatment is supportive, with reduction of hypertension, hyperthermia, and tachycardia. CAUSES OF STROKE UNRELATED TO AGE Pharyngeal Infection Pharyngeal infections have been associated with stroke caused by thrombotic occlusion of the carotid arteries in their cervical course. In childhood, stroke resulting from carotid occlusion more commonly occurs in the intracranial segment of the carotid artery. Infections of the cervical region such as tonsillitis, pharyngitis, cervical lymphadenitis, and necrotizing fasciitis have been found in children experiencing acute hemiplegia. In these instances, angiography has shown occlusion of the internal carotid artery located in its cervical segment. Neuroimaging has demonstrated ischemic infarction of the cortical region served by the middle cerebral artery, which arises from the carotid circulation. It is speculated that the soft tissue infection leads to an inflammatory arteritis. Vessel wall inflammation and direct pressure on the artery then lead to intravascular thrombosis and occlusion. Neurologic symptoms are noted in a patient with evidence of infection: fever, lethargy, sore throat or neck, difficulty swallowing, or cervical lymphadenopathy. In these cases, prompt and aggressive antibiotic treatment constitutes the cornerstone of care. In some cases, surgical débridement of the infected area is necessary. Thrombolytic agents have been used to recanalize the occluded carotid artery. However, standardized, controlled trials of such treatment have not been performed. Head and Neck Trauma Head and neck trauma is an important cause of stroke in children. Neurologic symptoms may be delayed more than 24 hours in their appearance in relation to the time of inciting trauma. Stroke caused by carotid artery injury has been well documented. Most often, these cerebrovascular events occur after head and neck trauma sustained in motor vehicle accidents, bicycle accidents, fights, or falls. Hemiparesis is a common symptom at presentation if the cause resides in the carotid artery. Carotid angiography reveals internal carotid artery occlusion. The site of occlusion most often exists at the level of the carotid bifurcation. Pathologically, an intimal tear is found with attendant thrombus blocking the arterial lumen. In some cases, arterial dissection is found. Vertebral artery injury from trauma may cause stroke in children. Traction injuries of the neck appear to cause vertebral artery injury. The vertebral artery is most vulnerable to traumatic injury at its atlantoaxial portion. The resultant strokes occur in the vertebrobasilar portion of the cerebral circulation. Symptoms are referable to the structures receiving blood from this system: brainstem, cerebellum, occipital lobes, and temporal lobes. Clinical symptoms of vertebrobasilar stroke include difficulty swallowing, ataxia, facial weakness, tinnitus, vertigo, anisocoria, extraocular movement palsies,
dysmetria, cortical blindness, and mental status changes. Because both the long sensory and the motor tracts course through the brainstem, symptoms of general sensorimotor impairment may be found. Vertebral artery injury in children has been reported in the setting of athletic endeavor or automobile accidents. The resultant vertebrobasilar strokes are caused by thrombosis or vertebral artery dissection. Anticoagulation with antiplatelet agents has been proposed as therapy. Migraine Headache Stroke may occur in the setting of migraine headache. The occurrence of focal motor deficits during a migraine headache denotes complicated migraine (see Chapter 37). Acute hemiparesis has been well documented during these episodes and is believed to reflect the involvement of the cerebral circulation derived from the carotid artery. Symptoms such as ataxia, cortical blindness, and cranial nerve dysfunction are correlated with vertebrobasilar circulation involvement. Focal symptoms may be fixed or may occur as TIAs. Initially, an association between migrainous stroke and discharged emboli from mitral valve prolapse was hypothesized, but studies have not supported the association. Although oral contraceptives confer hypercoagulability thought to predispose to stroke, the postulated additive risk for stroke with migraine headaches and oral contraceptives has been challenged. Angiographic studies on patients with focal deficits consistent with stroke in the setting of migraine headache reveal vasoconstriction of vessels in either the vertebrobasilar or the carotid circulations. The neuroanatomic position of the constricted vessels correlated with the location of the observed deficits. Ischemia provoked by vasoconstriction during prolonged migraine has been hypothesized as the mechanism of stroke in these patients. Calcium channel blockers have been used for treatment, but definitive studies of their efficacy are awaited.
SUMMARY AND RED FLAGS Acute hemiplegia most frequently represents stroke. Critical to the diagnosis of stroke are a history and physical examination findings that are consistent with the occurrence of stroke. Because stroke occurs most often in children as a consequence of an underlying process, circumspect consideration of the child’s condition to determine whether such a predisposing condition exists will help determine the diagnosis with much greater accuracy. Red flags in children with stroke include manifestations of underlying primary processes (e.g., trauma, medications, inborn errors, malignancy, coagulopathy), depressed level of consciousness, a positive family history of early-onset stroke (younger than 30 years), signs of increased intracranial pressure (see Chapter 40), a carotid bruit, hypertension, and the presence of prior TIAs. Not all hemiplegia or all other focal deficits represent acute cerebrovascular events. Hemiparetic seizures, with their most striking features of acute lateralized weakness and preserved mental state, have been described as a form of partial epilepsy. In addition, seizures can be followed by a postictal (Todd) paralysis that may mimic the motor deficit of stroke. A search for a history of previous seizures is essential. A postictal paralysis is short-lived and is not associated with neuroradiologic characteristics of recent stroke. Preservation of consciousness, which is not a feature of generalized seizures, may help differentiate between epilepsy and cerebrovascular events. The EEG can be helpful in establishing the occurrence of seizure, but the diagnosis remains a clinical one. Metabolic disturbances may cause focal motor deficits resembling stroke. Hypoglycemia and hyponatremia may each mimic stroke. Similarly, transient hemiparesis not associated with radiologic changes typical of stroke have been observed in juvenile diabetes
Chapter 41 Stroke in Childhood mellitus. A survey for the existence of conditions that include these metabolic disturbances is important. Serum electrolyte and glucose levels should be measured. Similarly, severe anemia causing reduced oxygen delivery to the brain may result in evanescent focal motor deficits; evaluation of hematocrit is essential in any patient suspected of having suffered stroke. Alternating hemiplegia of childhood may mimic stroke in children. This disorder appears to be sporadic in its occurrence. Early in its course, oculomotor and extrapyramidal features predominate, but eventually acute episodes of lateralized weakness supervene. The first symptoms of this disorder appear before the age of 18 months. Repeated episodes of lateralized hemiplegia are prominent. However, bilateral hemiplegia may occur. Extrapyramidal symptoms, oculomotor dysfunction, and dysautonomic features may also be present. Symptoms disappear during sleep. Developmental delay or mental retardation is present in all cases. Flunarizine, a calcium channel blocker, has shown some promise as a treatment in its apparent ability to reduce the frequency and duration of hemiplegic attacks, but experience with this drug is limited. Further study of this and other potential therapies are necessary. Finally, multiple sclerosis may manifest in childhood with visual or motor disturbances suggestive of ischemic stroke; lesions change in space and time, and their effects are not often compatible with lesions at a neuroanatomic site distal to an arterial supply. MRI reveals demyelination in multiple sclerosis and other demyelinating processes. REFERENCES General Fullerton HJ, Wu YW, Zhao S, et al: Risk of stroke in children: Ethnic and gender disparities. Neurology 2003;61:189. Ganesan V, Chong WK, Cox TC, et al: Posterior circulation stroke in childhood. Neurology 2002;59:1552. Kerr LM, Anderson DM, Thompson JA, et al: Ischemic stroke in the young. J Child Neurol 1993;8:266. Riela A, Roach S: Etiology of stroke in children. J Child Neurol 1993;8:201. Tournier-Lasserve E: New players in the genetics of stroke. N Engl J Med 2002;347:1711. The Settings of Stroke in Children Hypoxic-Ischemic Encephalopathy
Huppi PS, Inder TE: Magnetic resonance techniques in the evaluation of the perinatal brain: Recent advances and future directions. Semin Neonatol. 2001;6:195. Rivkin M: Hypoxic ischemic brain injury in the term newborn: Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol 1997;24:607. Robertson,R, Ben-Sira L, Robson CD, et al: Magnetic resonance line scan diffusion imaging of term neonates with hypoxic-ischemic brain injury. AJNR Am J Neuroradiol 20;1999:1658.
741 Neonatal Cerebral Venous Thrombosis
Rivkin M, Anderson M, Kaye E: Neonatal idiopathic cerebral venous thrombosis: An unrecognized cause of transient seizures or lethargy. Ann Neurol 1992;32:51. Wu YW, Miller SP, Chin K, et al: Multiple risk factors in neonatal sinovenous thrombosis. Neurology 2002;59:438. Intracranial Hemorrhage in the Neonate
Bergman I, Bauer R, Barmada M, et al: Intracerebral hemorrhage in the full-term infant. Pediatrics 1985;75:488. Children Aged 1 to 13 Years Congenital Heart Disease
Bogousslavsky J, Regli F: Ischemic stroke in adults younger than 30 years of age. Arch Neurol 1987;44:479. Jones H, Shekert R, Geraci J: Neurologic manifestations of bacterial endocarditis. Ann Intern Med 1969;71:21. Lechat P, Mas J, Lascault G, et al: Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148. Procoagulopathies
Golomb MR, MacGregor DL, Domi T, et al: Presumed pre- or perinatal arterial ischemic stroke: Risk factors and outcomes. Ann Neurol. 2001;50:163. Levine S, Deegan M, Futrell N, et al: Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases. Neurology 1990;40:1181. Nestoridi E, Buonanno FS, Jones RM, et al: Arterial ischemic stroke in childhood: The role of plasma-phase risk factors. Curr Opin Neurol 2002;15:139. Pihko H, Tyni T, Virkola K, et al: Transient ischemic cerebral lesions during induction chemotherapy for acute lymphoblastic leukemia. J Pediatr 1993;123:18. Strater R, Becker S, von Eckardstein A, et al: Prospective assessment of risk factors for recurrent stroke during childhood—A 5-year follow-up study. Lancet 2002;360:1540. Autoimmune Disorders
Belman A, Leicher C, Moshe S, et al: Neurologic manifestations of Shoenlein-Henoch purpura. Pediatrics 1985;75:687. Devinsky O, Petito C, Alonso D: Clinical and neuropathological findings in systemic lupus erythematosus: The role of vasculitis, heart emboli and thrombotic thrombocytopenic purpura. Ann Neurol 1988;23:380. Graf W, Milstein J, Sherry D: Stroke and mixed connective tissue disease. J Child Neurol 1993;8:256. Kohrman M, Huttenlocher P: Takayasu arteritis: A treatable cause of stroke in infancy. Pediatr Neurol 1986;2:154. Lanthier S, Lortie A, Michaud J, et al: Isolated angiitis of the CNS in children. Neurology 2001;56:837. Sigal L: The neurologic presentation of vasculitic and rheumatologic syndromes. Medicine 1987;66:157.
Idiopathic Cerebral Infarction in the Full-Term Neonate
Metabolic Disorders Causing Stroke
Butler I: Cerebrovascular disorders of childhood. J Child Neurol 1993;8:197. Coker S, Beltran R, Myers T, et al: Neonatal stroke: Description of patients and investigation into pathogenesis. Pediatr Neurol 1988;4:219. Lanska M, Lanska D, Horwitz S, et al: Presentation, clinical course and outcome of childhood stroke. Pediatr Neurol 1991;7:333. McKinstry RC, Miller JH, Snyder AZ, et al: A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology 2002;59:824-833.
Christodoulou J, Qureshi I, McInnes R, et al: Ornithine transcarbamoylase deficiency presenting with strokelike episodes. J Pediatr 1993;122:423. Goto Y, Horai S, Matsuoda T, et al: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): A correlative study of the clinical features and mitochondrial DNA mutation. Neurology 1992;42:545. Scheuerle A, McVie R, Beaudet A, et al: Arginase deficiency presenting as cerebral palsy. Pediatrics 1993;92:995. Tulinius M, Holme E, Kristiamsson B, et al: Mitochondrial encephalomyopathies in childhood, I and II. J Pediatr 1991;119:242.
Polycythemia
Barron T, Gusnard D, Zimmerman R, et al: Cerebral venous thrombosis in neonates and children. Pediatr Neurol 1992;8:112. Black V, Lubchenco L, Koops B, et al: Neonatal hyperviscosity: Randomized study of effect of partial plasma exchange transfusion on long-term outcome. Pediatrics 1985;75:1048.
Moyamoya Disease
Karasawa J, Touho H, Ohnishi H, et al: Long-term follow-up after extracranial-intracranial bypass surgery for anterior circulation ischemia in childhood moyamoya disease. J Neurosurg 1992;77:84.
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McLean M, Gebarski S, Van der Spek A, et al: Response of moyamoya disease to verapamil. Lancet 1985;1:163. Rooney C, Kaye E, Scott R, et al: Modified encephaloduroarteriosynangiosis as surgical treatment of childhood moyamoya disease: Report of 5 cases. J Child Neurol 1991;6:24. Sickle Cell Disease
Craft S, Schatz J, Glauser T, et al: Neuropsychologic effects of stroke in children with sickle cell anemia. J Pediatr 1993;123:712. Pavlakis S, Bello J, Prohovnik I, et al: Brain infarction in sickle cell anemia: Magnetic resonance imaging correlates. Ann Neurol 1988;23:125. Scahtz J, Brown RT, Pascual JM, et al: Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease. Neurology 2001;56:1109. Steen RG, Xiong X, Langston JW, et al: Brain injury in children with sickle cell disease: Prevalence and etiology. Ann Neurol 2003;54:564. Wang W, Kovnar E, Tonkin I, et al: High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease. J Pediatr 1991;118:377.
Bousser M, Chiras J, Bories J, et al: Cerebral venous thrombosis—A review of 38 cases. Stroke 1985;16:199. Cocaine Use and Stroke
Cregler L, Mark H: Medical complications of cocaine abuse. N Engl J Med 1986;315:1495. Klonoff D, Andrews B, Obana W: Stroke associated with cocaine use. Arch Neurol 1989;46:989. Toffol G, Biller J, Adams H: Nontraumatic intracerebral hemorrhage in young adults. Arch Neurol 1987;44:479. Causes of Stroke Unrelated to Age Pharyngeal Infection
Woerner S, Abildgaard C, French M: Intracranial hemorrhage in children with idiopathic thrombocytopenic purpura. Pediatrics 1981;67:453.
Bush J, Givner L, Whitaker S, et al: Necrotizing fasciitis of the parapharyngeal space with carotid artery occlusion and acute hemiplegia. Pediatrics 1984;73:343. Shillito J: Carotid arteritis: A cause of hemiplegia in childhood. J Neurosurg 1964;21:540. Tagawa T, Mimaki T, Yabuuchi H, et al: Bilateral occlusions in the cervical portion of the internal carotid arteries in a child. Stroke 1985;16:896.
Vascular Malformations
Head and Neck Trauma
Broechler J, Thron A: Intracranial arterial aneurysms in children. Neurosurg Rev 1990;13:309. Brown Y, Wiebers K, Forbes G: Unruptured intracranial aneurysms and arteriovenous malformations: Frequency of intracranial haemorrhage and relationship of lesions. J Neurosurg 1990;73:859. Ito M, Yishuhara M, Wachi A, et al: Cerebral aneurysms in children. Brain Dev 1992;14:263. Konsiolka D, Humphreys R, Hoffman H, et al: Arteriovenous malformations of the brain in children: A forty year experience. Can J Neurol Sci 1992;19:40.
Garg B, Ottinger C, Smith R, et al: Strokes in children due to vertebral artery trauma. Neurology 1993;43:2555. Hope E, Bodensteiner J, Barnes P: Cerebral infarction related to neck position in an adolescent. Pediatrics 1983;72:335. Lewis D, Berman P: Vertebral artery dissections and alternating hemiparesis in an adolescent. Pediatrics 1986;78:610.
Thrombocytopenia
Adolescents Fibromuscular Dysplasia
Smith D, Smith L, Hasso A: Fibromuscular dysplasia of the internal carotid artery treated by operative transluminal balloon angioplasty. Radiology 1985;155:645. Sexual Activity, Oral Contraception, and the Puerperium
Adams H, Butler M, Biller J, et al: Nonhemorrhagic cerebral infarction in young adults. Arch Neurol 1987;43:713.
Migraine Headache
Bogousslavsky J, Regli F, Van Melle G, et al: Migraine stroke. Neurology 1988;38:223. Caplan L: Migraine and vertebrobasilar ischemia. Neurology 1991;41:55. Conditions Resembling Stroke Bourgeois M, Aicardi J, Goutieres F: Alternating hemiplegia of childhood. J Pediatr 1993;122:673. Casaer P: Flunarizine in alternating hemiplegia in childhood. Neuropediatrics 1987;18:191. Hanson P, Chodos R: Hemiparetic seizures. Neurology 1978;28:920. Yarnell P: Todd’s paralysis: A cerebrovascular phenomenon. Stroke 1975;6:301.
42
Syncope and Dizziness
David A. Lewis*
Dizziness is a common but very nonspecific chief complaint about which some elaboration by the patient is generally required for the physician to understand exactly what the patient is feeling. The description of the sensation is critical in distinguishing whether it is caused by vertigo, disequilibrium, lightheadedness, presyncope, or even ataxia (Table 42-1). Although the differential diagnoses of these entities may overlap, there are conditions that are most specific to each. All of the entities just named are conditions that may affect children at any age, but older children are more capable of articulating the abnormal sensation they feel. Children younger than 6 years of age may present with nausea, vomiting, ataxia, or frank syncope. Syncope is the transient loss of consciousness and postural tone that results from inadequate cerebral perfusion. Syncope is a common phenomenon in children and adolescents that is usually benign. Fifteen percent to 20% of all young adults have had one episode of syncope in the past. It is critical to distinguish between syncope that is associated with exertion or activity versus syncope “at rest” (see later discussion). The history of the event, obtained from the patient or witnesses, is critical in establishing the differential diagnosis. Presyncope is the feeling that the person is “about to pass out.” The patient feels as if he or she is going to lose consciousness but does not. Presyncope may or may not reflect the same pathophysiologic process as true syncope. The diagnostic approach to presyncope, however, is essentially the same as for syncope. Dizziness must be considered a change in mental status. It may potentially herald serious underlying central nervous system dysfunction. Dizziness must be better defined to distinguish vertigo from lightheadedness. The principal distinction with dizziness is the description of motion; swaying, whirling, or spinning is characteristic of vertigo. Lightheadedness often accompanies hyperventilation and is therefore frequently associated with psychologic stress, including anxiety, depression, and panic attacks. The history surrounding episodes of lightheadedness is vital for formulating the differential diagnosis. The last of the “dizzy” feelings is disequilibrium. Disequilibrium refers to “balance problems” without vertigo. The characteristic historical feature is difficulty ambulating. A fairly rare complaint among children, disequilibrium in the young is most often caused by vestibular or cerebellar dysfunction and manifests as ataxia. Ataxia is an impairment of coordination of movement and balance; this impairment is generally associated with dysfunction of the cerebellum or of the sensory and/or motor pathways connecting to the cerebellum. There are transient forms and progressive degenerative conditions. The trick is distinguishing between the poor coordination and true ataxia. The common trait among all the “dizzy” feelings is primary or secondary central nervous system dysfunction. Dizziness should be considered a potential alteration in the patient’s level of consciousness and must be taken seriously.
SYNCOPE Syncope is a common phenomenon among children and adolescents. As many as 15% of children experience a syncopal event between the ages of 8 and 18 years. Before age 6 years, syncope is very unusual except in the setting of seizure disorders, breath-holding spells, and primary cardiac dysrhythmias. Syncope in children provokes great anxiety in parents, teachers, and other children who observe a syncopal episode. Fainting episodes cause a large number of health care visits and a surprising number of admissions to hospitals. The differential diagnosis of syncope is noted in Table 42-2. The pathophysiologic mechanism of syncope seems to follow a common pathway with many inciting stimuli. Cerebral perfusion is compromised by a transient decrease in cardiac output as a result of vasomotor changes, decreasing venous return, primary dysrhythmia, or impairment of cerebral vascular tone. Adolescents subjected to a head-up tilt-table test report blurred vision and constriction of visual fields before losing consciousness, as well as nausea, pallor, sweating, and dizziness, which are accompanied by hypotension (systolic blood pressure < 60 mm Hg) and by bradycardia (heart rate < 40 beats/minute) with an occasional junctional rhythm and even asystole (Fig. 42-1). Symptoms are relieved by returning to the supine position. Several situational factors can exacerbate this response, including ● ● ● ● ● ●
warm temperature a confined space, such as being in a crowded room anxiety or fear sudden surprise the sight of blood pain, such as from needlesticks or shots
Other situational factors include urination, swallowing, coughing, defecation, and hair combing. The response is caused by imbalance of parasympathetic and sympathetic tone, which results in peripheral vasodilatation, including venodilatation, but in no augmentation of venous return, because there is no accompanying increase in large skeletal muscle activity to augment systemic venous return and maintain cardiac filling. Subsequent vagal output results in inappropriate bradycardia and further compromises cardiac output. The child faints and becomes supine, which restores systemic venous return to the right side of the heart. At the same time, awakening is accompanied by increased sympathetic output, which restores the heart rate. The episode tends to be brief but may recur if the patient is “helped up” too quickly. One scenario in which this combination of events may be most dangerous is a hot, closed telephone booth, in which a patient cannot become supine and restore cardiac output. The magnitude of this vagal response should not be underestimated. In studies utilizing isoproterenol, despite the powerful β-adrenergic stimulation, susceptible patients become profoundly bradycardic and experience junctional rhythm or even asystole. In obtaining the history of a syncopal episode, attention should be paid to the time of day, time of last meal, activities leading up to the
*Deceased.
743
Section Six Neurosensory Disorders
744 Table 42-1. Syncope and Dizziness Vertigo
Presyncope
Disequilibrium
Patient complaint
“My head is spinning” “The room is whirling”
“I feel I might pass out” “I feel faint”
“I feel unsteady” “My balance is off”
Associated features
Motion, swaying, spinning, nystagmus
Poor balance No vertigo or ataxia
Usual cause
Vestibular disorders
Key differential diagnoses
Peripheral (labyrinthinecochlear) vs. Central neurologic disorder
Syncope: loss of postural tone, brief loss of consciousness Situational Impaired cerebral perfusion Neurocardiogenic (vagal) vs. Cardiac syncope vs. Neuropsychiatric syncope
event, and associated symptoms (palpitations, racing heart beat, chest pain, headache, shortness of breath, nausea, diaphoresis, visual changes, and hearing changes). Details, such as the patient’s position (syncope while supine suggests a cardiac arrhythmia) when symptoms appeared, duration of the episode, and characterization of the patient’s appearance during and immediately after the episode are also important. Almost without exception, by the time the patient presents to the office or emergency room, the physical examination findings in children and adolescents are normal. Therefore, the history becomes the most important piece of information for developing the differential diagnosis, diagnostic evaluation, and management plan. NEUROCARDIOGENIC SYNCOPE Neurocardiogenic syncope is a type of autonomic dysfunction that is also referred to as vasodepressor syncope, vasovagal syncope, and reflex syncope. Three mechanisms appear to exist: 1. The first response is primary bradycardia, sometimes to the extreme of sinus arrest and asystole, with subsequent hypotension (see Fig. 42-1). This is known as the cardioinhibitory response. 2. The second is a primary vasodepressor response that is characterized by hypotension, the heart rate being relatively preserved. 3. The third is a mixed and the most common response that features simultaneous hypotension and bradycardia. The common pathway resulting in central nervous system dysfunction is cerebral hypotension and is also known as the Bezold-Jarisch reflex (Fig. 42-2). For most children and adolescents, prodromal warning signs herald the impending episode and can, after the first episode, allow the child enough time to prevent fainting by sitting with the head between the knees or by lying supine. The physiologic mechanisms of neurocardiogenic syncope have been demonstrated with head-up tilt-table testing. Tilt-table testing can be performed with or without invasive blood pressure monitoring. The goal is to reproduce the patient’s symptoms under close monitoring. Various tilt angles and durations have been described, as has the use of isoproterenol as a provocative stimulus. There are data for normal adolescents, but there are minimal or no data regarding the reproducibility of tilt-table testing. If the history suggests the diagnosis of neurocardiogenic syncope with normal physical examination findings and a normal electrocardiogram (ECG), treatment may be empirically started without tilt-table testing (Table 42-3). The first line of treatment is the use of salt supplementation (1 g/day orally) with the mineralocorticoid fludrocortisone acetate (Florinef) (0.1 mg/day orally). The average patient gains about 1 kg of water weight into the circulating volume over 2 to 3 weeks, and the increased volume allows blood pressure
Lightheadedness
“I feel dizzy” “I feel disconnected, drugged” Anxiety, hyperventilation, paresthesias, respiratory alkalosis, panic attacks
Sensory and/or central Anxiety and/or depressive neurologic dysfunction disorders Sensory deficit Anxiety/depression vs. vs. Central neurologic Hyperventilation disease vs. Medication effects
to be maintained even in the presence of vasodilation. A tilt-table test is advisable if the patient does not respond to empirical volumeexpansion therapy. A second therapeutic choice is usually β-adrenergic receptor blockade, typically with atenolol or metoprolol. A second tilt-table test may be performed to confirm therapeutic success, but adolescent patients in particular have limited enthusiasm for a repeated tilt-table test. Alternative therapies may include theophylline or pseudoephedrine, disopyramide, or combinations of the drugs named earlier. There are several causes of autonomic or neurocardiogenic syncope. Excessive vagal tone may be primary or secondary to breath holding, cough, swallowing (deglutition syncope), micturition or defecation, carotid sinus pressure sensitivity, and orthostasis. Of these, breath-holding episodes are among the most common and frightening, representing a frequent mechanism of syncope in children under age 6 years. Onset of breath holding is rare before the age of 6 months; the incidence peaks at age 2 years and resolves by ages 5 to 7 years. The incidence of breath-holding spells is approximately 5% of 1- to 5-year-olds. The family history is positive for more than 30%; this may suggest an autosomal dominant disorder with incomplete penetrance. Both sexes are equally affected. Typically, the child is startled or agitated, and a period of crying terminates with a prolonged noiseless expiration, visible cyanosis, and collapse. The episode is totally involuntary. Provocations include pain, anger, fear, or frustration. These episodes result in a great deal of parental anxiety. That anxiety is magnified when monitoring illustrates that the episode is accompanied by reflex increase in vagal tone, often accompanied by asystole for 15 to 30 seconds. Fifteen percent of patients have a brief (seconds) anoxic convulsion after syncope. After the episode, many children sleep. Most affected children “outgrow” these episodes, which rarely affect future central nervous function, such as cognition. Fifteen percent to 20% have vasovagal syncope as older children or young adults. Pallid breath-holding spells occur in fewer than 25% of episodes. Stereotypically, pallid spells begin with a sudden fright or pain, the patient quiets, then develops pallor, apnea, and bradycardia or brief asystole. Fifty percent of these patients reproduce this sequence with brief proximal humerus Local pain Lytic, sclerotic Sunburst pattern Ewing sarcoma, osteomyelitis Lung, bones Skip lesions in the same bone Surgery, chemotherapy Limb salvage if tumor is resectable and the patient is near adult height 50%-60% survival Onset at age < 10 yr, large tumor size (>15 cm), symptoms < 2 months, metastasis
Childhood and adolescence White 1.5:1 Nonosseous, small round cell None Diaphysis, medullary cavity, cortical bone, soft tissue; femur > pelvis > tibia > humerus Pain, fever, increased ESR, FUO, weight loss Mottled, lytic Onion skin pattern Osteomyelitis, eosinophilic granuloma, lymphoma, neuroblastoma, rhabdomyocarcoma Lung, bones Surgery, radiotherapy Chemotherapy 60% survival without metastasis; 5%-15% with metastasis, primary site dependent Pelvis, soft tissue tumor, increased LDH, metastasis, increased circulating PMNs, decreased circulating lymphocytes
Adapted from Behrman RE (ed): Nelson Textbook of Pediatrics, 14th ed. Philadelphia, WB Saunders, 1992, p 1312. ESR, erythrocyte sedimentation rate; F, female; FUO, fever of unknown origin; LDH, lactate dehydrogenase; M, male; PMN, polymorphonuclear neutrophil.
sedimentation rate, and C-reactive protein level. Some infants present only with “pseudoparalysis.” When the hip joint is involved, the child holds the hip in a position of flexion, abduction, and external rotation. This position unwinds the hip capsule and allows it to hold the greatest volume of intracapsular fluid. This initially decreases pressure, but as the pus continues to accumulate, even this position fails to relieve symptoms. A hip joint effusion is usually not palpable, but there may be overlying soft tissue swelling and tenderness. Infections about peripheral joints, such as the knee, are more easily diagnosed. There is typically a joint effusion and perhaps soft tissue swelling, erythema, and increased warmth over the metaphysis if osteomyelitis is present. Osteomyelitis typically manifests with point tenderness over the involved site; with continued bone destruction and rupture of pus into the periosteum, tenderness becomes more diffuse. Infections can also occur about the ankle and foot. Infection of the foot is less common except as a sequela to puncture wounds through a tennis shoe, producing the classic Pseudomonas aeruginosa (or S. aureus) osteomyelitis-osteochondritis.
Figure 45-13. A, Anteroposterior radiograph of the distal femur in a 12-year-old girl with limping and nighttime knee pain for 6 months. There is a lucent lesion with surrounding sclerosis in the metaphysis. The lesion crosses the epiphysis; this is characteristic of a subacute osteomyelitis. B, Anteroposterior tomography clearly demonstrates the lucent nature of the lesion and its surrounding sclerosis.
Radiographic Evaluation. Plain radiographs are not helpful in the early diagnosis (first 7 to 10 days) of osteomyelitis, inasmuch as they are usually normal, but must be obtained in the assessment of the child. After 10 to 14 days of active infection, bone destruction or periosteal bone elevation is seen. A bone scan or MRI can be very helpful in establishing an early diagnosis. If a septic process about the hip is suspected, an ultrasound study may be beneficial in demonstrating an effusion. If this is present, arthrocentesis or hip aspiration is necessary. The synovial fluid analysis should include a cell count, measurement of protein and glucose levels, Gram stain, cultures, and sensitivity studies. Infections of peripheral joints, such as the knee, are more readily diagnosed by arthrocentesis.
Section Seven Orthopedic Disorders
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If an osteomyelitis of a metaphyseal region is suspected, the subperiosteal space and bone may be directly aspirated with a large-bore needle. The material should be sampled for culture and sensitivity. If pus is not obtained, a bone scan or MRI can usually confirm infection. Unfortunately, even in an acute infection, cultures from the joint or bone and blood are not always positive. S. aureus is the most common organism that produces osteomyelitis and the most common organism that produces septic arthritis in children 5 to 15 years of age. Haemophilus influenzae type b needs to be considered as a cause of septic arthritis in unimmunized children younger than 5 years. Neisseria gonorrhoeae infection is the most common cause of septic arthritis in sexually active adolescents. Neonatal osteoarticular infection is often caused by group B streptococcus or S. aureus, rarely by gram-negative organisms or Candida species. Patients with sickle cell anemia develop osteomyelitis as a result of Salmonella species or S. aureus infection and septic arthritis as a result of pneumococcal infection. Treatment. Treatment of septic arthritis and osteomyelitis of the
hip is always by surgical drainage (see Chapter 44) because the increased intracapsular pressure can tamponade the intracapsular vessels that supply the CFE, which results in avascular necrosis. Peripheral joints with septic arthritis, such as the knee and ankle, may be aspirated, treated with empirical antibiotics (nafcillin, methicillin, cefotaxime, ceftriaxone), and observed while the clinician is awaiting the results of cultures. The need for surgical drainage is based on the clinical response over a 24- to 48-hour period. If osteomyelitis is suspected but no pus is present within the metaphysis, this condition can also be treated empirically. When pus (abscess) is present, however, incision and drainage usually result in a more rapid resolution of infection and prevent secondary damage to the adjacent physeal plate. Treatment of osteomyelitis takes 4 to 6 weeks; this may be accomplished by an initial regimen of intravenous antibiotics; once signs of improvement occur (decreased erythrocyte sedimentation rate, decreased leukocyte count, decreased pain, negative blood culture, and decreased fever, usually after 10 to 14 days), oral antibiotics may be substituted. The bacteria must be available for minimal inhibitory concentration (MIC) serum determination, the family should be highly compliant with the treatment regimen, and follow-up should be ensured.
afebrile. Laboratory findings are usually within normal limits, but occasionally a minimal elevation of the white blood cell count or sedimentation rate may be seen. Radiographic Evaluation. Anteroposterior and Lauenstein
(frog) lateral radiographs of the pelvis are obtained to rule out the presence of other lesions. The radiographs in synovitis are normal. On occasion, ultrasonography of the hip may be useful in demonstrating a joint effusion. Bone scans may be necessary in difficult or unusual cases; in synovitis, these results are always normal. Treatment. The treatment of monoarticular synovitis of the hip is
symptomatic. Bed rest and avoidance of weight bearing until these symptoms resolve, followed by limited activities for 1 to 2 weeks thereafter, constitute the treatment of choice. The child’s activities should be limited until the symptoms have completely resolved. A rapid return to normal activities may result in exacerbation. When the diagnosis of monoarticular synovitis is in doubt, hip arthrocentesis may be necessary. The fluid that is aspirated shows a very low white blood cell count, and the cultures are negative. Trendelenburg Gait Developmental Origin Developmental Dysplasia of the Hip. Developmental dysplasia of the hip is a very common disorder affecting infants (Fig. 45-14), but its presence after walking age is relatively uncommon. Unfortunately, no matter how careful the initial screening evaluation, a small number of children are seen each year with a late diagnosis of developmental dysplasia. When the problem occurs unilaterally, the child walks with a mild Trendelenburg gait or demonstrates toewalking. With bilateral involvement, the child stands with an increased lumbar lordosis and has a waddling gait. There is functional impairment resulting from a lack of stability and associated muscle weakness, particularly in the hip abductors (gluteus medius). Clinical Examination. The most common physical finding in
the older child with a developmentally dislocated hip is limited hip abduction on the involved side. There may be a mild hip flexion contracture and apparent shortening of the extremity. The greater
Diskitis. See Chapter 46. Rheumatologic Causes Hip Monoarticular Synovitis. Transient monoarticular syn-
ovitis of the hip is the most common cause of limping in children. It can occur in all age groups, but the mean age at onset is 6 years; most patients are between 3 and 8 years of age. Hip monoarticular synovitis is characterized by acute onset of monoarthritic hip pain, an associated limp, and mild restriction of hip motion, especially abduction and internal rotation. The pain is felt in the groin, anterior thigh, or knee. Any child with nontraumatic anterior thigh or knee pain must be carefully evaluated for hip disease because these are the sites of referred pain. Septic arthritis and osteomyelitis must be excluded. The cause of this disorder remains uncertain. Suspected causes include (1) active or recent systemic viral syndrome, (2) trauma, and (3) allergic hypersensitivity. Approximately 70% of affected children have had a nonspecific viral upper respiratory infection 7 to 14 days before the onset of symptoms. Clinical Examination. The patient is usually ambulatory, and the hip is not held in the position of flexion, abduction, or external rotation unless a significant effusion has developed. The child walks with an antalgic (painful) gait on the involved side and is usually
Figure 45-14. Anteroposterior radiograph of the pelvis of an 18-month-old girl demonstrating a developmental dislocation of the left hip. The acetabulum is severely dysplastic, and the femoral head is displaced laterally and superiorly. The Shenton line is markedly disrupted, and there is delayed ossification in the capital femoral epiphysis in comparison with the normal right hip.
Chapter 45 Gait Disturbances trochanter lies above a line between the anterior-superior iliac spine and the ischial tuberosity (Nélaton line). In bilateral dislocations, the physical findings are more symmetrical but there is still limitation of hip abduction. Positive Trendelenburg signs are present on the involved side. The normal response to a Trendelenburg test occurs when the patient stands on the uninvolved leg and the abductor muscles are able to maintain balance by elevating the contralateral pelvis. A positive Trendelenburg sign, resulting from weakness, is demonstrated when the abductor muscles are unable to maintain pelvic balance and the patient compensates by leaning to the affected side.
841
Dodgin DA, DeSwart RJ, Stefko RM, et al: Distal tibial/fibular derotation osteotomy for correction of tibial torsion: Review of technique and results in 63 cases. J Pediatr Orthop 1998;18:95-101. Karol LA: Rotational deformities in the lower extremities. Curr Opin Pediatr 1997;9:77-80. Ruwe PA, Gage JR, Ozonoff MB, et al: Clinical determination of femoral anteversion: A comparison of established techniques. J Bone Joint Surg Am 1992;74:820-830. Strecker W, Keppler P, Gebhard F, et al: Length and torsion of the lower limbs. J Bone Joint Surg Br 1997;79:1019-1023. Metatarsus Adductus
Radiographic Evaluation. The diagnosis can be made from
routine anteroposterior and Lauenstein (frog) lateral radiographs of the pelvis (see Fig. 45-14). Specialized studies, such as MRI and CT, are usually not necessary. Ultrasound study is not usually necessary in the older child because the CFE is ossified. Treatment. Treatment of developmental dysplasia of the hip in
the older child is usually surgical. The procedure consists of an open reduction of the hip with a pelvic osteotomy, femoral varus shortening and derotation osteotomy, or a combination of both. The procedure selected depends on the age of the child and the severity of the deformity of the acetabulum and proximal femur. Lower Extremity Length Discrepancy. Lower extremity
length discrepancy in older children and adolescents has been discussed earlier in this chapter. Neuromuscular Origin Cerebral Palsy. Children with a spastic hemiplegia or diplegia
may have an associated painless limp caused by muscle spasticity and concomitant weakness of the antagonists. The history should focus on risk factors for cerebral palsy, prematurity, and other congenital anomalies external to the central nervous system, followed by a physical examination, with particular attention to the neurologic system. The neurologic examination reveals evidence of increased muscle tone, spasticity, hyperactive deep tendon reflexes, and pathologic reflexes, such as Babinski signs.
SUMMARY AND RED FLAGS Conditions associated with limp must be divided into acute, painful lesions and chronic, painless lesions. Infection and trauma must be considered emergencies, as should conditions that are limb or articular threatening, such as septic arthritis and osteomyelitis of the hip, avascular necrosis, or SCFE. In addition, signs of spinal cord involvement (see Chapter 46) suggest acute processes that warrant immediate attention to prevent permanent paralysis. Red flags include acute hip pain, fever with limp, neurologic manifestations (including bowel and bladder dysfunction), point tenderness, the presence of a mass, and signs of weight loss or hematologic abnormalities such as pallor or bruising.
Asirvatham R, Stevens PM: Idiopathic forefoot-adduction deformity: Medial capsulotomy and abductor hallucis lengthening for resistant and severe deformities. J Pediatr Orthop 1997;17:496-500. Bleck EE: Metatarsus adductus: Classification and relationship to outcomes of treatment. J Pediatr Orthop 1983;3:2-9. Farsetti P, Weinstein SL, Ponseti IV: The long-term functional and radiographic outcomes of untreated and non-operatively treated metatarsus adductus. J Bone Joint Surg Am 1994;76:257-265. Talipes Equinovarus (Clubfoot)
Alkjaer T, Pedersen EN, Simonsen EB: Evaluation of the walking pattern in clubfoot patients who received early intensive treatment. J Pediatr Orthop 2000;20:642-647. Cuevas de Alba C, Guille JT, Bowen JR, et al: Computed tomography for femoral and tibial torsion in children with clubfoot. Clin Orthop 1998;353:203-209. Ezra E, Hayek S, Gilai AN, et al: Tibialis anterior tendon transfer for residual dynamic supination deformity in treated clubfeet. J Pediatr Orthop B 2000; 9:207-211. Karol LA, Concha MC, Johnston CE: Gait analysis and muscle strength in children with surgically treated clubfeet. J Pediatr Orthop 1997;17:790-795. Kuo KN, Hennigan SP, Hastings ME: Anterior tibial tendon transfer in residual dynamic clubfoot deformity. J Pediatr Orthop 2001;21:35-41. Macnicol MF, Nadeem RD, Forness M: Functional results of surgical treatment in congenital talipes equinovarus (clubfoot): A comparison of outcome measurements. J Pediatr Orthop B 2000;9:285-292. Roye BD, Vitale MG, Gelijins AC, et al: Patient-based outcomes after clubfoot surgery. J Pediatr Orthop 2001;21:42-49. Calcaneovalgus Foot
Mosca, VS: Other conditions of the foot. In Morrissy RT, Weinstein SL (eds): Pediatric Orthopaedics, 5th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, p 1178. Hypermobile Pes Planus
Akrali O, Tiner M, Ozaksoy D: Effects of lower extremity rotation on prognosis of flexible flatfoot in children. Foot Ankle Int 2000;21:772-774. Staheli LT, Chew DE, Corbet M: The longitudinal arch: A survey of 882 feet in normal children and adults. J Bone Joint Surg Am 1987;69:426-428. Sullivan JA: Pediatric flatfoot: Evaluation and management. J Am Acad Orthop Surg 1999;7:44-53. Wenger DR, Mauldin D, Speck G, et al: Corrective shoes and inserts as treatment for a flexible flatfoot in infants and children. J Bone Joint Surg Am 1989;71:800-810. Equinus Gait (Toe-Walking)
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Neuromuscular Disorders
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Rotational Abnormalities
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Femoral/Tibial Torsion
Congenital Tendo Achilles Contracture (Idiopathic Toe-Walking)
Bruce RW Jr: Torsional and angular deformities. Pediatr Clin North Am 1996;43:867-881.
Eastwood DM, Dennett X, Shield LK, et al: Muscle abnormalities in idiopathic toe-walkers. J Pediatr Orthop B 1997;6:215-218.
Sutherland DH, Olshen R, Cooper L, et al: The development of gait. J Bone Joint Surg Am 1980;62:336-353.
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Eastwood DM, Menelaus MB, Dickens DR, et al: Idiopathic toe-walking: Does treatment alter the natural history? J Pediatr Orthop B 2000; 9:47-49. Sala DA, Shulman LH, Kennedy RF, et al: Idiopathic toe-walking: A review. Dev Med Child Neurol 1999;41:846-848. Shulman LH, Sala DA, Chu ML, et al: Developmental implications of idiopathic toe-walking. J Pediatr 1997;130:541-546. Stricker SJ, Angulo JC: Idiopathic toe-walking: A comparison of treatment methods. J Pediatr Orthop 1998;18:289-293. Habitual Toe-Walking
Griffin PP, Wheelhouse WW, Shiavi R, et al: Habitual toe-walkers: A clinical and electromyographic gait analysis. J Bone Joint Surg Am 1977;59:97-101. Lower Extremity Length Discrepancy
Dahl MT: Limb length discrepancy. Pediatr Clin North Am 1996;43:849-866. Ballock RT, Wiesner GL, Myers MT, Thompson GH: Hemihypertrophy. Concepts and controversies. J Bone Joint Surg Am 1997;79:1731-1738. Herzenberg JE, Paley D: Leg lengthening in children. Curr Opin Pediatr 1998;10:95-97. Song KM, Halliday SE, Little DG: The effect of limb-length discrepancy on gait. J Bone Joint Surg Am 1997;79:1690-1698. Stanitski DF: Limb-length inequality: Assessment and treatment options. J Am Acad Orthop Surg 1999;7:143-153.
Wall EJ: Legg-Calvé-Perthes disease. Curr Opin Pediatr 1999;11:76-79. Weinstein SL: Natural history and treatment outcomes of childhood hip disorders. Clin Orthop 1997;344:222-242. Slipped Capital Femoral Epiphysis
Carney BT, Weinstein SL, Noble J: Long-term follow-up of slipped capital femoral epiphysis. J Bone Joint Surg Am 1991;73:677-674. Givon U, Bowen JR: Chronic slipped capital femoral epiphysis: Treatment by pinning in situ. J Pediatr Orthop B 1999;8:216-222. Kennedy JG, Hresko MT, Kasser JR, et al: Osteonecrosis of the femoral head associated with slipped capital femoral epiphysis. J Pediatr Orthop 2001;21:189-193. Loder RT, Richards BS, Shapiro PS, et al: Acute slipped capital femoral epiphysis: The importance of physeal stability. J Bone Joint Surg Am 1993;75:1134-1140. Matava MJ, Patton CM, Luhmann S, et al: Knee pain as the initial symptom of slipped capital femoral epiphysis: An analysis of initial presentation and treatment. J Pediatr Orthop 1999;19:455-460. Reynolds RA: Diagnosis and treatment of slipped capital femoral epiphysis. Curr Opin Pediatr 1999;11:80-83. Weinstein SL: Natural history and treatment outcomes of childhood hip disorders. Clin Orthop 1997;344:222-242. Wells D, King JD, Roe TF, et al: Review of slipped capital femoral epiphysis associated with endocrine disease. J Pediatr Orthop 1993;13:610-614. Sprains/Strains
Limping General
Barkin RM, Barkin SZ, Barkin AZ: The limping child. J Emerg Med 2000; 18:331-339. Connolly LP, Treves ST: Assessing the limping child with skeletal scintigraphy. J Nucl Med 1998;29:1056-1061. Fischer SU, Beattie TF: The limping child: Epidemiology, assessment and outcome. J Bone Joint Surg Br 1999;81:1029-1034. Lett AI, Skaggs DL: Evaluation of the acutely limping child. Am Fam Physician 2000;61:1011-1018. Myers MT, Thompson GH: Imaging the child with a limp. Pediatr Clin North Am 1997;44:637-658.
Saperstein AL, Nicholas SJ: Pediatric and adolescent sports medicine. Pediatr Clin North Am 1996;43:1013-1034. Occult Fractures
Aronson J, Garvin K, Seibert J, et al: Efficiency of the bone scan for occult limping toddlers. J Pediatr Orthop 1992;12:38-44. Mellick LB, Reesor K: Spiral tibial fractures of children: A commonly accidental spiral long bone fracture. Am J Emerg Med 1990;8: 234-237. Tenenbien M, Reed MH, Black GB: The toddler’s fracture revisited. Am J Emerg Med 1990;8:208-211. Neoplasia
Tarsal Coalition
Blakemore LC, Cooperman DR, Thompson GH: The rigid flatfoot: Tarsal coalitions. Foot Ankle Clin 1998;3:609-631. Bohne WH: Tarsal coalition. Curr Opin Pediatr 2001;13:29-35. Vincent KA: Tarsal coalition and painful flatfoot. J Am Acad Orthop Surg 1998;6:274-281.
Copley L, Dormans JP: Benign pediatric bone tumors. Pediatr Clin North Am 1996;43:949-966. Himelstein BP, Dormans JP: Malignant bone tumors of childhood. Pediatr Clin North Am 1996;43:967-984. Tuten HR, Gabos PG, Keimar SJ, et al: The limping child: A manifestation of acute leukemia. J Pediatr Orthop 1998;18:625-629.
Legg-Calvé-Perthes Disease
Septic Arthritis/Osteomyelitis
Guille JT, Lipton GE, Szoke G, et al: Legg-Calvé-Perthes disease in girls. A comparison of the results seen in boys. J Bone Joint Surg Am 1998;80:1256-1263. Herring JA: The treatment of Legg-Calvé-Perthes disease. A critical review of the literature. J Bone Joint Surg Am 1994;76:448-458. Herring JA, Neustadt JB, Williams JJ, et al: The lateral pillar classification of Legg-Calvé-Perthes disease. J Pediatr Orthop 1992;12:143-150. Loder RT, Schwartz EM, Hensinger RN: Behavioral characteristics of children with Legg-Calvé-Perthes disease. J Pediatr Orthop 1993;13: 598-601. Martinez AG, Weinstein SL, Dietz FR: The weight-bearing abduction brace for the treatment of Legg-Perthes disease. J Bone Joint Surg Am 1992;74:12-21. Meehan PL, Angel D, Nelson JM: The Scottish Rite abduction orthosis for the treatment of Legg-Perthes disease. J Bone Joint Surg Am 1992; 74:1-12. Noonan KJ, Price CT, Kupiszewski SJ, et al: Results of femoral varus osteotomy in children older than nine years with Perthes’ disease. J Pediatr Orthop 2001;21:198-204. Salter RB, Thompson GH: Legg-Calvé-Perthes disease: The prognostic significance of the subchondral fracture and a two-group classification of the femoral head involvement. J Bone Joint Surg Am 1984;66:479-499. Thompson GH, Price CT, Roy D, et al: Legg-Calvé-Perthes disease: Current concepts. Am Acad Orth Surg 2002;51:367-384.
Blyth MJ, Kincaid R, Craigen MA, et al: The changing epidemiology of acute and subacute haematogenous osteomyelitis in children. J Bone Joint Surg Br 2001;83:99-102. Kim HK, Alman B, Cole WB: A shortened course of parenteral antibiotic therapy in the management of acute septic arthritis of the hip. J Pediatr Orthop 2000;20:44-47. Luhmann JD, Luhmann SJ: Etiology of septic arthritis in children: An update for the 1990’s. Pediatr Emerg Care 1999;15:40-42. Lyon RM, Evanich JD: Culture negative septic arthritis in children. J Pediatr Orthop 1999;19:655-659. Newton PO, Ballock RT, Bradley JS: Oral antibiotics of bacterial arthritis. Pediatr Infect Dis J 1999;18:1102-1103. Oudjhane K, Ozouz EM: Imaging of osteomyelitis in children. Radiol Clin North Am 2001;39:251-266. Poyhia T, Azouz EM: MR imaging evaluation of subacute and chronic bone abscesses in children. Pediatr Radiol 2000;30:763-768. Rasool MN: Primary subacute haematogenous osteomyelitis in children. J Bone Joint Surg Br 2001;83:93-98. Sonnan GM, Henry NK: Pediatric bone and joint infections. Diagnosis and antimicrobial management. Pediatr Clin North Am 1996;43:933-947. Waagner DC: Musculoskeletal infections in adolescents. Adolesc Med 2000;11:375-400. Wall EJ: Childhood osteomyelitis and septic arthritis. Curr Opin Pediatr 1998;10:73-76.
Chapter 45 Gait Disturbances Wang MN, Chen WM, Leck S, et al: Tuberculosis osteomyelitis in young children. J Pediatr Orthop 1999;19:151-155. Hip Monoarticular Synovitis
Do TT: Transient synovitis as a cause of painful limps in children. Curr Opin Pediatr 2000;12:48-51. Kocher MS, Zurakowski D, Kasser JR: Differentiating between septic arthritis and transient synovitis of the hip in children: An evidence-based clinical prediction algorithm. J Bone Joint Surg Am 1999;81:1662-1670. Developmental Dysplasia of the Hip
DeKleuver M, Kooijman MA, Pavlov PW, et al: Triple osteotomy of the pelvis for acetabular dysplasia: Results at 8 to 15 years. J Bone Joint Surg Br 1997;79:225-229. Kerry RM, Simonds GW: Long-term results of the late non-operative reduction of developmental dysplasia of the hip. J Bone Joint Surg Br 1998; 80:78-82.
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Kim HT, Kim JI, Yoo CI: Diagnosing childhood acetabular dysplasia using the lateral margin of the sourcil. J Pediatr Orthop 2000;20:709-717. Kim HT, Wenger DR: The morphology of residual acetabular deficiency in childhood hip dysplasia: Three-dimensional computed tomographic analysis. J Pediatr Orthop 1997;17:637-647. Lin CJ, Romanus B, Sutherland DH, et al: Three-dimensional characteristic of cartilaginous and bony components of dysplastic hips in children: Three-dimensional computed tomography quantitative analysis. J Pediatr Orthop. 1997;17:152-157. Olney B, Latz K, Asher M: Treatment of hip dysplasia in older children with a combined one-stage procedure. Clin Orthop 1998;347:215-223. Vedantam R, Capelli AM, Schoenecker PL: Pemberton osteotomy for the treatment of developmental dysplasia of the hip in older children. J Pediatr Orthop 1998;18:254-258.
46
Back Pain in Children and Adolescents
John G. Thometz*
Persistent back pain in children necessitates a thorough evaluation to rule out disorders that can result in significant morbidity, such as infection or tumor. Back pain in younger children is unusual. The prevalence of complaints of low back pain increases with age, ranging from 1% at 7 years of age to about 20% by the teenage years. In adolescents, back pain is frequently mild and often resolves spontaneously. The complaints are often related to overactivity in sports, work, or a specific traumatic event. As noted in adults, back pain is not a disease but a symptom and is often associated in adolescents with headaches, emotional problems, daytime tiredness, and conduct disorders. Activity modification and rehabilitation or exercises for the spine are sufficient to prevent recurrent episodes of back pain. Severe or persistent back pain necessitates a thorough history, physical examination, and appropriate imaging studies to evaluate the child for potentially serious pathologic processes.
Vertebral growth occurs in an orderly manner throughout childhood and adolescence. About 50% of vertebral column height is present by age 2 years. Acceleration of vertebral growth occurs during the adolescent growth spurt but contributes less to total height than does lower limb growth; the sitting heights of siblings in early and late adolescence are often remarkably similar. Spinal growth slows at menarche in girls and at the time of voice change in boys and is usually complete 2 to 3 years later. Developmental abnormalities of the column, such as idiopathic scoliosis, most commonly first appear just before the growth spurt. Alterations in spinal configuration caused by congenital deformities of vertebral segments change most rapidly during periods of rapid spinal growth: before age 2 years and at the time of the adolescent growth spurt. There is a high association of genitourinary tract, cardiac, and neural abnormalities in patients with congenital abnormalities of the spine. Warning signs in patients with congenital spine deformities include leg-length inequality, foot-size asymmetry, high foot arches, hairy patches or hemangiomas or a mass over the spine, sacral dimpling, enuresis, toe walking, asymmetry or abnormality in the lower extremity deep tendon reflexes, and lower extremity weakness.
EVALUATION OF THE PEDIATRIC SPINE Examination of the spine should be part of the routine physical examination in the healthy child and adolescent. Even in patients who present with back pain as a chief complaint, the most important diagnostic steps are a detailed history and a thorough and systematic examination (Table 46-1). When findings on screening examinations are abnormal or when a patient presents with complaints of back pain, a more detailed examination is required. The spinal column, spinal cord, and spinal nerves are intimately related, and disorders affecting any one of these elements produce symptoms and signs in the others. Detailed examination of strength in the muscles of the spine and lower extremities (Fig. 46-1), sensation (Fig. 46-2), abdominal and lower extremity reflexes, anal sphincter tone, and perianal sensation should be performed when the primary examination suggests involvement of the neural structures that pass through the spinal column. Persistent or severe back pain is uncommon in young children and may be associated with serious underlying disease. Interpretation of the results of patient evaluation requires an understanding of the normal sequence of growth and development of the spine, knowledge of normal spinal alignment, and an understanding of the age-related differential diagnosis of potential spinal disorders in children.
NORMAL SPINAL ALIGNMENT The normal trunk is symmetric when viewed from the front or the back (Fig. 46-3). The shoulders and pelvis are parallel to each other and to the ground. The distance between the right and left elbows and the sides of the trunk is equal. When the trunk is viewed from the side, a series of curves is present (see Fig. 46-3). A convex anterior lordotic curve is present in the cervical region. The spine is concave anteriorly in a kyphotic pattern in the thoracic region. The normal lumbar spine is lordotic, and the sacrum and coccygeal regions are kyphotic. Normal adult sagittal alignment develops gradually; children younger than 10 years typically have less cervical lordosis and more lumbar lordosis than adults. Healthy children often are quite swaybacked. Injuries, infections, tumors, inflammation, and developmental abnormalities of the spine often produce alterations in these expected contours. Range of motion is demonstrated in Figure 46-4.
BACK PAIN OF BRIEF DURATION
NORMAL GROWTH AND DEVELOPMENT OF THE SPINE
Few children younger than 10 years sustain significant injuries of the spinal column or associated musculature in routine play and organized sports activities; extremity injuries are far more common. When the trunk is involved, contusions and abrasions are much more common than ligament sprains and muscle strains. When a child presents with back pain of brief duration after a play or sports-related injury, a careful examination should be performed. If there are no other associated injuries and the screening examination shows no alterations in trunk configuration or lower extremity strength or sensation (see Figs. 46-1 and 46-2), no further workup is necessary. A brief period of rest for 1 to 2 days, followed by gradual
Formation of the vertebral column begins during the third week of gestation and is complete by the end of the first trimester. Further growth and primary ossification of the spinal column occurs during the second and third trimesters; however, the cartilaginous model of the spine is complete by week 12 of embryonic development. *This chapter is an updated and edited version of the chapter by Peter V. Scoles that appeared in the first edition.
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Table 46-1. Guidelines for Primary Examination
of the Back History Is there a history of back pain? If so, what is the Frequency? Duration? Relationship to activity? Antecedent trauma? Is there associated pain in legs? Is there incontinence or enuresis? Is walking painful? Have there been systemic signs of chronic illness? Is there a family history of deformity? Is there a family history of disk disease? Physical Examination General Appearance Are the right and left sides of the trunk symmetric? Are there hairy patches, nevi, sinuses, or dimpling over the midline of the spine? Are the pelvis and shoulders level? Is there normal kyphosis and lordosis? On forward bending, is a rib hump present? Motion Can be patient easily bend forward and touch his or her toes? Is normal hamstring flexibility present? Lower Extremities Are leg lengths equal? Is strength normal in the major motor groups of the lower limbs? Is sensation normal in the lower limbs? Are reflexes normal at the knees and ankles? Are pathologic reflexes present?
resumption of activities, is appropriate treatment. Routine radiographic evaluation is not necessary when the duration of symptoms is short and the physical examination findings are normal. Signs of systemic illness (fever, weight loss) or neurologic deficits warrant an immediate evaluation.
Acute back injuries occur more frequently in adolescence, as the size of participants and potential forces generated in recreational activities increase. If there are no other associated injuries and the screening examination findings are normal, no further radiologic workup is necessary. A period of rest followed by gradual resumption of activities is appropriate treatment. The importance of a comprehensive and balanced conditioning exercise program should be stressed to young athletes. Most sports-related injuries can be prevented by preparticipation conditioning, appropriate warm-up, careful supervision, and resting when fatigued. Trauma sufficient to cause spine fractures may occur as a result of motor vehicle or bicycle accidents, falls, and diving and gymnastic injuries. The frequency and severity of spine trauma rises in later adolescence as exposure to potentially violent forces in sports and motor vehicles increases. In such cases, there is a clear relationship between the accident and the onset of symptoms. Injury to the spinal column should be suspected in all individuals whose level of consciousness is impaired after an accident, regardless of the presence or absence of symptoms. Children with suspected acute spinal injury should be immobilized on backboards designed for children until definitive imaging studies can be performed and interpreted. Immobilization of the child’s cervical spine on a solid backboard should be avoided. The child’s occiput projects farther posteriorly than that of the adult, and flexion of the neck occurs if the child’s neck is immobilized on a standard backboard. Spinal immobilization boards for children are readily available and have a cut-out section to accommodate the occiput. When such boards are not available, a blanket or firm mattress should be interposed between the trunk and the backboard to prevent neck flexion.
PERSISTENT BACK PAIN Persistent or severe back pain is uncommon in young children but is more common in adolescents. The implications of severe or persistent back pain are more serious in younger patients than in adolescents. Persistent back pain in young children is not usually the result of congenital spinal deformity or developmental disorders of the spine. As a child enters and passes through the adolescent growth spurt, back pain may arise from a small number of congenital and developmental disorders of the spinal column. Degenerative
Figure 46-1. Motor control of the lower extremity. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 926.)
Chapter 46 Back Pain in Children and Adolescents
Lateral cutaneous nerve
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Obturator Posterior cutaneous
Femoral
Femoral Peroneal
A
Peroneal
Cutaneous branch of Tibial (sciatic) nerve
B
Figure 46-2. Sensory innervation of the lower extremity. A, Peripheral nerve innervation. B, Dermatomal (root) innervation. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 927.)
disorders of the spine such as intervertebral disk herniation are uncommon causes of back pain in childhood. In evaluating a patient, it is important to try to distinguish musculoskeletal-mechanical disorders from those with more generalized systemic signs or those suggestive of a neoplasia (Fig. 46-5).
The differential diagnosis of persistent back pain in children younger than 10 years includes intervertebral diskitis and vertebral body osteomyelitis, neoplasia of the vertebrae, primary neoplasia of the spinal cord, and metastatic neoplasia (Table 46-2). In older children and adolescents, congenital variations in the formation of the
Figure 46-3. A, Normal posture with normal lumbar lordosis. B, Exaggerated lumbar lordosis caused by pelvic tilting. C, “Paunchy” posture. D, Spastic scoliosis caused by muscle spasm. E, Normal posture without scoliosis. F, The normal orientation of the lumbar spine is that of mild lordosis. Exaggerated lordosis may predispose the patient to mechanical back pain. (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 908.)
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Figure 46-4. Back range of motion. A, Flexion. Note the normal reversal of lumbar lordosis during flexion (arrow). B, Extension. C, Persistent lordosis during back flexion as a result of muscle spasm (arrow). D, Lateral flexion. E, Lateral torsion (rotation). (From Reilly BM: Practical Strategies in Outpatient Medicine, 2nd ed. Philadelphia, WB Saunders, 1991, p 909.)
lower lumbar spine are sometimes responsible for chronic back pain (see Table 46-1). Developmental round back (kyphosis) is occasionally associated with midthoracic back pain in middle and late adolescence. Diskitis, skeletal neoplasia, and tumors of the spinal cord and nerves also occur in adolescence. In documenting the history, special attention must be given to the nature of the onset of symptoms, the presence of radiating pain in the legs, bowel and bladder function, associated abdominal pain, and the presence or absence of fever. Although this issue is controversial, some authorities believe that school-aged children who carry an excessively heavy backpack are at risk for back pain and alterations of gait or posture. To alleviate this, it is recommended that the backpack be of appropriate size with wide padded straps and back padding. In addition, the weight limit of the pack should not exceed 10% to 15% of the child’s body weight. The pack should be lifted with bending of the knees, and the straps should be adjusted so that the pack fits on the back and not below the waist.
SPECIFIC DIAGNOSIS INTERVERTEBRAL DISKITIS Intervertebral diskitis is the term applied to a number of processes that are characterized by back or leg pain and radiographically by narrowing of the intervertebral joint space between two adjacent vertebral segments (Figs. 46-6 and 46-7). Magnetic resonance imaging (MRI) studies suggest that diskitis may begin as a microabscess within the vertebral body adjacent to the vertebral endplate. The disk becomes infected from perforating vascular channels across the endplate. Vascular channels may also perforate the endplate on the opposite side of the disk, leading to involvement of the opposite vertebral body. In some patients, the symptoms resolve spontaneously without treatment. There is controversy as to whether antibiotic therapy is necessary in all patients with diskitis.
Most authorities believe that diskitis is a bacterial infection, usually caused by Staphylococcus aureus. Tuberculosis infection of the spine must also be considered in patients who have spent significant time outside the United States or in high-risk patients such as those who are immunocompromised. Surgical drainage, a critical component of effective treatment of other closed-space infections of the musculoskeletal system, is not usually required in most patients with intervertebral diskitis. Clinical Findings Three age-dependent patterns of presentation have been noted for intervertebral diskitis. Children younger than 3 years (the most common age) often present with irritability and refusal to walk or apparent dysfunction (limp, antalgic gait) of the lower extremities. Patients may have very tight hamstrings, loss of lumbar lordosis (the lumbar spine is the most common site), and refusal to allow passive motion of the lumbar spine. Patients between the ages of 3 and 8 years often have pain referred to the abdomen, particularly when the disk involves the lower thoracic spine. Adolescents with diskitis often have back pain; the discomfort often radiates into both legs. Additional features at all ages include low-grade fever; refusal to bear weight (sitting or standing); hyperlordosis; and, if intraspinal inflammation is present, decreased lower extremity muscle strength, decreased tone, and alterations of deep tendon reflexes. The erythrocyte sedimentation rate is usually elevated; the white blood cell count is usually normal but may be elevated in late cases. Early in the process, radiographs of the spine are often normal. Over a certain time, the disk space narrowing develops with subsequent erosion of the vertebral endplates (see Fig. 46-6). Traditionally, a bone scan has been recommended for assessment of diskitis. However, MRI is more sensitive than the bone scan. The MRI reveals the extent of the inflammatory process better and can delineate the degree of bone destruction (if any), the presence of abscess formation, or intraspinal inflammations (see Fig. 46-7).
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Back Pain
Mechanical pain Yes
No
Equivocal
No
Short duration Negative PE
> 2 weeks’ duration or night pain
Systemic symptoms
Neurologic symptoms
Conservative Rx
Radiograph
Radiograph, CBC, ESR, CRP
Radiograph and MRI
Remains significant
Improves
Conservative Rx Improves
Abnormal
Localized lesion
Diffuse lesions Osteopenia
CT if needed to better define; MRI if appears infected
CBC, ESR, CRP, serum BMT
Sx continue
Bone scan with SPECT Normal
Abnormal
Conservative Rx
Thin-slice CT with recon.
Improves
Normal
Sx continue
As indicated: biopsy, CBC, CRP, ESR Reevaluate; if pain disabling, MRI
Pain localized? No
Yes
Bone scan
HNP
Normal
Conservative Rx
Bone scan
Surgery if Sx continue
CT
CT or MRI to define involved area
Other lesions
Biopsy?
Biopsy?
Figure 46-5. Approach to back pain in children. BMT, bone marrow testing; CBC, complete blood cell count; CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; HNP, herniated nucleus propulsus; MRI, magnetic resonance imaging; PE, physical examination results; recon., reconstruction; Rx, treatment; SPECT, single photon emission computed tomography; Sx, signs.
Treatment The diagnosis of intervertebral diskitis should be suspected in young children with fever and unexplained back or leg pain and in previously healthy toddlers who become irritable and refuse to walk. Vertebral body osteomyelitis is a major consideration in the differential diagnosis and can usually be diagnosed with radiographs and MRI. After appropriate laboratory studies, including blood cultures, have been performed, treatment should be started. A bacterial cause is likely if fever, leukocytosis, and elevation of the sedimentation rate are present. Antibiotic therapy should be started in such cases, because S. aureus is the most commonly responsible organism. Knowing the antibacterial sensitivity patterns of community-acquired S. aureus helps the clinician choose the appropriate antibiotic (clindamycin, vancomycin, or methicillin). In immunocompromised hosts, broader spectrum antibiotic coverage is essential. If an organism is recovered, antibiotic coverage can be adjusted appropriately. Initial therapy should be intravenous; oral antibiotics can be considered as pain decreases and laboratory studies return to normal. A total of 4 to 6 weeks of therapy is recommended for patients with infectious intervertebral diskitis. Immobilization of the spine is used for persistent symptoms. Patients without systemic signs of infection and in whom laboratory
studies show no leukocytosis and only moderate elevation of the sedimentation rate are occasionally managed by antiinflammatory agents and rest. Patients who remain ill or worsen after the initiation of rest and antibiotic treatment should undergo surgical biopsy and drainage. Biopsy should also be performed in patients in whom tuberculous intervertebral disk space infection is suspected (positive exposure history, positive purified protein derivative findings; see Chapter 2). The evolution of radiographic findings lags behind clinical findings in intervertebral diskitis. Although patients with intervertebral diskitis may experience disk space narrowing and endplate erosion during the course of treatment, normal radiographs and bone scans at the time of initial evaluation do not preclude the diagnosis. Radiographic changes continue long after the inflammatory process has resolved. Progressive disk space narrowing, intervertebral disk space calcification, and spontaneous intervertebral arthrodesis are potential late findings. Lack of focal increased isotope uptake on bone scans obtained 2 to 3 weeks after the onset of symptoms significantly lessens the likelihood of intervertebral diskitis. In such patients, careful study for other potential diagnoses is essential. Tumors of the spinal cord may manifest in a similar manner without causing the changes in
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Table 46-2. Differential Diagnosis of Back Pain
Inflammatory Diseases Diskitis* Vertebral osteomyelitis (pyogenic, tuberculosis) Spinal epidural abscess Pyelonephritis* Perinephric abscess Pancreatitis Paraspinal muscle abscess, myositis Psoas abscess Endocarditis Pelvic osteomyelitis Pelvic inflammatory disease Rheumatologic Diseases Pauciarticular juvenile rheumatoid arthritis* Reactive arthritis Ankylosing spondylitis Psoriatic arthritis Ulcerative colitis, Crohn disease Fibrositis, fibromyalgia Developmental Diseases Spondylolysis (in adolescence)* Spondylolisthesis (in adolescence)* Scheuermann syndrome (in adolescence)* Scoliosis Spinal dysraphism Mechanical Trauma and Abnormalities Muscle strain/sprain* Hip/pelvic anomalies Herniated disk (rare) Juvenile osteoporosis (rare) Overuse syndromes (common with athletic training and in gymnasts and dancers)* Vertebral stress fractures Lumbosacral sprain* Seat-belt injury Trauma (direct injury; e.g., motor vehicle accident)* Strain from heavy knapsacks
Figure 46-6. Intervertebral diskitis. There is loss of intervertebral disk space height between vertebral segments L3 and L4, with early endplate erosion on the anteroinferior surface of L3 and anterosuperior surface of L4.
Neoplastic Diseases Primary vertebral tumors (osteogenic sarcoma, Ewing sarcoma) Metastatic tumor (neuroblastoma, rhabdomyosarcoma) Primary spinal tumor (neuroblastoma, lipoma, cysts, astrocytoma, ependymoma) Malignancy of bone marrow (ALL, lymphoma) Benign tumors (eosinophilic granuloma, osteoid osteoma, osteoblastoma, bone cyst) Other Disk space calcification (idiopathic, ?S/P diskitis) Conversion reaction Sickle cell anemia* Nephrolithiasis Hemolysis (acute) Hematocolpos S/P lumbar puncture Modified from Behrman R, Kliegman R (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 711. *Common. ALL, acute lymphocytic leukemia; S/P, status post.
Figure 46-7. Intervertebral diskitis, magnetic resonance image. Note the increased marrow signal from the vertebral bodies adjacent to the narrowed L4 intervertebral disk. The normal bright signal is missing from the involved disk itself, and there is evidence of soft tissue abscess formation anterior to the involved disk space.
Chapter 46 Back Pain in Children and Adolescents
F
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F
Figure 46-8. Stress leading to fracture of the pars interarticularis.
Flexion
Extension
the vertebral segments necessary to produce alterations on bone scanning. In such patients, MRI is invaluable.
SPONDYLOLYSIS AND SPONDYLOLISTHESIS The most common abnormalities of the lower lumbar and lumbosacral spine—spina bifida occulta, at L5 or S1, and spondylolysis, usually at L5 to S1—are often noted as incidental radiologic findings in entirely asymptomatic individuals. A few individuals with spondylolysis (defect in the pars interarticularis without slippage) experience back pain and progressive slippage deformity, known as spondylolisthesis. As a consequence of the normal lordotic tilt of the lumbar spine, shear forces are generated between the L5 and S1 vertebral segments. Forward displacement of L5 on S1 is normally prevented by the stable articulation of the superior facets of S1 and the inferior facets of L5. Defective formation of the posterior elements of the lumbosacral joint or defects in the bone connection between the body and the arch of the fifth lumbar vertebra render the anterior junction of L5 and S1 unstable and may lead to relative displacement. Cause Spondylolysis and spondylolisthesis in children and adolescents usually involve the fifth lumbar and first sacral units. Spondylolysis is not present at birth, but with growth and activity, it is seen by age 6 years in about 4% of children and 6% of adults. Spondylolysis appears to be less common in black persons and much more common in some North American Eskimo groups; the lowest incidence has been reported in black girls, and the highest in white boys. The maleto-female ratio is 2:1. The disorder appears to be multifactorial; both hereditary and mechanical factors have been implicated. Relatives of patients with spondylolysis are much more likely to be affected than are individuals in the general population, although the degree of slippage is not as well correlated. Fatigue fracture of the posterior elements of L5 may be responsible for acutely painful spondylolysis in some preadolescent and adolescent athletes (Figs. 46-8 and 46-9). Activities that involve repeated trunk flexion and extension have been implicated; adolescent divers and gymnasts are reported to be susceptible to spondylolysis and spondylolisthesis. A high rate of spondylolysis has been reported in Scheuermann disease (thoracic kyphosis), which may be related to compensatory excessive lumbar lordosis. In addition, an increased incidence of spondylolisthesis has been noted among both patients with myelodysplasia and those with cerebral palsy. Acute fracture-dislocation of vertebral units resulting from violent trauma in a strict sense is one form of spondylolisthesis, but because it differs so greatly from other types of spondylolisthesis in cause, presentation, and treatment, it is usually considered as a separate entity.
R
Presentation Symptoms in patients with spondylolysis and spondylolisthesis are quite variable; many patients are asymptomatic. Some patients with minimal slips have extreme pain, while others with moderate to severe slips have little or no discomfort. Symptomatic patients complain of aching in the lumbar and lumbosacral regions. Buttock and posterior thigh pain may be present, but radicular symptoms of nerve root compression are usually absent unless the spondylolisthesis is severe. In severe cases, bowel and bladder dysfunction may also be present. Discomfort is usually increased by exercise and relieved by rest. Signs vary with the severity of spondylolisthesis. Asymptomatic patients with slips of mild severity may have no outward manifestations of vertebral abnormality. Patients with moderate to severe slips usually have tenderness on palpation of the lumbar spine and increased lumbar lordosis. Spasm of the hamstring muscles may extend the sacral spine, causing the buttocks to seem flattened or heart-shaped in appearance. In severe slips, a step-off of L5 on S1 can be palpated. A flexible scoliotic deformity caused by paraspinal muscle spasm may be present. Neurologic examination findings are usually normal in children with spondylolysis. Symptoms and signs of nerve root compression and mechanical instability are much more common in adult patients with progressive or severe untreated adolescent spondylolisthesis.
Figure 46-9. Clinical picture of severe spondylolisthesis.
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Hamstring muscle spasm is a common finding in patients with symptomatic spondylolisthesis and at times may be the chief presenting problem. Affected patients are unable to flex far enough forward to touch their toes without bending their knees. When severe, hamstring spasm results in a loss of normal lumbar lordosis and produces a flattened appearance of the low back. Hamstring muscle spasm also interferes with gait; stride length is shortened, and patients run with a peculiar stiff-legged posture. The cause of hamstring spasm in spondylolisthesis is unclear; it does not appear to be caused by compression of spinal nerves, and it is rarely accompanied by other signs of nerve root compromise. Most authorities believe it is a result of abnormal strain on the hamstring muscles caused by mechanical instability of the lumbosacral junction. Radiographic Assessment If spondylolysis is suspected, radiographic assessment should consist of an anterior/posterior lateral right and left oblique views of the lumbar spine (Fig. 46-10). The oblique view of the lumbar spine illustrates the defect in the pars interarticularis. In cases of unilateral spondylolysis, there may be hypertrophy of the opposite pars or pedicle. A computed tomographic (CT) scan is helpful in determining the anatomy of the defect and can help assess the status of healing during treatment. CT scans also may identify sites of nerve root compression. The bone scan (single photon emission computed tomography scan) is sensitive in identifying the stress fracture before disruption is evident on radiographs. Immobilization at this point may heal the lesion. If the clinician suspects an associated herniated disk, MRI is indicated. The plain radiographs illustrate the degree of slippage. This must be documented to see whether progression is occurring over time. The most common classification system notes the position of the posterior border of the L5 vertebral body with regard to the S1 body. When the slip is less than 25% of the width of the first sacral body, the slip is considered mild. Slips exceeding 50% are considered severe. These cases are of concern in that the progression may proceed to the point at which L5 dislocates in front of the S1 vertebral body, which is called spondyloptosis.
Figure 46-10. Spondylolisthesis. Slippage of L5 on the underlying body of S1 has occurred as a consequence of defective formation of the posterior elements of L5. In this case, slippage is moderate, measuring slightly more than 25% of the width of the S1 vertebral segment.
Treatment In asymptomatic patients with a mild slip, no treatment is required; likelihood of progression is low. However, if significant progression occurs (even if a patient is asymptomatic), a posterolateral fusion is recommended. When a slip exceeds 50%, the likelihood of continued progression is high, and surgical stabilization should be performed. Both symptomatic and asymptomatic patients with this severe condition should undergo surgical stabilization. Initial treatment of patients with symptomatic spondylolysis should be conservative. The examiner must also rule out other causes of back discomfort. Activity restriction with antiinflammatory medication is the initial treatment. When the pain is severe, a brace or corset is helpful. Then abdominal and paraspinal strengthening exercises are instituted to help relieve symptoms. Most patients with symptomatic spondylolysis or mild spondylolisthesis respond to conservative therapy and are able to return to sports. However, a small percentage of patients do not respond to conservative therapy; for these patients, surgical stabilization may be necessary. Patients with a severe slip who have a neurologic deficit that does not respond to conservative management also require surgical intervention. A fusion in situ (L5 to S1) is the most commonly performed surgical procedure for patients with a slip of less than 50%. Extension of the fusion to L4 is necessary to create a satisfactory fusion in patients with a more significant slip.
IDIOPATHIC KYPHOSIS Abnormal increases in expected thoracic kyphosis in children and adolescents produce round back deformities (Fig. 46-11). These may be congenital, neuromuscular, or idiopathic in origin. Mild to moderate increases in kyphosis cause little deformity and few symptoms. Severe kyphosis is disfiguring, often causes back pain, and may lead to spinal cord compromise. Round back posture is often encountered in otherwise healthy adolescents at school screening examinations. Affected patients are usually asymptomatic, although their parents often report poor posture. A history should be obtained and physical examination performed. Complaints of severe back pain or leg pain, enuresis, and findings of lower extremity weakness or increased reflex tone in patients with round back are ominous findings and warrant referral. If accentuated kyphosis is present, radiographic follow-up is indicated. Two radiologic patterns are common. The majority of individuals, especially younger adolescents, have thoracic kyphotic curves of 20 to 45 degrees, with no underlying structural vertebral changes. Usually such curves correct easily on passive or active hyperextension. For such children, no treatment except for a thoracic hyperextension exercise program and periodic follow-up examination is necessary. More severe kyphosis with accompanying structural changes in vertebral bodies at the apex of the deformity is present in a small subset of adolescents with kyphosis. Affected individuals often have kyphotic curves greater than 60 degrees and show little correction with hyperextension. Roentgenograms show vertebral wedging, endplate irregularity, and kyphosis (Fig. 46-12). Scheuermann kyphosis (an osteochondrosis) occurs in approximately 5% to 8% of the population, affecting boys 5 to 10 times more often than girls. The cause remains unclear but may be the result of disruption of growth of the anterior portion of the vertebral body and consequent wedging of multiple vertebral bodies. Back pain is usually mild; many affected patients have no pain at all. The deformity in most affected patients is minimal and only rarely is cosmetically unacceptable. Late neurologic complications are extremely rare. Treatment depends on the degree of deformity and the age of the patient. Skeletally immature individuals with significant deformity
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Figure 46-12. Scheuermann kyphosis. Lateral radiographs of the midthoracic spine in an asymptomatic 16-year-old boy with moderately severe kyphosis. There is severe wedging, loss of vertebral height, and endplate irregularity present on these films. His radiographic findings appear far worse than his symptoms and signs. If further collapse were to develop and the kyphosis became more severe, surgical intervention would be necessary.
Figure 46-11. Preoperative (A and B) and postoperative (C and D) views of an adolescent boy with severe kyphosis secondary to Scheuermann disease. He required both anterior and posterior spinal fusion. He now has a markedly improved appearance and no further progression of the kyphosis. (From Renshaw TS: Pediatric Orthopedics. Philadelphia, WB Saunders, 1986, p 53.)
may improve with a program of exercise and use of a Milwaukee or modified Boston brace. Bracing does not reverse a deformity, but it may prevent progression. Older patients with back pain usually respond to a back-strengthening exercise program. Patients with unacceptable deformity who are too old for brace treatment require surgical correction. Often this requires a combination of anterior release and posterior spinal instrumentation and fusion. Congenital vertebral malformations that produce kyphotic deformities develop during the first trimester of gestation and, like other congenital abnormalities of the spine, are often associated with abnormalities of the genitourinary tract or the spinal cord. Kyphosis that results from congenital vertebral deformities is often obvious early in life and may be rapidly progressive (Fig. 46-13). The spinal
cord may become tented over the apex of the deformity, producing symptoms and signs of spasticity in the lower extremity and bladder. Progression of deformity is dangerous; congenital kyphosis is the spinal deformity most often associated with paraplegia. Patients should be promptly referred for orthopedic evaluation.
INTERVERTEBRAL DISK HERNIATION Intervertebral disk rupture is much less common in children than in adults. Because most such patients are treated nonoperatively, the absolute incidence of the disorder is not known. In the United States, fewer than 1% of patients undergoing diskectomy are younger than 16 years. The frequency of symptomatic intervertebral disk herniation may be more common in Asian persons than in white persons, perhaps because of the smaller size of the spinal canal. Some patients have a significant history of trauma. In other patients, congenital anomalies of the lumbar spine, such as transitional vertebra or spina bifida occulta, are noted. There may be a family history of low back pain or herniated disks. An autosomal dominant trait has been linked to the COL 9A2 collagen IX gene. The symptoms of a herniated lumbar disk in adolescents differ somewhat from those in adults; this may delay recognition. The initial complaint in adolescents is significant low back discomfort; it is only months later that the symptoms of leg discomfort become more noticeable or prominent. Pain typically is aggravated by activity and
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Figure 46-13. A, Congenital kyphosis secondary to failure of vertebral bodies to form at T12 and L1. B, The clinical appearance of the child. Thoracolumbar kyphosis is obvious. (From Renshaw TS: Pediatric Orthopedics. Philadelphia, WB Saunders, 1986, p 44.)
relieved with rest. Symptoms may be intermittent. The affected adolescent has poor back mobility, often with paravertebral muscle spasm. Lumbar lordosis may diminish, and there is a tendency to walk bent forward. Hamstring tightness with limited straight-leg raising is almost universal. Neurologic signs are less likely to be prominent in the adolescent with herniated disk than in the affected adult. Plain radiographs are needed as an initial study. These usually are normal other than for the loss of lumbar lordosis. The MRI is the procedure of choice for diagnosing a disk herniation. In rare cases, adolescents may develop a lesion that is a fracture of the posterior vertebral apophysis, which displaces posteriorly into the spinal canal and acts like a herniated disk. This is an avulsion fracture that is identified with either a CT scan or MRI. When a patient has severe symptoms, treatment should begin with bed rest, analgesics, and antiinflammatory agents. When the symptoms have begun to abate, physical therapy for lumbar and paraspinal strengthening is helpful. A lumbar corset may be helpful for patients who also have significant symptoms. Patients who present with progressive neurologic deficits require early surgical excision. Similarly, patients who fail to respond to a significant period of nonoperative management also require disk surgery. The long-term results of a disk excision are good in 70% to 80% of the patients. Spinal fusion is not required unless the patient shows evidence of instability, which is quite rare. SCOLIOSIS Idiopathic scoliosis, a combination of lateral deviation and rotation of vertebral bodies, does not always produce back pain. When painful scoliosis is present, a careful search for the cause of the symptoms must be undertaken. Infection, tumor, a spinal cord syringomyelia or diastematomyelia (more common with left thoracic curves), and occult fractures may produce clinical findings that resemble idiopathic scoliosis but, in contrast to idiopathic scoliosis, cause significant chronic pain as well. Any patient with painful scoliosis should have a careful evaluation for other spinal anomalies causing the pain.
Etiology Idiopathic scoliosis begins in the immature spine, although progression of preexisting curvatures may occur in adult life. The cause of idiopathic scoliosis remains unknown. Hormonal factors appear to play a role in curve progression, inasmuch as severe curves occur much more often in girls. Some studies have demonstrated abnormalities of proprioception and vibratory sensation in affected patients, which suggests that abnormalities of posterior column function may contribute to the development of curvature. Other investigators have implicated cerebellar or muscular (myopathy) dysfunction as a possible cause of spinal imbalance. No clear genetic pattern has been established. Curves occur more frequently in individuals with affected first-degree relatives, but transmission is not mendelian. Although curvature is more likely to develop in the daughters of affected mothers than in other children, the magnitude of curvature in an affected individual is not related to the magnitude of curvature in relatives. It appears likely that a combination of genetic predisposition and other undefined factors is responsible for development and progression of idiopathic scoliosis. Classification Idiopathic curves are grouped into infantile (birth to 3 years), juvenile (4 to 10 years), and adolescent categories on the basis of age at onset of curvature. The infantile form differs enough from the other varieties to be considered a distinct entity. The distinction between juvenile and adolescent scoliosis is not as sharp. Infantile Idiopathic Scoliosis
Infantile idiopathic scoliosis is rare in the United States, probably accounting for fewer than 1% of new cases of idiopathic scoliosis. It is more common in Europe. The majority of patients are boys, and most curves are convex toward the left rather than the right, as in the other varieties of idiopathic scoliosis. Some infants suspected of having idiopathic deformity actually have subtle congenital vertebral
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abnormalities. The diagnosis of idiopathic deformity is appropriate only when radiographic studies show no evidence of congenital vertebral anomalies (e.g., hemivertebra) and there are no signs of spinal dysraphism or of neuropathic or myopathic disorders. Although many infantile curves resolve spontaneously, others progress relentlessly and are very difficult to treat effectively. Observation is appropriate until age 6 months in infants with idiopathic scoliosis, but prompt referral should be made if curves persist or increase during the period of observation. Juvenile Idiopathic Scoliosis
Juvenile idiopathic scoliosis begins before the adolescent growth spurt. Some curves are probably undetected cases of infantile scoliosis. Others, particularly those that occur in older children, may be early manifestations of adolescent idiopathic scoliosis. Some curves remain small and, in fact, may resolve spontaneously. Others remain stable until the onset of the growth spurt and then progress unless treated. Still others progress steadily throughout childhood and adolescence. Some are associated with intraspinal anomalies (syrinx). There is no reliable method of predicting the behavior of juvenile curves at the time of diagnosis, but, in general, highmagnitude curves in young patients are more likely to increase with growth than are smaller curves in older children. The majority of patients with juvenile curves greater than 30 degrees at the time of diagnosis require some form of active treatment. Treatment must begin at the time progression is first documented if severe deformity is to be prevented. Adolescent Idiopathic Scoliosis
Most cases of idiopathic scoliosis in North America develop around the time of the adolescent growth spurt (Figs. 46-14 and 46-15). Often parents and children are unaware of the presence of curvature at outset. Nerve root impingement, intervertebral disk disease, and spinal cord compression are uncommon in young patients with idiopathic scoliosis. Large curves are more common in girls than in boys (7:1 ratio). Pain is so rare that children and adolescents with painful curves must be carefully studied in order to exclude neoplastic and inflammatory processes of the spinal column or neural canal. Idiopathic scoliosis is usually a painless disorder during childhood and adolescence. Severe structural curves may cause no pain until degenerative changes develop in adulthood. School Screening Programs School screening for spinal deformity is common in North America. Most programs concentrate on children in the late juvenile and early adolescent periods. The most common screening method employed is the forward-bend test, based anatomically on the vertebral rotation that accompanies lateral spinal deviation (see Fig. 46-14). Associated clinical findings include shoulder asymmetry, unequal distances between the medial borders of the elbows and the flanks, and apparent leg-length inequality or pelvic tilt. Breast asymmetry, caused by forward rotation of the chest wall on the side of the curve concavity and backward displacement of the chest wall on the convex side of the curve, is often present in affected girls. The threshold for “identification” on screening examination is subjective, and it is not surprising that the incidence of spine asymmetry detected by school screening programs varies with the method of screening and the experience of the examiner. A range of 3% to 20% has been reported. Follow-up radiographic studies of children thought to have abnormal curvatures on school screening examinations indicate an incidence of scoliosis in screened children of less than 15% (range, 0.4% to 14%). The incidence of curves greater than 20 degrees at the time of primary screening is probably less than 0.5%. Simple devices such as the scoliometer determine spine
Figure 46-14. A, Adolescent idiopathic scoliosis, viewed from the back. Note the right-sided thoracic prominence. When the patient bends forward (B), the rib prominence is even more apparent. This is secondary to rotation of the ribs and spine. The rib prominence is also quite evident when viewed from the front (C). (From Renshaw TS: Pediatric Orthopedics. Philadelphia, WB Saunders, 1986, p 47.)
asymmetry by measuring the angle of trunk rotation at the apex of the rib hump. An angle of more than 7 degrees is an appropriate criterion for referral. The first response to a positive school screening examination should be a repeated physical examination. If asymmetry is confirmed, a single standing posteroanterior spine film, including vertebral levels T1 to S1, should be obtained. Lateral films, bending films, and oblique views are not necessary. Referral is appropriate for skeletally immature children or adolescents with curves greater than 20 degrees. Natural History The natural history of curvature in patients with spine asymmetry is highly variable. Factors that appear to be associated with risk of progression include the magnitude of curvature at the time of detection, the chronologic and skeletal age of the patient, the pattern of curvature, and the menarcheal status. Immature patients with largemagnitude curves are far more likely to experience progression than are more mature patients with small curves. Progression of curves after skeletal growth is uncommon in idiopathic thoracic curves of less than 30 degrees at the end of growth but is likely to occur in patients with curves greater than 50 degrees at maturity. Uncontrolled curve progression causes significant problems in adult life. Unacceptable deformity, back pain, chronic fatigue, and decreased work capacity are common. Premature degenerative arthritis and nerve root impingement caused by deformity and osteophytic spurring occur in patients with lumbar curves or double thoracic-lumbar curves. Asymptomatic decreased vital capacity is
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Improved instrumentation and internal fixation devices, intraoperative monitoring of spinal cord function, and autologous transfusion has improved the safety and efficacy of surgical correction. In most cases, patients can be out of bed within 3 to 4 days of surgery and are walking within 5 days of surgery. Return to school is usually possible within 3 weeks; most activities of normal life, including sports, can be resumed within 6 months. In many instances, no postoperative immobilization is required; in other cases, a removable lightweight plastic orthosis can be employed. Prolonged periods of immobilization in a plaster cast are uncommon. TUMORS OF THE SPINAL COLUMN Persistent back pain, muscle spasm, and abnormal trunk posture are ominous findings in children. Neoplastic disease must be considered in patients with no other obvious source of pain (see Table 46-2). Primary Lesions of Bone The most common primary bone tumors affecting the spinal column in children are osteoid osteoma (Fig. 46-16), osteoblastoma (Fig. 46-17), eosinophilic granuloma, and aneurysmal bone cysts (see Chapter 45). Although benign, these lesions may cause considerable back pain and local bone destruction. Osteogenic sarcoma, a malignant lesion of bone, occurs less commonly in the spine than in the long bones of children. Unexplained pain is the hallmark of spinal neoplasia and is usually the presenting complaint. At times, pain may be severe and unresponsive to nonnarcotic analgesics. In other instances, as in osteoid osteoma, the relief of symptoms that occurs with nonsteroidal antiinflammatory agents is so characteristic that it is considered a diagnostic finding. Paraspinal muscle spasm,
Figure 46-15. Adolescent idiopathic scoliosis. The patient, a 13-yearold girl, had a severe double-curve pattern with significant accompanying deformity but no pain. Surgical treatment was warranted to halt progression and restore spinal alignment.
common in patients with thoracic curves; symptomatic cardiopulmonary compromise (cor pulmonale) may develop in patients with curves greater than 80 degrees. Treatment The goals of treatment in idiopathic scoliosis are to bring a patient to skeletal maturity with a cosmetically acceptable, balanced, and stable curve that is unlikely to progress in adult life. Mature adolescents with curves less than 30 degrees need no treatment beyond initial evaluation. Further progression of curvature is unlikely to occur in these individuals. Patients with juvenile scoliosis and less mature adolescents with curves between 10 and 20 degrees should be monitored at 6-month intervals with single standing posteroanterior spine radiographs. If progression occurs, they should be referred for orthopedic care. Active treatment is indicated for growing patients with curves greater than 30 degrees. Brace treatment remains the standard method of nonoperative treatment of idiopathic curvature. Surgical treatment is appropriate for patients with curves too severe for brace treatment. Documented progression in spite of nonoperative treatment is another indication for surgical intervention.
Figure 46-16. Osteoid osteoma of the spine. Technetium bone scanning shows increased uptake in the T10 vertebral body in a 15-year-old boy. Note the scoliosis that accompanies this painful lesion. The condition did not respond to antiinflammatory medications, and surgical excision was necessary.
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astrocytomas or ependymomas also occur in the neural contents of the spinal canal. In such patients, standard radiography often shows only loss of lordosis or scoliosis secondary to muscle spasm. MRI demonstrates the abnormality, but definitive diagnosis usually requires biopsy. The success of treatment is often related to promptness of diagnosis. Early referral of patients with unexplained back pain is essential for appropriate treatment. Leukemia
Figure 46-17. The patient presented with left-sided lumbar back pain. Note the destruction of the vertebral pedicle at L4 (arrows). This proved to be an osteoblastoma. Children with back pain should be suspected of having a tumor of the spine or spinal cord until it is proven otherwise. (From Renshaw TS: Pediatric Orthopedics. Philadelphia, WB Saunders, 1986, p 57.)
tenderness in the soft tissues on the side of the spinal column, and alterations in spinal configuration are common. Scoliosis, loss of lumbar lordosis, or accentuations of thoracic kyphosis may be present. Initial evaluation of patients with suspected spinal tumors should include standard anteroposterior and lateral radiographs of the spine (see Fig. 46-17). These may not show small lesions hidden in vertebral pedicles or posterior elements; other studies are often necessary. Technetium bone scanning is particularly useful (see Fig. 46-16). MRI and CT scans are usually necessary to localize lesions for surgical treatment. Prompt referral is essential when spinal neoplasia is suspected. The success of treatment depends in large part on early discovery and intervention.
Tumors of Neural Elements Back pain, lower extremity weakness, and sphincter disturbances are common manifestations of neoplasms of the spinal cord. Although such lesions are rare, they must be suspected in children with unexplained back or leg pain, weakness, sensory or reflex abnormalities, bowel or bladder incontinence, or unexplained gait abnormalities. Neuroblastoma is the most common lesion, but sarcomas (including Ewing sarcoma, rhabdomyosarcoma, and hemangiosarcoma) and
Skeletal involvement is common in patients with leukemia; back pain or limb pain may be the presenting symptom in some children. Proliferation of abnormal hematopoietic tissue in the marrow of long bones or vertebral bodies causes pain and weakens their structure. Clinical symptoms and signs in children with leukemic skeletal involvement may be confusing. Fever, localized pain and swelling, and elevations of the white blood cell count and erythrocyte sedimentation rate may be mistaken as signs of septic arthritis, osteomyelitis, or intervertebral disk space infection. The presence of abnormal white blood cells on the peripheral blood cell count or of thrombocytopenia increases the likelihood of bone marrow tumor rather than infection. Osteopenia, periosteal elevation, and metaphyseal lucencies are common radiographic findings in leukemic involvement of long bones. These may be difficult to detect in patients with spinal involvement. Vertebral compression and wedging are sometimes present and may mimic acute fracture or, on occasion, osteomyelitis (Fig. 46-18). The absence of a history of trauma should alert the examiner to search for other causes of the radiographic abnormality. Preservation of intervertebral disk space height with collapse of adjacent vertebral segments is an indication that the vertebral bodies rather than the intervertebral disk are the sites of the abnormality. Technetium bone scanning is useful for detecting other areas of involvement, although it is not as reliable in leukemia as in other spinal lesions. MRI is useful for detecting areas of spinal involvement not visible on plain radiographs and for assessing the extent of intraspinal infiltrate or spinal cord compression present. The diagnosis of leukemia can be established by bone marrow aspiration. Biopsy of involved vertebral segments is rarely necessary. Support of the spine in a custom-fabricated orthosis is useful for relieving pain and preventing further vertebral collapse during the initial phases of treatment. Prolonged brace treatment may be necessary to prevent vertebral compression fractures that may accompany the osteopenia resulting from steroid therapy. Surgical decompression and fusion may be required in rare cases of acute vertebral compression and spinal cord compromise.
SUMMARY AND RED FLAGS Back pain in children may be referred pain from intraabdominal or retroperitoneal disease (see Table 46-2) or may represent direct involvement of the spinal cord, vertebral bodies, or paraspinal musculature. In most children with normal examination findings, back pain is benign, short-lived, and responsive to rest or nonsteroidal antiinflammatory agents. Chronic persistent back pain, pain associated with lower extremity or bowel and bladder neurologic deficits, cutaneous lesions over the lumbar spine, systemic signs (as in inflammatory bowel disease, leukemia, osteomyelitis), acute pain, and tenderness with neurologic dysfunction after trauma are red flags. Signs of cord involvement are particularly ominous and are emergencies. Spinal cord involvement above T10 produces symmetric weakness, increased deep tendon reflexes, up-going toes, and an appropriate sensory loss; conus medullaris involvement (T10 to L2) produces symmetric weakness,
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Figure 46-18. Osteomyelitis at T11 and T12. Note the destruction of the disk space and vertebral bodies with beginning of anterior ossification. In this patient, fusion occurred spontaneously, and the patient is now asymptomatic. (From Renshaw TS: Pediatric Orthopedics. Philadelphia, WB Saunders, 1986, p 59.)
increased knee and decreased ankle deep tendon reflexes, a saddletype anesthesia, and up- or down-going toes on Babinski testing; and cauda equina involvement (below L2) produces asymmetric weakness, loss of deep tendon reflexes, and down-going toes. Such findings represent an acute emergency that warrants immediate imaging (MRI) and therapy, which may include high-dose corticosteroids, radiation therapy, or laminectomy to prevent permanent paralysis.
Balagué F, Dudler J, Nordin M: Low-back pain in children. Lancet 2003;361:1403-1404. Bell DF, Erlich MG, Zaleske DJ: Brace treatment for symptomatic spondylolisthesis. Clin Orthop 1988;236:192-198. Brown R, Hussain M, McHugh K, et al: Discitis in young children. J Bone Joint Surg Br 2001;83:106-111. Cassar-Pullicino VN, Eisenstein SM: Imaging in scoliosis: What, why and how? Clin Radiol 2002;57:543-562. Conrad EU, Olszewki AD, Berger M, et al: Pediatric spinal cord tumors with spinal cord compromise. J Pediatr Orthop 1992;12:454-460. Deyo RA, Weinstein JN: Low back pain. N Engl J Med 2001;344:363-370. Edgar M: A new classification of adolescent idiopathic scoliosis. Lancet 2002;360:270-271. Fernandez M, Carrol CL, Baker CJ: Discitis and vertebral osteomyelitis in children: An 18-year review. Pediatrics 2000;105:1299-1304. Frennerd AK, Danielson BI, Nachemson AL: Natural history of symptomatic isthmic low-grade spondylolisthesis in children and adolescents: A seven year follow up study. J Pediatr Orthop 1991;11:209-213. Hadley MN: Management of pediatric cervical spine and spinal cord injuries. Neurosurgery 2002;50:S85-S99. Letts MH, Haasbeek J: Hematocolpos as a cause of back pain in premenarchal adolescents. J Pediatr Orthop 1990;10:731-732. Lowe TG: Scheuermann disease. J Bone Joint Surg Am 1990;72:940-945. Nussinovitch M, Sokolover N, Volovitz B, et al: Neurologic abnormalities in children presenting with diskitis. Arch Pediatr Adolesc Med 2002; 156:1052-104. Paassilta P, Lohinvia J, Goring HHH, et al: Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 2001;285:1843-1849. Pizzutillo PD, Hummer CD: Nonoperative treatment of painful adolescent spondylolysis or spondylolisthesis. J Pediatr Orthop 1989;9:538-540. Prahinski JR, Polly DW Jr, McHale KA, et al: Occult intraspinal anomalies in congenital scoliosis. J Pediatr Orthop 2000;20:59-63. Rogalsky RJ, Black GB, Reed MH: Orthopedic manifestations of leukemia in children. J Bone Joint Surg Am 1986;68:494-501. Sachs B, Bradford D, Winter RB, et al: Scheuermann kyphosis. Follow-up of Milwaukee brace treatment. J Bone Joint Surg Am 1987;69:50-57. Seitsalo SK, Osterman H, Hyvarinen K, et al: Progression of spondylolisthesis in children and adolescents. A long term followup of 272 patients. Spine 1991;16:417-421. Sponseller PD: Sizing up scoliosis. JAMA 2003;289:608-609. Watson KD, Papageorgiou AC, Jones GT, et al: Low back pain in schoolroom children: The role of mechanical and psychosocial factors. Arch Dis Child 2003;88:12-17. Weinstein SL, Dolan LA, Spratt KF, et al: Health and function of patients with untreated idiopathic scoliosis. JAMA 2003;289:559-566.
47
Lymphadenopathy
John R. Schreiber
Brian W. Berman
the more common sites for lymphadenopathy in small children. In contrast, the inguinal nodes drain the areas surrounding and including the urethra, the vagina, and the penis and may be enlarged, particularly in adolescents with venereal diseases. The inguinal nodes also drain the distal extremities and may enlarge with soft tissue infections of the lower extremities.
Lymphadenopathy, defined as enlarged lymph nodal tissue measuring more than 1 cm in diameter, is common in children. Enlarged nodes are a feature of many illnesses because of the role of the nodes in filtering pathogens, the anatomy of the lymph node chains, and the cellular proliferation that occurs in nodal tissue after exposure to infectious agents or by infiltration with malignant cells. Most of the illnesses manifesting with enlarged lymph nodes represent common bacterial or viral infections that improve either spontaneously or after appropriate antimicrobial therapy. Some serious illnesses, particularly malignancy, can first manifest as lymphadenopathy. A thorough history, careful physical examination, and knowledge of the anatomy of tissues drained by lymph nodes, as well as of the type of adenopathy caused by various illnesses, often lead to the appropriate diagnosis without the need for complex diagnostic procedures.
HISTORY The history is important in the evaluation of lymphadenopathy and often yields distinct clues to the appropriate diagnosis. First, the character and temporal course of the adenopathy are important. Rapid onset of unilateral lymphadenopathy in the groin after trauma to the lower extremity, for example, suggests infection originating in the traumatized extremity. In contrast, progressive enlargement of nodes noticed in several areas of the body that is accompanied by weight loss, fevers, night sweats, or other systemic illness is suggestive of diseases associated with involvement of multiple organ systems, such as lymphoma or tuberculosis. Second, the age of the child who has the enlarged lymph node or nodes is important in the consideration of the cause (Table 47-1). Most neonates with adenopathy have been exposed to an infectious agent in utero (e.g., cytomegalovirus [CMV], syphilis, toxoplasmosis). In contrast, toddlers with adenopathy (depending on whether it is regional or diffuse) tend to have either focal infections that drain into the affected nodal chain (cervical chain lymphadenopathy with pharyngitis) (see Fig. 47-2) or a systemic viral infection that results in diffusely enlarged nodes. Similarly, malignancy manifested as adenopathy is rare in neonates but more common in toddlers and older children. The history should focus on presence of chronic illness, weight loss, systemic signs and symptoms, an immunodeficiency that would predispose to opportunistic infection, and the use of medications (procainamide, sulfasalazine, phenytoin, or tetracycline) that may be associated with lupus-like illnesses and adenopathy. The family history may reveal the presence of infection, such as human immunodeficiency virus (HIV) or tuberculosis, in the parents or close relatives, or group A streptococcal infection or mononucleosis in a close contact. The family history should include place of birth, HIV risk (such as intravenous drug use), and travel history to determine whether the child is from or has been exposed to geographic areas with high rates of infections (e.g., tuberculosis in an incarcerated family member; travel to the Ohio River valley for histoplasmosis). Activities during travel are also important, such as the consumption of unprocessed cheeses or unpasteurized milk products, particularly from other countries that may contain pathogens, such as Brucella species or Mycobacterium bovis. The social history may provide further clues. Is the child from a socioeconomic or immigrant ethnic group that has a more intense exposure to such infections as tuberculosis? Is there an adult in the household who is currently ill or taking medication? Is there an adult with a high risk of infection with tuberculosis (recent immigration from an endemic area, recent incarceration, known HIV infection,
MECHANISM OF LYMPHADENOPATHY The lymphatic system consists of lymphatic vessels (afferent and efferent) that connect lymphatic tissues, including lymph nodes, to the peripheral circulation via postcapillary venules. The lymph nodes contain both B and T cells, which lie in a supportive framework within a connective tissue capsule (Fig. 47-1). The lymphatic fluid or “lymph”-containing antigens, bacteria, or other pathogens, as well as various lymphocytes and macrophages, enter through afferent lymphatic vessels; the cells within the node then interact with antigens. This interaction allows production of T cell and/or B cell humoral immune responses in the host’s effort to clear the antigen or the pathogen. Efferent lymphatic vessels then carry lymphcontaining antigen-sensitized lymphocytes from the nodes back to the peripheral circulation via the thoracic duct. Enlargement of the nodes can be caused by several factors. First, when nodes fulfill their normal function, hyperplasia occurs as a consequence of proliferation by nodal and newly arrived lymphoid cells. This proliferation is a response to antigenic stimulation. Such responses are particularly active in children, which explains the frequent observation of lymphadenopathy associated with some pediatric infections. Second, bacteria or their products that have traveled to the nodes may stimulate the arrival of inflammatory cells, such as neutrophils, and cause enlargement and symptoms of lymphadenitis (erythema and tenderness). Third, malignant cells either may arise in the node itself and proliferate, causing enlargement, or may arrive from distant cancerous sites and also infiltrate the nodal tissue. Finally, in rare genetic storage diseases, macrophages laden with abnormally metabolized lipids may lodge in lymph nodes, causing lymphadenopathy. The regional areas drained by each lymph node group are also important in determining the cause of lymphadenopathy. The superficial cervical lymph nodes, for example, drain lymph from distinct areas of the head, neck, and throat (Fig. 47-2) and may enlarge if a local infection is present. These nodes, in turn, drain into the deep cervical nodes and eventually the thoracic duct. Because viral and bacterial pharyngitis and otitis media are common infections in children, the cervical and occipital areas, respectively, are some of 861
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Figure 47-1. Diagrammatic representation of the structure of a lymph node. (From Faller DV: Diseases of the lymph nodes and spleen. In Wyngaarden JB, Smith LH, Bennett JC [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 979.)
homeless, intravenous drug use)? Does the family diet include raw meat that may predispose to acquisition of toxoplasmosis (a more common cause of toxoplasmosis than exposure to kitty litter in the United States)? The presence of animals in the household or in households the child frequents may play a significant role in the lymphadenopathy. The presence of cats or, more often, kittens that scratch the child, for example, is often omitted from the parent’s history of the patient unless such questions are specifically asked. Furthermore, some families may deny presence of household pets but forget to mention that the child plays with a neighbor’s pet or with cats that are present in a barn or the neighborhood. Adolescents should be questioned about sexual activity and other risk factors for HIV or other sexually transmitted diseases, such as
Retro-auricular
Parotid
syphilis or lymphogranuloma venereum, a cause of diffuse or inguinal lymphadenopathy.
PHYSICAL EXAMINATION Careful visual inspection yields an overall impression of size and distribution of significant lymphadenopathy as well as the presence of an associated infection. Overall physical appearance may indicate whether systemic signs, such as cachexia, are present. Palpation of the nodes, however, is necessary to appreciate the actual size and regions of lymphadenopathy. All areas in which lymphadenopathy is commonly present, including the cervical, auricular, axillary,
Buccal
Occipital Jugulodigastric node Submental Submandibular
Superfic. cervical (post. group)
Jugulo-omohyoid node Jugular tr.
Superfic. cervical (ant. group)
Deep cervical Transverse cervical nodes
A
B
R. lymphatic Transverse duct Thoracic duct cervical tr.
Figure 47-2. The superficial (A) and deep cervical (B) lymph nodes that drain the head and neck. ant., anterior; post., posterior; R., right; superfic., superficial; tr., tributary. (From O’Rahilly RO: Gardner-Gray-O’Rahilly Anatomy: A Regional Study of Human Structure, 5th ed. Philadelphia, WB Saunders, 1986, p 719.)
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Table 47-1. Differential Diagnosis of Systemic Generalized Lymphadenopathy Infant
Common Causes Syphilis Toxoplasmosis CMV HIV
Rare Causes Chagas disease (congenital) Congenital leukemia Congenital tuberculosis Reticuloendotheliosis Metabolic storage disease Histiocytic disorders
Child
Adolescent
Viral infection EBV CMV HIV Toxoplasmosis
Viral infection EBV CMV HIV Toxoplasmosis Syphilis
Serum sickness SLE, JRA Leukemia/lymphoma Tuberculosis Sarcoidosis Fungal infection Plague Langerhans cell histiocytosis Chronic granulomatous disease Sinus histiocytosis
Serum sickness SLE, JRA Leukemia/lymphoma Tuberculosis Sarcoidosis Fungal infection Plague Drug reaction (immune)
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; JRA, juvenile rheumatoid arthritis (as Still disease); SLE, systemic lupus erythematosus.
epitrochlear, inguinal, and supraclavicular areas, should be palpated because lymphadenopathy in certain regions is linked to systemic or local illness (Table 47-2). Regional lymphadenopathy usually reflects pathologic processes within the lymphatic drainage distribution of that particular nodal chain. Enlarged cervical nodes commonly indicate the presence of infection in the oropharyngeal cavity. Similarly, posterior auricular nodes are seen with scalp infections and otitis media but are also common with rubella and some other viral illnesses such as parvovirus (fifth disease). The diagnosis of rubella or parvovirus infection is considered if there is a rash and fever in conjunction with posterior auricular nodes. The presence of supraclavicular nodes is usually pathologic and is a red flag for a serious illness such as malignancy. Supraclavicular nodes that are palpated on the right side often reflect a mediastinal tumor or invasive mediastinal infection, such as histoplasmosis. Supraclavicular nodes on the left side are often the result of metastatic spread of an abdominal tumor. The presence of either type of node mandates an urgent evaluation, including computed tomography (CT) or magnetic resonance imaging. Epitrochlear nodes, if unilateral, commonly indicate the hand or arm as a source of distal infection. Palpable bilateral epitrochlear lymph nodes usually reflect systemic illness, such as syphilis, sarcoidosis, or lymphoma. Inguinal node enlargement is common and is probably caused by the frequent occurrence of minor trauma and infections in a child’s legs and feet. Significantly enlarged inguinal nodes, however, may be present with venereal diseases, such as syphilis, chlamydial urethritis, lymphogranuloma venereum, or with urinary tract infection, lymphoma, or abdominal tumors. In addition to the location, the characteristic feel of the nodes often yields some clues as to the cause of the adenopathy: ●
●
●
●
erythematous, tender, and warm: acute bacterial infection with suppurative adenitis tender, nonerythematous, and soft: viral infection or other systemic infection firm, hard, rubbery, and nontender: lymphoma or other infiltrating tumor hard, matted, immobile, and nontender: tumor, metastatic or local; fibrosis that follows acute infection
LABORATORY AND IMAGING EVALUATION Many previously healthy children with acute lymphadenopathy require few, if any, laboratory or imaging studies. No laboratory testing may be required for well-appearing children whose acute, localized adenopathy can be attributed to an infection in the vicinity of the node. Patients with localized cutaneous bacterial infections causing adenopathy also may not need laboratory investigations before the initiation of antimicrobial therapy unless there is suspicion of bacteremia or invasive spread of the infection to underlying tissues. Acute cervical adenopathy accompanying pharyngitis in children older than 18 months may necessitate a throat culture for group A streptococcus. The additional presence of hepatomegaly or splenomegaly should raise suspicion of Epstein-Barr viral (EBV) infections (mononucleosis). The clinician could obtain a complete blood cell count with white blood cell differential (to identify lymphocytosis and atypical lymphocytes) and EBV titers (or a monospot heterophile antibody test in children older than 10 years). Supraclavicular adenopathy, acute cervical adenopathy accompanied by respiratory distress, or prolonged cervical adenopathy warrants anteroposterior and lateral radiographs of the neck and/or chest, a complete blood cell count with white blood cell differential, and placement of a purified protein derivative (PPD) tuberculosis skin test. CT with contrast is necessary in certain situations to fully delineate cervical adenopathy that is excessively large or that impinges on the airway, or to determine whether mediastinal adenopathy is present. Children presenting with prolonged diffuse lymphadenopathy, hepatomegaly or splenomegaly, weight loss, night sweats, fevers, recurrent infections, or failure to thrive must be more thoroughly studied. Only after the complete blood cell count and differential and chest radiograph are analyzed should other diagnostic studies be considered. HIV, EBV, and CMV studies (culture, polymerase chain reaction, and serologic profiles) may be obtained for some children. Because the diagnoses of leukemia (through bone marrow aspiration, biopsy), lymphoma (through bone marrow aspiration, biopsy), systemic lupus erythematosus (through antinuclear antibody,
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Table 47-2. Common Sites of Local Lymphadenopathy
DIFFERENTIAL DIAGNOSIS
and Associated Diseases Cervical Oropharyngeal infection (viral or group A streptococcal, staphylococcal) Scalp infection Mycobacterial lymphadenitis (tuberculosis and nontuberculous mycobacteria) Viral infection (EBV, CMV, HHV-6) Cat-scratch disease Kawasaki disease Thyroid disease Anterior Auricular Conjuctivitis Other eye infection Oculoglandular tularemia Posterior Auricular Otitis media Viral infection (especially rubella, parvovirus) Supraclavicular Malignancy or infection in the mediastinum (right) Metastatic malignancy from abdomen (left) Lymphoma Tuberculosis Epitrochlear Hand infection, arm infection* Lymphoma† Sarcoid Syphilis Inguinal Urinary tract infection Venereal disease (especially syphilis or lymphogranuloma venereum) Lower extremity suppurative infection Plague Hilar (Not Palpable, Found on Chest Radiograph or CT) Tuberculosis† Histoplasmosis† Blastomycosis† Coccidioidomycosis† Leukemia/lymphoma† Hodgkin disease† Metastatic malignancy* Sarcoidosis† Axillary Cat-scratch disease Arm infection Malignency of chest wall Leukemia/lymphoma Brucellosis *Unilateral. †
Bilateral.
CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6.
double-stranded DNA antibodies), and cat-scratch disease (through biopsy and/or Bartonella serologic profile) require more invasive and expensive tests, the physician should first consider all aspects of the history and physical examination before ordering laboratory studies.
INFECTIONS OF THE OROPHARYNX Pharyngeal infection is the most common cause of local lymphadenopathy in children (see Chapter 1). Many of these pharyngeal infections are associated with cervical lymphadenopathy; are viral in origin; and include adenovirus, parainfluenza, influenza, rhinovirus, and enterovirus as possible causes. EBV and CMV also commonly cause exudative pharyngitis and cervical lymphadenopathy. The chief complaint usually includes pain with swallowing (particularly pain with swallowing of acidic juices) and with talking, as well as tender, enlarged lymph nodes in the neck. Systemic manifestations, such as fever, muscle aches, and rhinorrhea, also may be present. An examination of the throat usually reveals a symmetric erythematous posterior pharynx with enlarged tonsils, often with exudates. Exudates can be seen with both viral and bacterial causes of pharyngitis and adenopathy, and thus do not reliably enable the examiner to discriminate between the two causes. Herpes stomatitis (mucocutaneous involvement) or pharyngitis (oropharyngeal vesicles) is associated with bilaterally enlarged, tender, nonerythematous cervical nodes. Bacterial infection of the pharynx is also commonly associated with enlarged, tender cervical lymph nodes. Group A β-hemolytic streptococcus is the most common pathogen to cause such infections and is difficult to differentiate clinically from viral causes of pharyngitis and lymphadenopathy; thus, throat culture or rapid antigen detection is necessary. An associated sandpapery rash or beefy-red tonsils with palatal petechiae are not usually seen with viral pathogens and should make the examiner consider group A streptococci and toxinmediated scarlet fever as a likely cause. Other bacteria also can cause pharyngitis and cervical adenopathy, including non–group A streptococci, as well as anaerobic organisms, such as Fusobacterium species. Anaerobic organisms can lead to painful oral gingivitis or stomatitis and pharyngitis (Vincent angina) that may progress to peritonsillar abscess. Asymmetry in the tonsils and the pharyngeal tissue surrounding the tonsils and uvula deviation away from the abscess may be seen with peritonsillar abscesses, along with unilateral tender, enlarged cervical lymph nodes. Another important syndrome that may occur after acute bacterial pharyngitis may manifest with high fever, and unilateral lateral neck swelling that may be confused with adenopathy. Such a constellation of findings, called Lemierre syndrome, is associated with septic thrombosis of the internal jugular vein, usually caused by invasion of the blood stream by Fusobacterium organisms, and should lead to prompt hospitalization, blood cultures, treatment with intravenous antibiotics, and imaging of the internal jugular vein via Doppler flow ultrasonography or CT with contrast enhancement. Acute cervical lymphadenopathy or lymphadenitis (inflammation of the cervical lymph nodes with tender enlargement) is most likely to occur with group A streptococcal infection. Staphylococcus aureus infection and infection with oral bacteria, including non–group A streptococci and anaerobes such as Fusobacterium species, may also occur, presumably with the pharynx as the portal of entry. Other common sites for acute lymphadenitis are the submandibular nodes. Usually, these nodes quickly diminish in size after institution of antibiotics with appropriate coverage for these pathogens (e.g., amoxicillin/clavulanic acid, ampicillin/sulbactam, clindamycin). Suppuration of the nodes with drainage is less common than adenitis and generally rules out viral infection as the primary cause. Acute suppurative cervical adenitis can be seen in infections of the face and scalp and is usually caused by group A streptococcal or S. aureus infection. Management of suppuration includes incision and drainage or, less often, excision of the suppurative node; Gram stain; bacterial, fungal, and mycobacterial cultures of the drainage; and institution of appropriate antimicrobial therapy (Fig. 47-3). Total
Chapter 47 Lymphadenopathy
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1. Trauma or distal infection present Yes 2. Systemic symptoms absent
Fever? Rash? Mucositis?
No
Yes Yes
Yes
Rule out Epstein-Barr virus, cytomegalovirus Rule out Kawasaki disease
3. Antimicrobial therapy
4. Symptoms resolve?
Yes
Complete antimicrobial course
No 5. Evidence of fluctuance or abscess
No
History of cat scratch? Careful search for papule?
Yes
Yes
Probable cat scratch Bartonella serology, consider biopsy
No 6. Incision and drainage/culture, Gram and AFB stains
PPD* placed (+) Excise for AFB Stain, culture CXR TB work-up
(+/–)
(–)
?Atypical AFB—follow if no TB risk Excise if enlarges or drains
* 5 mm induration if high risk or obvious close contact; 10 mm induration if younger than 4 years or chronic illness; 15 mm induration or more if 4 years or older without any risk factor. Figure 47-3. Paradigm for the management of typical acute regional lymphadenopathy (e.g., cervical, axillary, inguinal) in children. AFB, acid-fast bacillus: tuberculosis (TB); CXR, chest radiograph; PPD, purified protein derivative.
excision should be performed if atypical mycobacterial infection is suspected, because draining fistulas may form if a needle biopsy or partial resection is performed. Fine-needle aspiration may reduce the risk of sinus formation. INFECTIONS OF THE EXTREMITIES Bacterial infections of the skin and soft tissues (erysipelas, abscess, cellulitis, fasciitis) of the extremities are common causes of localized lymphadenopathy and adenitis. These infections, primarily caused by group A β-hemolytic streptococci or S. aureus, may drain into and inflame single or multiple regional lymph nodes. Any laceration or insect bite that becomes superinfected may yield adenopathy “upstream” from the infected site. On occasion, penetrating injuries to the feet that occur in wet areas or through damp shoes may yield infections with other bacteria, such as Pseudomonas aeruginosa. These penetrating infections usually manifest with cellulitis or osteomyelitis; lymphadenopathy is noted during the physical examination. The most common sites of infection include the foot or leg, leading to unilateral inguinal lymphadenitis, and the hand or arm, causing axillary lymphadenitis or, less commonly, unilateral inflammation of the epitrochlear nodes. EPSTEIN-BARR VIRUS INFECTION Infection with EBV is a common cause of both regional and diffuse lymphadenopathy. This virus classically causes a “mononucleosis”
syndrome in adolescents (Fig. 47-4), consisting of acute pharyngitis that may have a prolonged course, with tender, firm cervical adenopathy (but sometimes with generalized adenopathy); malaise; fever; weight loss; and anorexia. Approximately 10% of patients become jaundiced; more than 80% have mild hepatitis that is clinically silent but can be documented with liver enzyme studies. Splenomegaly is present in more than 50% of patients and, in rare cases, progresses to splenic rupture. A small number of patients also have parapharyngeal lymphoid hyperplasia, which causes difficulty swallowing or breathing and can produce significant problems, leading to dehydration or airway obstruction. Small children with EBV infection often present with atypical symptoms or may be completely asymptomatic. Nonspecific rash (often after ampicillin or allopurinol therapy), fever, and mild cervical adenopathy may be the major symptoms on presentation, or the child may be significantly ill with high fever and pharyngitis. Young children with acute EBV infection are more likely to have hepatosplenomegaly, rash, and eyelid edema than are young adults. The diagnosis of EBV infection in older children focuses on the characteristic clinical syndrome and a relative lymphocytosis seen in the differential white blood cell count (40% to 50%), which shows a substantial percentage of atypical lymphocytes (10% to 20%). Heterophile immunoglobulin M (IgM) antibodies, which are non–EBV directed and agglutinate sheep and horse red blood cells, are found in more than 80% of young adults with EBV and are at maximal titer 3 to 4 weeks after infection. Heterophile antibodies are rarely found in young children (younger than 5 years) with EBV
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75
Sp
om
eg
Pe rio rb ita l
y
0
th
Skin rash
pa
25
no
tis illi ns to is, git l yn ta m ar la the Ph Pa nan e
aly
50
Figure 47-4. The clinical course of acute Epstein-Barr mononucleosis. Adenopathy occurs early in the infection and can persist for weeks. (Modified from Rapp CE, Hewston JF: Infectious mononucleosis and the Epstein-Barr virus. Am J Dis Child 1978;132:78.)
e Ad
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100
ve
r
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infections. In young children, antibody titers directed to specific EBV antigens are necessary to confirm the diagnosis (Fig. 47-5). IgM antibodies against viral capsid antigen (VCA) followed by immunoglobulin G (IgG) directed to VCA and early antigens (EAs) are the most common antibody profile. Antibodies to nuclear antigens develop weeks later and, if present with EA IgG, are indicative of infection in the recent past. Approximately 20% of children present after the VCA IgM has already declined. In these children, VCA and EA IgG are present. Because group A streptococcal infection can present in a manner similar to, or be present simultaneously with, EBV infection, and because other viruses can initially cause pharyngitis and tender, enlarged cervical lymph nodes, differentiating these various causes of pharyngitis and lymphadenopathy is important. Acute streptococcal pharyngitis improves after institution of penicillin therapy; EBV infections do not, and they also have a more prolonged clinical course. In addition, severe malaise and splenomegaly do not occur with most bacterial or viral causes of pharyngitis and cervical lymphadenopathy. These findings prompt the clinician to consider EBV infection. Similarly, most viral causes of cervical adenopathy and pharyngitis (except CMV) are not associated with the brisk atypical lymphocytosis commonly seen with EBV infections, and they are not usually associated with abnormal liver function results. CYTOMEGALOVIRUS INFECTION CMV infection in children can be associated with a mononucleosislike syndrome and lymphadenopathy. CMV mononucleosis is associated with fever and malaise similar to that seen in EBV; in contrast to EBV, however, CMV mononucleosis does not usually cause severe, exudative tonsillopharyngitis or the production of heterophilspecific or EBV-specific antibodies. CMV mononucleosis can be associated with an atypical lymphocytosis and diffuse lymphadenopathy in the normal host. Although CMV culture (especially from the urine) is frequently positive in children with CMV infection, many children, especially those in day care, are silently infected and excrete CMV in absence of clinical signs and symptoms. Therefore, CMV culture is less useful in the toddler age group. Women who are pregnant when they have primary CMV infections (often through sexual contact) are at risk of delivering a child with congenital CMV infection through transplacental infection or through contact with infected cervical secretions at the time of delivery. Infants with congenital CMV may have many complications and clinical findings, but lymphadenopathy is not a common finding. Identifying CMV in the urine of the neonate in the first week of life confirms congenital infection.
The diagnosis in older children is usually made serologically, in tests measuring both IgM and IgG antibodies directed to CMV or by obtaining a throat or blood specimen for culture (leukocyte) that is positive for CMV. HUMAN HERPESVIRUS 6 INFECTION Infection with the human herpesvirus 6 (HHV-6), in addition to causing roseola, has been associated with a mononucleosis-like syndrome with diffuse or cervical adenopathy in individuals who are seronegative for EBV and CMV. Human herpesvirus 7 may produce a similar clinical pattern as that seen in HHV-6. Elevated or rising titers of antibodies to HHV-6 have been found in patients with documented acute EBV and CMV infections. It is unclear whether these seroconversions represent false-positive results caused by antigens cross-reactive among EBV, CMV, and HHV-6 or whether the HHV-6 rising antibody titers may represent a reactivation of old HHV-6 disease. CAT-SCRATCH DISEASE Cat-scratch disease is caused by a small gram-negative bacillus, Bartonella henselae (formerly Rochalimaea henselae). B. henselae also causes bacillary angiomatosis in patients with HIV infection. Cat-scratch disease occurs several days after exposure to a scratch or, less commonly, a bite of a cat or kitten (more than 90% of patients with clinical cat-scratch disease report contact with cats). A papule at the site of the trauma usually develops, followed in 7 to 14 days by regional lymphadenopathy. Most patients with cat-scratch disease have a single enlarged, often tender lymph node. Axillary nodes are the most likely to be enlarged, probably because the upper extremities are the part of the body most likely to be scratched or bitten. The next most common sites are the neck and jaw, followed by the inguinal region. Although single nodes are most commonly affected, regional adenopathy may also occur. Generalized lymphadenopathy is extremely rare in the normal host. Approximately half the patients have low-grade fever and malaise; a small number have high fevers (>39.5° C) and more severe systemic symptoms. In most patients, the swollen, inflamed nodes regress spontaneously within several weeks; approximately 10% progress to have purulent fluid drainage that is culture-negative by standard techniques. Uncommon complications include encephalopathy that resolves spontaneously; erythema nodosum; oculoglandular syndrome of Parinaud, in which the cat-scratch disease organism is inoculated into the eye and causes conjunctivitis and preauricular
Chapter 47 Lymphadenopathy
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Geometric Mean Antibody Titer
640
Geometric Mean Antibody Titer
640
Geometric Mean Antibody Titer
Not Infected
640
160 40 10 0
Long Past Primary Infection
Figure 47-5. Serologic patterns in individuals not infected with Epstein-Barr virus (EBV) (top), infected with EBV in the past (middle), and acutely infected with EBV (bottom). EA, early antigen; EBNA, EpsteinBarr nuclear antigen; IgA, IgG, and IgM, immunoglobulins A, G, and M; VCA, viral capsid antigen. (From Henle W, Henle G: Serodiagnosis of infectious mononucleosis. Resid Staff Physician 1981;27:37.)
160 40 10 0
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adenopathy; thrombocytopenia; hepatitis or splenitis with granulomas; transverse myelitis; and, in rare cases, osteolytic bone lesions. The diagnosis is based on the history of contact with kittens or cats and the classic clinical manifestation, including a careful search for an entrance site papule. The “gold standard” for diagnosis is the pathologic sample of tissue from the involved node, which shows granulomas, central necrosis, and organisms seen on Warthin-Starry silver stain. The decision to perform a biopsy is usually reached when there is no clear history of a cat’s scratch or when the presentation is atypical and cannot be differentiated from other, more serious illness, such as mycobacterial adenitis. Serologic tests for Bartonella species have good sensitivity and specificity and have proved useful in confirming the diagnosis of cat-scratch disease in children with appropriate history of exposure to cats and regional adenopathy. The treatment of cat-scratch disease has not been adequately studied. Various antibiotics have been used in an uncontrolled manner. There are anecdotal reports of clinical improvement after
IgG
IgG
IgM
EA-R
EBNA
Heterophil
administration of several antibiotics, including rifampin, gentamicin, ciprofloxacin, and trimethoprim-sulfamethoxazole. One prospective, randomized study of a small number of patients showed clinical benefit from azithromycin. Because cat-scratch disease is a selflimited illness in most children, most clinicians do not routinely use antimicrobial therapy.
CHRONIC GRANULOMATOUS DISEASE Chronic granulomatous disease (see Chapter 51) comprises a group of rare inherited disorders of neutrophil function, characterized by recurrent pyogenic infections, which are often accompanied by lymphadenopathy and/or abscess formation. Most cases are inherited in an X-linked manner; 30% are autosomal recessive. Chronic granulomatous disease should be considered in a young child (often a boy) who presents with recurrent fever and infection, pneumonia, adenopathy, and abdominal pain. Family history often reveals
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another relative with the disease or recalls a death from an infection in a young child. The diagnosis is made by neutrophil nitroblue tetrazolium testing or by chemiluminescent studies, which demonstrate the defective neutrophil oxidation. Common pathogens contain catalase and include S. aureus and Aspergillus species. HUMAN IMMUNODEFICIENCY VIRUS HIV infection may manifest with diffuse lymphadenopathy. Many HIV-infected children also have failure to thrive, poor weight gain, and evidence of other infections (oral thrush or opportunistic pneumonias such as that caused by Pneumocystis carinii). HIV-infected children are also more likely than normal hosts to have other infectious causes of lymphadenopathy, such as tuberculosis, or noninfectious causes, such as lymphoma. It is important to obtain a history of HIV risk factors. Regional lymphadenopathy is not a common manifestation of HIV infections unless the adenitis represents another bacterial or mycobacterial infection. MYCOBACTERIAL INFECTIONS Tubercular cervical adenitis is not common in the United States. In the past, it was often associated with ingestion of raw, contaminated milk and infection with M. bovis. Regional or diffuse lymphadenopathy caused by infection with Mycobacterium tuberculosis is also unusual in developed countries; however, it is increasing in frequency in children in the United States as a result of an increase in the number of adults actively infected. This increase is attributable to several issues, including immigration from endemic areas, reduction in tuberculosis control programs, the likelihood of HIV-infected individuals to have a high mycobacterial burden, noncompliance by infected individuals with multidrug treatment regimens, and drug resistance by the organism. Most adenitis caused by mycobacteria in the United States is caused by atypical strains that are not serious pathogens in the normal host. Several historical and clinical criteria can be used to differentiate tuberculous adenitis from atypical mycobacterial infections. Most children with tuberculosis have a history of exposure to an adult with active tuberculosis. Infection with atypical mycobacteria is more common in the southern parts of the United States. Children with tuberculous adenitis may have hilar lymphadenopathy because the lungs are usually the source of primary infection. Evidence of extralymphatic disease also is common in children with tuberculosis; such disease includes pneumonia, pleural effusions, bone marrow suppression, liver function abnormalities, and miliary disease. Disseminated tuberculosis may manifest with diffuse lymphadenopathy, and it should be sought if pulmonary infiltrates and systemic symptoms are present. Such extralymphatic disease and diffuse lymphadenopathy are rare in normal children with adenitis caused by atypical mycobacteria but may occur in HIV-infected children infected with atypical mycobacteria. The most common mycobacterial infection in children in the United States is infection of the lymph nodes with the atypical mycobacteria, primarily in the Mycobacterium avium-intracellulare complex as well as Mycobacterium kansasii, Mycobacterium scrofulaceum, and Mycobacterium marinum. The lymph nodes involved are unilateral and cervical in most infections, presumably because the organism enters via the oropharynx. Most frequently, a previously healthy child presents with unilateral lymphadenitis or adenopathy in the cervical, submandibular, or submaxillary region. Although fever may be present, other significant systemic symptoms are usually not present. In a small number of patients, the affected node spontaneously ruptures and drains before the visit to the physician. The drainage is not usually grossly purulent and may be a clue that atypical mycobacteria are the cause of the infected node. The “gold standard” for diagnosis of lymphadenitis caused by atypical mycobacteria is acid-fast staining and culture of the excised
node. Incision and drainage or needle aspiration of these nodes may lead to chronically draining sinus tracts, which may leave scars; thus, this method is contraindicated. Fine-needle aspiration may be beneficial. The usual clinical scenario involves a young, preschool-aged child with an enlarged cervical node that responds poorly to antibiotics. The child has no history of a cat’s scratch and is otherwise clinically well. A tuberculin skin test (which should be placed in children with lymphadenopathy) (see Fig. 47-3) often yields 5 to 9 mm of induration because atypical mycobacteria have antigens cross-reactive to those of tuberculosis. This amount of induration is considered indeterminate for tuberculosis in low-risk patients and suggests that the adenopathy is caused by an atypical mycobacterium. Skin tests with antigens from the various atypical mycobacteria are very sensitive and specific for infection; however, these antigens are not consistently available. In rare cases, infection with atypical mycobacteria yields skin test results in the positive range of more than 15-mm induration, which mandates a more extensive workup that focuses on the possibility that the adenitis is caused by M. tuberculosis infection. Gradual resolution of lymphadenitis sometimes occurs in children with atypical mycobacterial infections. Excisional biopsy is not necessary if the diagnosis is made presumptively from skin test results of less than 10 mm of induration, if other infections are ruled out, if resolution occurs, and if the child is at low risk for infection with M. tuberculosis (see Chapter 2). If the node does not improve, continues to enlarge, or spontaneously drains, excision is recommended and is usually curative. Fine-needle aspiration (for culture and acid-fast staining) may also be used if the node is in an area where excision is impractical. Chemotherapy with antitubercular drugs for atypical mycobacterial adenitis is controversial for several reasons. First, most of the atypical mycobacteria tend to be resistant to the usual antitubercular drugs, and multiple, potentially toxic regimens are required. Second, because this is a self-limited infection that sometimes resolves or can be cured with excision, long courses of chemotherapy seem unwarranted. Finally, although there have been no controlled trials, use of antitubercular therapy seems to have limited efficacy in comparison with excision. Antitubercular therapy should not be initiated without adequate cultures.
TOXOPLASMOSIS Toxoplasma gondii is a protozoan organism that is a parasite of cats. Many other animals, including humans, can be incidentally and chronically infected hosts in which the parasite cannot complete its life cycle. Human acquisition of toxoplasmosis in childhood can result from contact with cat feces or soil that contains oocysts, which infect the child when they are ingested. Alternatively, the ingestion of raw or undercooked meat, particularly lamb and pork that contain tissue cysts, may lead to infection. Adults in the United States are more likely to be infected from ingestion of raw meat than from contact with oocysts in cat feces and soil. Finally, infection can be transmitted to the fetus, especially when a pregnant woman is acutely infected with toxoplasmosis. Although many of the fetal infections are asymptomatic, transplacental infection with toxoplasmosis can result in severe neurologic damage, chorioretinitis, aseptic meningitis, and significant systemic illness manifesting with the classic triad of hepatosplenomegaly, intracranial calcifications, and hydrocephalus. Although lymphadenopathy can occur in the newborn with congenital toxoplasmosis, it is a more common symptom of acute toxoplasmosis in older children and young adults. The most common symptoms in children who acquire toxoplasmosis are lymphadenopathy, fever, malaise, myalgia, and pharyngitis. The nodes most commonly affected include anterior and posterior cervical and axillary, which may be tender; involvement is usually bilateral. The lymph node enlargement seen in toxoplasmosis is caused by reticular hyperplasia and inflammation. Most laboratory results are normal, but the white blood cell count may show an
Chapter 47 Lymphadenopathy absolute lymphocytosis with atypical lymphocytes, which can cause confusion with EBV or CMV mononucleosis. The diagnosis is made primarily with serologic studies. If tissue is available after biopsy, actual parasite forms can sometimes be demonstrated. Various diagnostic techniques can be used on the patient’s serum, including indirect immunofluorescence, complement fixation, and enzyme-linked immunosorbent assay. A fourfold rise in IgG titer or the presence of IgM antibodies is diagnostic. In neonatal infections, tests measuring IgM have become more sensitive and specific. Antigen tests and cultures that grow the parasite are also available, but primarily on an investigational level. Effective therapy consists of sulfonamides combined with pyrimethamine. Early treatment is especially important in the infant with congenital infection because treatment may improve neurologic outcome. Pregnant women newly infected with toxoplasmosis can be treated with spiramycin, which concentrates in the placenta and interrupts transplacental infection of the fetus; sulfonamides and pyrimethamine also eradicate the parasite from the fetus. These therapies significantly improve the previously poor outcome of the congenitally infected infant. Treatment of older children with acute toxoplasmosis is more controversial. Many investigators do not treat immunologically normal individuals unless symptoms are persistent and severe. In contrast, individuals with T cell deficiencies, such as those with HIV infection, can develop severe disseminated toxoplasmosis, involving the central nervous system and retina. In these patients, prolonged therapy is mandatory. SYPHILIS Syphilis, caused by the spirochete Treponema pallidum, is common in the United States (see Chapter 29). Numerous factors caused a resurgent epidemic of syphilis in the 1980s and 1990s, including difficulty in eradicating the organism in patients with HIV, prostitution to obtain crack cocaine in the inner cities, and lack of attention to prenatal screening and syphilis control programs. Syphilis remains primarily a sexually transmitted disease. Pregnant women with syphilis who are untreated readily transmit the disease to the fetus, causing congenital syphilis. Congenital syphilis leads to significant sequelae. The natural course of syphilis in adults includes three major clinical manifestations: ●
●
●
primary syphilis, in which the individual develops a painless chancre at the site of inoculation secondary syphilis, in which the organism hematogenously disseminates to many organs tertiary syphilis, in which gummatous lesions develop in end organs, such as the brain, heart, and bones
Lymphadenopathy can be seen as one of the manifestations of syphilis in several situations. In primary syphilis, in which the inoculation site is usually the genital area, regional lymphadenopathy with painless, firm nodes occurs at the time that a chancre is observed. Thus, inguinal adenopathy in an adolescent who is sexually active mandates further examination and workup for sexually transmitted diseases such as syphilis. In secondary syphilis, the organism has disseminated, causing multiple organs to be involved with the infection. The classic manifestations are protean and usually include nonvesicular rashes. Lymphadenopathy, regional or generalized, is common and often includes epitrochlear nodes (a hint that syphilis may be the diagnosis if no other explanation is found on the examination of the extremity). Systemic symptoms may be present with fever, malaise, anorexia, and weight loss. Syphilis therefore should be at the top of the differential diagnosis in sexually active adolescents with rash and lymphadenopathy. Infants with congenital syphilis may also have generalized lymphadenopathy, although this finding is less common than other systemic symptoms, such as hepatosplenomegaly, snuffles, and periosteal reactive disease.
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The diagnosis has been complicated by the inability to grow the organism in vitro. Darkfield examination of tissue from chancres or mucous lesions shows numerous spirochetes, but darkfield methods are often unavailable to routine laboratories. Serologic study continues to be the primary mode of diagnosis. Nontreponemal serologic studies rely on the production by the infected host of antibodies to nonspecific lipoidal host tissue antigens that arise as a result of infection with the spirochete. These tests include the Venereal Disease Research Laboratory (VDRL) test, the serologic test for syphilis, and the rapid plasma reagin (RPR) test. Levels of these antibodies decline after adequate treatment and are extremely useful in confirming eradication of the infection. False-positive reactions can occur, particularly in individuals with connective tissue disorders or mononucleosis. In contrast, the fluorescent treponemal antibody absorption test (FTA-ABS) measures antibodies directed specifically to T. pallidum and can be used as a confirmatory test in individuals with positive results on screening tests. These antibodies also usually remain present for the life of the infected individual, even if the patient receives adequate therapy. Thus, in contrast to the VDRL test, the FTA-ABS has little use in monitoring the efficacy of treatment. The mainstay of treatment for syphilis remains penicillin, although doxycycline or tetracycline may be used in nonpregnant, HIV-negative adults with proven penicillin allergy. In all other situations, desensitization of penicillin-allergic individuals is suggested by the Centers for Disease Control and Prevention. Neonates may require relatively long courses of intravenous penicillin because of the difficulties in ruling out and treating presumed neurosyphilis. Infants should be treated for congenital syphilis if physical examination findings, laboratory findings, or radiographic data suggest disease; if the cerebrospinal fluid VDRL test result is reactive; if the VDRL titer is four or more times higher than the mother’s titer; or if the mother had syphilis without documentation of appropriate treatment and declining VDRL titers. Treatment should also be considered if follow-up of the infant is likely to be inadequate or if an adequate workup is not possible. Aqueous crystalline penicillin intravenously for 10 days is the treatment of choice. However, if the cerebrospinal fluid test result is negative, some authorities recommend intramuscular procaine penicillin for 10 days instead or one dose of intramuscular benzathine penicillin with follow-up if risk factors are low but the diagnosis cannot be excluded. Persons with HIV infection also require prolonged high-dose penicillin therapy because syphilis appears to be particularly difficult to eradicate in immunodeficient individuals.
ACUTE LEUKEMIA, LYMPHOMA, AND OTHER MALIGNANCIES Lymphadenopathy is frequently among the presenting findings in patients with leukemia or lymphoma. Enlarged lymph nodes may be noted in an isolated, regional, or generalized distribution with or without systemic symptoms, such as fever, malaise, night sweats, weight loss, and anorexia. Malignant nodes are usually firm, rubbery, and nontender and may be matted. Unlike many of the acute lymphadenopathies caused by infectious agents, most lymph nodes that are malignant gradually increase in size over time. Approximately 50% of children with acute lymphoblastic leukemia have adenopathy at the time of diagnosis. Nodal disease may be either localized (often cervical) or generalized and is frequently accompanied by other signs and symptoms, including fevers, malaise, weight loss, pallor, bone pain, petechiae and bruising, splenomegaly, or hepatomegaly. The complete blood count usually demonstrates anemia, thrombocytopenia, leukocytosis or leukopenia, circulating blasts, or some combination thereof. Some patients, however, may have initial normal peripheral blood laboratory results. Acute myelogenous leukemia is less common in children but may manifest in a similar manner. Bone marrow biopsy and aspiration must be performed, and the findings are diagnostic.
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Hodgkin disease often manifests with painless cervical or supraclavicular lymphadenopathy in older school-aged children and adolescents. Nodes are firmer than those seen in patients whose nodes are enlarged in reaction to infections. In a small number of children with Hodgkin disease, the size of the nodes may wax and wane for several months before a definitive diagnosis is made. Supraclavicular nodes usually indicate intrathoracic disease, which is present in 60% to 70% of patients at the time of diagnosis. Axillary or inguinal nodes may also be the sites of presenting lymphadenopathy. Approximately 30% of patients with Hodgkin disease have systemic symptoms at presentation, including fatigue, weight loss, fevers, night sweats, and poor appetite. Some patients with Hodgkin disease also have unusual symptoms, such as pruritus, hemolytic anemia, and chest pain after alcohol ingestion. Such systemic symptoms with lymphadenopathy are red flags for immediate workup for malignancy. Diagnosis is confirmed by biopsy of involved nodes and/or bone marrow aspiration if the tumor has spread to the bone marrow. Non-Hodgkin lymphoma is a relatively common childhood malignancy and often manifests with mediastinal or pleural disease. Adenopathy in the supraclavicular, cervical, or axillary regions is usually present and may occur in the absence of chest involvement. Systemic symptoms are variable at the time of diagnosis. Lymph nodes, as with other malignancies, tend to be firm and rubbery. Their size may increase relatively rapidly over several weeks. Because lymphoblastic lymphoma may represent a variant of acute lymphoblastic leukemia, the signs and symptoms of leukemia and lymphoma may merge. Non-Hodgkin lymphoma of B cell origin (Burkitt and non-Burkitt lymphoma) in children in the United States usually originates in an intraabdominal site, and regional adenopathy, if present, is then in the inguinal or iliac regions. The African variety of Burkitt lymphoma often manifests as an expanding jaw mass. Disseminated neuroblastoma may manifest as diffuse adenopathy in younger children. Such children often have primary adrenal or paraspinal masses with bone metastasis and have nonspecific systemic symptoms, abdominal mass, bone pain, and sometimes symptoms of spinal cord compression. Other tumors, such as rhabdomyosarcoma and thyroid cancer, manifest in rare cases with lymphadenopathy caused by local or disseminated metastasis. SINUS HISTIOCYTOSIS Sinus histiocytosis is a rare disorder characterized by massive lymphadenopathy in the cervical region; it is associated with fever, elevated sedimentation rate, leukocytosis, and polyclonal hypergammaglobulinemia. The symptoms tend to resolve spontaneously after several months, and the condition is probably caused by an immunoregulatory disorder. Diagnosis is made from biopsy of the involved nodes and pathologic examination.
MANAGEMENT STRATEGIES REGIONAL LYMPHADENOPATHY The typical child with acute regional lymphadenopathy (see Fig. 47-3) presents with enlarged nodes, commonly in the cervical region. A thorough history and careful physical examination should reveal whether nodes are definitively involved (in comparison with the parotid gland); whether infection is present at other sites, such as the pharynx; whether other causes (e.g., cat’s scratch) exist for the adenopathy; and whether the nodes have the characteristics of malignancy. In many cases, no other abnormalities are found on examination, and systemic signs are minimal. Laboratory tests should include a complete blood cell count and differential as well as measurement of the erythrocyte sedimentation rate and the C-reactive
protein. In the child with fever and a tender cervical lymph node, oral antibiotics (with activity against mouth flora, streptococci, and staphylococci) should be started; if the lymphadenopathy persists or worsens, intravenous antibiotics are indicated. A PPD test should be undertaken, and if the results are negative and symptoms resolve, it is reasonable to complete the antimicrobial course orally. In contrast, if the lymphadenopathy continues or becomes frank lymphadenitis with erythema and tenderness despite antimicrobial therapy, further workup is indicated. Imaging the involved area is helpful but not always necessary. Although ultrasonography can reveal enlarged nodes or a fluid-filled abscess or cyst, CT with contrast enhancement of the area is the best method for defining the extent of inflamed nodes and whether an abscess is present. If an abscess is found, incision and drainage, followed by appropriate bacterial and mycobacterial cultures and stains, are appropriate. If atypical mycobacteria are suspected on the basis of a borderline positive PPD result or clinical presentation, excisional biopsy is preferred because incision and drainage often leads to draining sinus tracts that are difficult to heal. Enlarged nodes that do not recede in several weeks with appropriate antimicrobial therapy and without explanation (such as acute EBV infection) also should raise the suspicion of malignancy. GENERALIZED LYMPHADENOPATHY In the child with generalized lymphadenopathy, the cause may be infectious, immunologic, or malignant. Infectious causes, such as HIV, EBV, toxoplasmosis, secondary syphilis, and CMV infections, can generally be determined quickly through serologic testing. Noninfectious causes, such as systemic lupus erythematosus and serum sickness, can also generally be excluded by serologic studies and/or a careful history. If the generalized lymphadenopathy cannot be attributed to an infectious or other cause, and especially if there are systemic symptoms, malignancy should be considered. In addition, enlarging nodes that do not recede in several weeks, despite a diagnosis of a “viral” infection, should also raise concern for possible malignancy. An abnormal complete blood cell count demonstrating a depressed white blood cell, red blood cell, or platelet count or a chest radiograph or CT study demonstrating mediastinal adenopathy or pleural disease is highly suggestive of malignancy. Because serious disseminated infections, such as tuberculosis and histoplasmosis, can manifest in a similar manner, fine-needle aspiration or biopsy of an involved node or bone marrow aspiration is crucial. Excision of a node is preferred in some cases in order to obtain adequate tissue for pathologic study, stains, or cultures.
SUMMARY AND RED FLAGS Lymphadenopathy is one of the most common manifestations of childhood diseases. Most often, localized adenopathy is associated with a bacterial infection in the vicinity of the node or with a viral pharyngitis. Even generalized adenopathy does not usually indicate a serious underlying disease. Adenopathy usually resolves either spontaneously or after appropriate antibiotic therapy. When adenopathy is accompanied by weight loss, recurrent fevers, night sweats, or other systemic signs or symptoms, a more serious cause must be vigorously sought. The presence of supraclavicular nodes is usually pathologic and is a red flag for serious illness. Obviously, adenopathy associated with hepatomegaly, splenomegaly, or an abdominal mass must be quickly investigated. Furthermore, if the adenopathy does not diminish or resolve after antibiotic therapy or after 3 weeks, a more thorough evaluation is necessary. In children with known immunodeficiencies, the cause of the adenopathy may be far more serious. These children are more prone to infections, and malignancies occur at a higher frequency in these children than in the general population.
Chapter 47 Lymphadenopathy REFERENCES General References Grossman M, Shiramizu B: Evaluation of lymphadenopathy in children. Curr Opin Pediatr 1994;6:68. Kelly CS, Kelly RE Jr: Lymphadenopathy in children. Pediatr Clin North Am 1998;45:875. Cervical Adenopathy Alvarez A, Schreiber J: Lemierre’s syndrome in adolescent children— Anerobic sepsis with internal jugular vein thrombophlebitis following pharyngitis. Pediatrics 1995;96:354. Barton LL, Feigin RD: Childhood cervical lymphadenitis: A reappraisal. J Pediatr 1974;84:846. Brook I: Aerobic and anaerobic bacteriology of cervical adenitis in children. Clin Pediatr 1980;19:693. Peters TR, Edwards KM: Cervical lymphadenopathy and adenitis. Pediatr Rev 2000;21:399. Epstein-Barr Viral Infections Case Records of the Massachusetts General Hospital: Case 24-1994. N Engl J Med 1994;330:1739. Cohen JI: Epstein-Barr virus infection. N Engl J Med 2000;343:481. Rapp CE, Heweston JF: Infectious mononucleosis and the Epstein-Barr virus. Am J Dis Child 1978;132:78. Sumaya CV, Ench Y: Epstein-Barr virus infectious mononucleosis in children: I. Clinical and general laboratory findings. Pediatrics 1985; 75:1003. Cat-Scratch Disease Bass JW, Freitas BC, Freitas AD, et al: Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch diseases. Pediatr Infect Dis J 1998;17:447. Bass JW, Vincent JM, Person DA: The expanding spectrum of Bartonella infections: II. Cat scratch disease. Pediatr Infect Dis J 1997;16:163.
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Carithers HA: Cat-scratch diseases: An overview based on a study of 1,200 patients. Am J Dis Child 1985;139:1124. Schutze GE: Diagnosis and treatment of Bartonella henselae infections. Pediatr Infect Dis J 2000;19:1185. Human Immunodeficiency Virus Baroni CD, Uccini S: The lymphadenopathy of HIV infection. Am J Clin Pathol 1993;99:397. Mycobacterial Infections Huebner RE, Schein MF, Cauthen GM, et al: Usefulness of skin testing with mycobacterial antigens in children with cervical adenopathy. Pediatr Infect Dis J 1992;11:450. Wolinsky E: Mycobacterial lymphadenitis in children: A prospective study of 105 nontuberculous cases with long term follow-up. Clin Infect Dis 1995; 20:954. Toxoplasmosis Frenkel JK: Toxoplasmosis. Pediatr Clin North Am 1985;32:917. Montoya JG, Remington JS: Studies on the serodiagnosis of toxoplasmic lymphadenitis. Clin Infect Dis 1995;20:781. Sexually Transmitted Diseases 1998 Guidelines for treatment of sexually transmitted diseases. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998;47(RR-1):1. Leukemia and Lymphoma Shad A, Magrath I: Non-Hodgkin’s lymphoma. Pediatr Clin North Am 1997;44:863. Sinus Histiocytosis Stones DK, Havenga C: Sinus histiocytosis with massive lymphadenopathy. Arch Dis Child 1992;67:521.
48
Pallor and Anemia
Brian W. Berman
of the medical history is fundamental in the assessment of the pale patient (Table 48-3). In addition, the examiner must determine the duration of the anemia, its association with other symptoms, and history of any chronic illness (weight loss, fever, malaise).
Pallor, a perceptible reduction in the usual color and tone of the skin and/or mucosa, may result from alterations of cutaneous blood flow, anemia, or unknown mechanisms. Under normal circumstances, the pink appearance of the lips, mucosa, and, in white or Asian persons, skin is influenced by the nature and character of these tissues, the adequacy of vascular perfusion, and the concentration of hemoglobin. Pallor is a highly nonspecific finding that may be a manifestation of a wide diversity of diseases, or it may be normal for a given individual. Parental perception of pallor frequently generates considerable anxiety. Although pallor is most often intuitively associated with anemia by families as well as by physicians, an open-minded, broad diagnostic perspective is appropriate (Table 48-1). Anemia is the condition in which hemoglobin concentration (or hematocrit) is more than two standard deviations below the mean. Anemia is clinically relevant only when the low hemoglobin concentration results in a decreased oxygen-carrying capacity in the blood. By definition, 2.5% of the general population have a hemoglobin or a hematocrit level below the defined limits of normal. This fact must be kept in mind in the evaluation of children with mild anemia for which no explanation can be identified. Hemoglobin concentration varies considerably with age and sex (Table 48-2). Newborns have relatively high levels of circulating hemoglobin, which is an intrauterine adaptation to a relatively hypoxic environment. During the first 2 months of life, hemoglobin production markedly diminishes as a physiologic nadir is reached. The mean hemoglobin level rises gradually during childhood for both boys and girls until puberty, when boys achieve a level approximately 20% higher than that of girls. The average hemoglobin level in black children is slightly lower (0.5 g/dL) than those in white or Asian children. It is appropriate to consider the hemoglobin concentration of a given patient in the context of age and sex. Anemia occurs as the result of one (or a combination) of three pathophysiologic mechanisms: ● ● ●
Table 48-1. Causes of Pallor in Children, Based on
Etiologic Mechanism I. Anemia II. Decreased Tendency of the Skin to Pigment A. Physiologic (fair-skinned individuals) B. Limited sun exposure III. Alteration of the Consistency of the Subcutaneous Tissue A. Edematous states Increased intravascular hydrostatic pressure (e.g., congestive heart failure) Decreased intravascular oncotic pressure (hypoproteinemia) Increased vascular permeability (e.g., vasculitis) B. Hypothyroidism IV. Decreased Perfusion of the Cutaneous/Mucosal Vasculature A. Hypotension Cardiogenic shock (pump failure or rhythm disturbance) Hypovolemia (blood loss, dehydration) Anaphylaxis Sepsis Acute adrenal insufficiency Vasovagal syncope B. Vasoconstriction Increased sympathetic activity (hypoglycemia, pheochromocytoma) Neurologic complications (head trauma, seizures, migraine)
acute blood loss impaired production of erythrocytes increased destruction of red blood cells (RBCs), known as hemolysis
Under normal circumstances, the body’s RBC mass is maintained at a level appropriate to support tissue oxygen needs through the oxygensensing regulatory feedback stimulus of the hormone erythropoietin. Produced in the kidney, erythropoietin acts to stimulate the production of mature RBCs within the bone marrow. Over a 3- to 5-day period, RBC precursors mature into reticulocytes, which are released into the peripheral blood. In 24 to 48 hours, reticulocytes become mature RBCs, which then circulate in the peripheral blood for approximately 120 days. Senescent RBCs are removed from the circulation by reticuloendothelial cells within the spleen, liver, and bone marrow. A metabolic by-product of hemoglobin catabolism is bilirubin (see Chapter 20).
V. Chronic Medical Conditions A. Malignant disease B. Atopy C. Chronic inflammatory disease Juvenile rheumatoid arthritis Inflammatory bowel disease D. Cardiopulmonary disease (including cystic fibrosis) E. Diabetes mellitus F. Congenital and acquired immunodeficiencies
HISTORY The child with pallor is not necessarily anemic. An assessment of sun exposure and familial patterns of complexion is crucial because many patients are, by nature, intrinsically pale. A careful evaluation
From Reece RM: Manual of Emergency Pediatrics, 4th ed. Philadelphia, WB Saunders, 1992.
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Table 48-2. Values (Normal Mean and Lower Limits of Normal) for Hemoglobin,
Hematocrit, and MCV Determination Hemoglobin (g/dL) Age (yr)
0.5-1.9 2-4 5-7 8-11 12-14 Female Male 15-17 Female Male 18-49 Female Male
Mean
Lower Limit
Hematocrit (%) Mean
Lower Limit
MCV (fL) Mean
Lower Limit
12.5 12.5 13.0 13.5
11.0 11.0 11.5 12.0
37 38 39 40
33 34 35 36
77 79 81 83
70 73 75 76
13.5 14.0
12.0 12.5
41 43
36 37
85 84
78 77
14.0 15.0
12.0 13.0
41 46
36 38
87 86
79 78
14.0 16.0
12.0 14.0
42 47
37 40
90 90
80 80
From Nathan DC, Oski F: Hematology of Infancy and Childhood, 4th ed. Philadelphia; WB Saunders, 1993. MCV, mean corpuscular volume.
Table 48-3. Historical Clues in Evaluation of Anemia Variable
Age
Family history and genetic considerations
Nutrition
Drugs
Diarrhea
Infection
Comments
Iron deficiency rare in the absence of blood loss before 6 mo in term or before doubling birth weight in preterm infants Neonatal anemia with reticulocytosis suggests hemolysis or blood loss; with reticulocytopenia, it suggests bone marrow failure Sickle cell anemia and β-thalassemia appear as fetal hemoglobin disappears (4-8 mo of age) X-linked: G6PD deficiency Autosomal dominant: spherocytosis Autosomal recessive: sickle cell, Fanconi anemia Family member with early age of cholecystectomy (bilirubin stones) or splenectomy; hemolysis Ethnicity (thalassemia with Mediterranean origin), (G6PD deficiency in blacks, Greeks, and Sephardic Jews) Race (β-thalassemia in whites; α-thalassemia in blacks and Asians; SC and SS in blacks) Cow’s milk diet and iron deficiency Strict vegetarian and vitamin B12 deficiency Goat’s milk and folate deficiency Pica, plumbism, and iron deficiency Cholestasis, malabsorption, and vitamin E G6PD-susceptible agents Immune-mediated hemolysis (e.g., penicillin) Bone marrow suppression Phenytoin-increasing folate requirements Malabsorption of vitamins B12 and E and iron Inflammatory bowel disease and anemia of chronic disease or blood loss Milk protein allergy–induced blood loss Intestinal resection and vitamin B12 deficiency Giardia and iron malabsorption Intestinal bacterial overgrowth (blind loop) and vitamin B12 deficiency Fish tapeworm and vitamin B12 deficiency Epstein-Barr virus, cytomegalovirus, and bone marrow suppression Mycoplasma and hemolysis Parvovirus and bone marrow suppression Chronic infection Endocarditis Malaria and hemolysis Hepatitis and aplastic anemia
Adapted from Scott JP: Hematology. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 519. G6PD, glucose-6-phosphate dehydrogenase.
Chapter 48 Pallor and Anemia Dietary history is important as it relates to sources of iron. Infants, particularly those delivered prematurely and those consuming large amounts of cow’s milk or formula without iron supplementation, are at risk for iron deficiency anemia, as are children and adolescents who consume little meat. Patients or breast-fed infants of mothers who follow a strict vegan diet may become deficient in vitamin B12. A history of pica suggests possible lead toxicity, iron deficiency, or both. A neonatal history of hyperbilirubinemia supports a possible diagnosis of congenital hemolytic anemia, such as hereditary spherocytosis, which is further supported by a family history of anemia, splenectomy, and/or cholecystectomy (resulting from gallstones caused by chronic hyperbilirubinemia). Medication history is pertinent because certain drugs, including antimalarial agents and sulfonamide antibiotics, can induce oxidantassociated hemolysis in the patient deficient in glucose-6-phosphate dehydrogenase (G6PD), whereas other medications may cause immune hemolysis (penicillin) or decreased RBC production (chloramphenicol). Travel history may suggest exposure to infections, such as malaria.
PHYSICAL EXAMINATION The general appearance of the child provides a clue as to the severity and chronicity of the problem. Severe anemia that develops slowly over weeks or months is often well tolerated. Vital signs (including orthostatic blood pressure), height, weight, and growth percentiles offer further insight into the severity of the problem. The findings of a thorough physical examination define the degree of pallor (conjunctiva, palms, skin), reveal the presence of underlying disease (all organ systems), and uncover signs of trauma. Isolated pallor in a well-appearing child who does not have evidence of systemic disease is usually much less ominous than that noted in a child with bruising, adenopathy, hepatosplenomegaly, or abdominal mass. Table 48-4 lists some clues that may assist in determining the underlying cause of the anemia. Prominent cheekbones, dental malocclusion, and frontal bossing may occur in patients with chronic hemolytic anemias (sickle cell disease, thalassemia major) because of the expansion of bone marrow space. Tortuosity of conjunctival vessels occurs in the sickling syndromes. Splenomegaly is often present in children with congenital hemolytic anemia (see Chapter 19). Lymphadenopathy and hepatosplenomegaly may indicate the presence of infiltrative disease of the bone marrow and visceral organs, such as leukemia. Purpura in the anemic child is suggestive of associated thrombocytopenia, which may accompany aplastic anemia or leukemia. Many congenital anomalies have been associated with hematologic syndromes. Patients with Fanconi anemia (constitutional aplastic anemia) are often short and hyperpigmented with hypoplastic “finger-like” thumbs, radial bone anomalies, and structural renal abnormalities. Patients with Diamond-Blackfan anemia (congenital hypoplastic anemia) are often short and have a “curious, intellectual” facial expression. When pallor is related to chronic inflammation or infection or systemic disease, a diligent general physical examination may yield substantive information, such as hypertension and short stature in the child with chronic renal disease, joint inflammation in the child with rheumatologic disorders, digital clubbing in the child with advanced cyanotic cardiopulmonary diseases, and poor nutritional status in the child with inflammatory bowel disease. Recent onset of pallor is suggestive of anemia. The child who has always appeared somewhat pale but has been otherwise well and is manifesting normal growth and development may merely be expressing an intrinsic constitutional characteristic. In such instances, the child and other family members often have light hair and skin complexion. An unremarkable general medical history and physical examination support a physiologic explanation for pallor.
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Some children may appear pale as a result of limited sun exposure, as might occur during the winter in cooler climates. Children with malignant disease or chronic illness (e.g., rheumatologic disorders, inflammatory bowel disease, chronic cardiopulmonary disorders, diabetes) may have a pale appearance that is unrelated or out of proportion to the degree of associated anemia. Atopic children often have distinctly pale mucosa as a result of local edema. Children with generalized edema caused by hypoproteinemia, congestive heart failure, or vasculitis often appear pale as a result of excess interstitial fluid within the mucosal or cutaneous tissues. Patients with hypothyroidism are pale because of myxedematous changes in the skin, subcutaneous tissue, and mucosa. The rare child with pheochromocytoma can appear pale on the basis of catecholamine-induced vasoconstriction.
LABORATORY EVALUATION The initial laboratory test in a child with pallor should be a complete blood cell count (CBC) including a white blood cell (WBC) differential and platelet count. Anemia as a cause of pallor does not occur until the hemoglobin level falls below 8 to 9 g/dL. “False anemia” (resulting from laboratory error, sampling difficulty, or “statistical anemia”) should be considered whenever a child is said to be anemic, particularly when laboratory findings do not seem consistent with clinical impressions. Capillary blood sampling can be associated with substantial error, depending on the difficulty in performing the procedure and the use of mechanical force necessary to promote blood flow. When laboratory or sampling errors are supected, it is always appropriate to obtain a repeated venipuncture sample. “Statistical anemia” relates to the fact that, by definition, 2.5% of the general population has hemoglobin levels below the lower limit of normal. This phenomenon should be considered when mild, unexplained normocytic anemia is identified in a healthy child. Nearly all laboratories perform CBCs with the use of automated technology systems. Hemoglobin concentration (grams per deciliter), RBC count (cells per cubic millimeter), and mean corpuscular volume (MCV) (expressed in femtoliters [fL]) are directly measured. Hematocrit value, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration are derived values and are less accurate. Other useful information reported includes RBC distribution width (RDW), WBC count (cells per cubic millimeter), and platelet count. Careful attention should be given to the hemoglobin value, the MCV, the RDW, the shape of the RBCs, and any abnormalities in the number of platelets or WBCs. The reticulocyte count, reported as a percentage of total RBCs, is essential in categorizing anemia. An appropriately elevated reticulocyte count implies a response of the bone marrow to either hemolysis or acute or chronic blood loss. In cases of acute blood loss, the reticulocyte count is not elevated for 3 to 4 days. The reticulocyte count is therefore most helpful for cases in which the anemia has been present for more than a few days. The MCV may provide very helpful information but must always be viewed in conjunction with a review of the peripheral blood smear, RDW, and reticulocyte count. A varied population of smaller and larger RBCs (e.g., reticulocytes) may yield a falsely normal MCV and be diagnostically misleading. Microcytosis may be associated with several commonly encountered anemias, including iron deficiency, thalassemia, lead toxicity, and anemia of chronic disease (Table 48-5). Macrocytosis, an unusual finding in children, is associated with vitamin B12 or folate deficiency, syndromes associated with elevated production of fetal-like RBCs (Fanconi anemia, Diamond-Blackfan anemia), and some cases of hypothyroidism (see Table 48-5). Normal standards for MCV are age related; a simple guideline is that the lower normal limit of MCV for children older than 6 months of age is 70 fL plus the patient’s age in years until the adult standard of 80 to 100 fL is reached (see Table 48-2).
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Table 48-4. Physical Findings in the Evaluation of Anemia System
Skin
Head Eyes
Ears Mouth
Chest Abdomen
Extremities
Rectal Nerves
Observation
Hyperpigmentation Café-au-lait spots Vitiligo Partial oculocutaneous albinism Jaundice Petechiae, purpura Erythematous rash Butterfly rash Frontal bossing Microcephaly Microphthalmia Retinopathy Optic atrophy, blindness Blocked lacrimal gland Kayser-Fleisher ring Blue sclera Deafness Glossitis Angular stomatitis Cleft lip Pigmentation Telangiectasia Leukoplakia Shield chest or widespread nipples Murmur Hepatomegaly Splenomegaly Nephromegaly Absent kidney Absent thumbs Triphalangeal thumb Spoon nails Beau line (nails) Mees line (nails) Dystrophic nails Edema Hemorrhoids Heme-positive stool Irritable, apathy Peripheral neuropathy Dementia Ataxia, posterior column signs Stroke
Significance
Fanconi anemia, dyskeratosis congenita Fanconi anemia Vitamin B12 deficiency Chédiak-Higashi syndrome Hemolysis Bone marrow infiltration, autoimmune hemolysis with autoimmune thrombocytopenia, hemolytic uremic syndrome Parvovirus, Epstein-Barr virus SLE autoantibodies Thalassemia major, severe iron deficiency, chronic subdural hematoma Fanconi anemia Fanconi anemia Hemoglobin SS, SC disease Osteopetrosis Dyskeratosis congenita Wilson disease Iron deficiency Osteopetrosis B12 deficiency, iron deficiency Iron deficiency Diamond-Blackfan syndrome Peutz-Jeghers syndrome (intestinal blood loss) Osler-Weber-Rendu syndrome (blood loss) Dyskeratosis congenita Diamond-Blackfan syndrome Endocarditis: prosthetic valve hemolysis Hemolysis, infiltrative tumor, chronic disease, hemangioma, cholecystitis Hemolysis, sickle cell disease (early), thalassemia, malaria, lymphoma, Epstein-Barr virus, portal hypertension Fanconi anemia Fanconi anemia Fanconi anemia Diamond-Blackfan syndrome Iron deficiency Heavy metal intoxication, severe illness Heavy metals, severe illness, sickle cell anemia Dyskeratosis congenita Milk-induced protein-losing enteropathy with iron deficiency Portal hypertension Intestinal hemorrhage Iron deficiency Deficiency of vitamins B1, B12, and E, lead poisoning Deficiency of vitamins B12 and E Vitamin B12 and E deficiency Sickle cell anemia, paroxysmal nocturnal hemoglobinuria
Adapted from Scott JP: Hematology. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 520. SLE, systemic lupus erythematosus.
An individual with small RBCs may have a normal or nearnormal hemoglobin level if the RBC count is increased, as occurs in patients with thalassemia minor, who often have RBC counts of more than 5 × 106. The mean corpuscular hemoglobin concentration reflects the concentration of hemoglobin per cell and would be expected to be low in patients with anemias in which RBCs are “underhemoglobinized,” such as the hypochromic anemia of iron deficiency. The RDW is derived from the histogram of RBC volumes. A normal RDW (11.5% to 14.5%) implies a uniform population of RBCs of similar size (in β-thalassemia trait, a uniform population of small cells exists; hence the MCV is low and the RDW is normal or minimally elevated). An elevated RDW is seen in iron deficiency (in which the population of small cells is variably sized; hence the MCV is low and the RDW is elevated) or some hemolytic anemias
(in which the RDW is elevated because of the presence of large reticulocytes) (Table 48-6). Anemias are categorized on the basis of the adequacy of the reticulocyte response. The reticulocyte count, normally about 1% to 2%, is expressed as a percentage of the total number of RBCs; in some patients with moderate or severe anemia, the reticulocyte count may appear elevated, but in absolute terms, it may be insufficient. Therefore, the reticulocyte count must be corrected: corrected reticulocyte count =
reticulocyte count × hemoglobin (normal hemoglobin for age)
If the corrected reticulocyte count is greater than 2%, then the bone marrow is producing RBCs at an accelerated pace (Fig. 48-1).
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Table 48-5. Causes of High or Low Mean Corpuscular
Table 48-6. Red Blood Cell Distribution Width (RDW)
Volume
in Common Anemias of Childhood
Low mean corpuscular volume Iron deficiency Thalassemias Lead toxicity Anemia of chronic disease Copper deficiency Sideroblastic anemia Hemoglobin E High mean corpuscular volume Normal newborn Elevated reticulocyte count Vitamin B12 or folate deficiency Diamond-Blackfan anemia (congenital hypoplastic anemia) Fanconi anemia Aplastic anemia Down syndrome Hypothyroidism (occasionally) Oroticaciduria Lesch-Nyhan syndrome Drugs (zidovudine, chemotherapy) Chronic liver disease
Anemia
MCV
Elevated RDW (Nonuniform Population of RBCs) Hemolytic anemia with elevated reticulocyte High count Iron deficiency anemia Low Anemias due to red blood cell fragmentation: Low DIC, HUS, TTP Megaloblastic anemias: vitamin B12 or folate High deficiency Normal RDW (Uniform Population of RBCs) Thalassemias Acute hemorrhage Fanconi or aplastic anemia
Low Normal High
DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; MCV, mean corpuscular volume; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.
Corrected Reticulocyte Count
2%
Mean corpuscular volume
Normal Low Iron deficiency Thalassemia Lead Chronic disease Sideroblastic anemia
High Vitamin B12/folate Diamond-Blackfan Fanconi anemia
Isolated anemia Acute infection Transient erythroblastopenia Anemia of chronic disease Renal disease Hypothyroidism Drug induced
Pancytopenia Aplastic anemia Leukemia Drug induced
* Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis, stomacytosis, or paroxysomal nocturnal hemoglobinuria Glucose-6-phosphate dehydrogenase, pyruvate kinase, or glucose phosphate isomerase deficiencies.
Hemolysis Intrinsic Membrane defect* Enzyme defect Hemoglobinopathy (Sickle cell anemia)
Blood loss
Extrinsic Immune-autoimmune Infection Microangiopathy Disseminated intravascular coagulation Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Liver disease Paroxysmal nocturnal hemoglobinuria Hypersplenism Mechanical injury Toxins Nutritional Metabolic Wilson disease
Figure 48-1. Diagnostic approach to anemia. *Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis, stomatocytosis, or paroxysmal nocturnal hemoglobinuria. †Glucose6-phosphate dehydrogenase, pyruvate kinase, or glucose phosphate isomerase deficiencies.
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The WBC count, differential, and platelet count may provide extremely pertinent information. The presence of immature leukocytes on a smear, which may be associated with either a high or a low WBC count, is suggestive of leukemia. Leukopenia and thrombocytopenia occurring in a patient with anemia of underproduction are suggestive of aplastic anemia or infiltrative bone marrow disease, such as leukemia or neuroblastoma metastasis to the marrow. Thrombocytosis may be present in patients with iron deficiency, blood loss, inflammatory disease, infection, malignancy, or asplenia. The serum indirect bilirubin, lactate dehydrogenase, and urinary urobilinogen levels are elevated in patients with increased rates of RBC destruction. An elevated serum direct bilirubin level is seen only if hepatobiliary complications supervene (biliary tract stones, hepatitis). A low serum iron level, elevated total iron-binding capacity, and a low percentage of iron saturation (% saturation = serum iron/total iron binding capacity × 100) and/or decreased serum ferritin level are helpful in establishing a diagnosis of iron deficiency. Hemoglobin electrophoresis is necessary to define abnormal hemoglobins, such as sickle hemoglobin or hemoglobin C. Assessment of RBC enzyme levels (e.g., G6PD) may be necessary when infectionor medication-related hemolytic anemia is suspected in a male of Mediterranean or African descent. True macrocytic anemia may necessitate assessment of serum vitamin B12 and folate levels. Bone marrow aspirate and biopsy are appropriate whenever leukemia or aplastic anemia is seriously suspected. If autoimmune hemolytic anemia is suspected because anemia, jaundice, reticulocytosis (may be absent if antibody reacts with reticulocytes), splenomegaly (not universally), and microspherocytes are noted, a direct Coombs test should be performed to detect the presence of an autoantibody on the RBC surface.
Abnormalities of RBC structure may be readily apparent on inspection of the peripheral blood smear and provide helpful diagnostic hints (Table 48-7, Fig. 48-2). From a practical clinical perspective, it is best to consider the differential diagnosis of pallor in the context of the acuteness and severity of the clinical findings (Fig. 48-3). The well-appearing child may need only a CBC, which might provide reassurance to the parents. The pale child who appears mildly or moderately ill requires a laboratory evaluation for anemia as well as studies to detect any suspected underlying disease. The pale child who appears seriously ill requires urgent evaluation and appropriate therapeutic intervention. The only obligatory laboratory study is a CBC, with other laboratory assessments dictated on the basis of the suspected diagnosis (blood glucose, electrolyte, blood urea nitrogen [BUN], and creatinine measurements and blood culture). If hemorrhage or severe anemia is suspected, a type and cross-match must be sent to the blood bank; two large intravenous lines must be secured; and frequent serial evaluations of hemoglobin, blood pressure, pulse, perfusion, and end-organ function (central nervous system for mental status, renal function for urine output) must be assessed.
DIFFERENTIAL DIAGNOSIS OF ANEMIA The classification of anemia is presented in Figure 48-1 and Figure 48-4. Anemia Caused by Acute Blood Loss Significant loss of blood on an acute or subacute basis leads to anemia. A period of about 24 hours may be required for full intravascular
Table 48-7. Peripheral Blood Morphologic Findings in Various Anemias
Microcytes Iron deficiency Thalassemias Lead toxicity Anemia of chronic disease Macrocytes Newborns Vitamin B12 or folate deficiency Diamond-Blackfan anemia Fanconi aplastic anemia Liver disease Down syndrome Hypothyroidism
Basophil Stippling Thalassemia Lead intoxication Red Blood Cell Fragments, Helmet Cells, Burr Cells Disseminated intravascular coagulation Hemolytic-uremic syndrome Thrombotic thrombocytopenic purpura Kasabach-Merritt syndrome Waring blender syndrome Uremia Hypersegmented Neutrophils Vitamin B12 or folate deficiency
Spherocytes Hereditary spherocytosis Immune hemolytic anemia
Blasts Leukemia (All or AML) Severe infection (rarely)
Sickled Cells Sickle cell anemias (SS disease, SC disease, S–β-thalassemia)
Leukopenia/Thrombocytopenia Aplastic or Fanconi anemia Leukemia
Elliptocytes Hereditary elliptocytosis Target Cells Hemoglobinopathies (especially hemoglobin C and thalassemia) Liver disease ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia.
Chapter 48 Pallor and Anemia
A
879
B
Figure 48-2. Morphologic abnormalities of the red blood cell. A, Normal. B, Macrocytes (folic acid deficiency). C, Hypochromic microcytes (iron deficiency). D, Spherocytes (hereditary spherocytosis). E, Target cells (hemoglobin CC disease). F, Schistocytes (hemolyticuremic syndrome). (From Behrman RE, Kliegman RM [eds]: Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 521.)
C
D
E
F
equilibration after acute blood loss; the fall in hemoglobin level occurs gradually. In patients with severe acute blood loss, the primary concern is intravascular volume, which cannot be assessed by hemoglobin level. In this situation, the patient’s condition is best assessed by measurement of blood pressure, heart rate, adequacy of peripheral perfusion (capillary refill time), and mental status. In most instances, an obvious history of blood loss is apparent (epistaxis, hematemesis, trauma), but severe occult blood loss may also occur. Large amounts of blood may accumulate in the gastrointestinal tract before the development of hematemesis, hematochezia, or melena. Intraabdominal bleeding may occur after trauma or may result from an ulcer (see Chapters 14 and 17) and may be associated with progressive anemia in the absence of an obvious source of blood loss. The clinical history coupled with the physical examination (including rectal examination) and tests for occult blood in the stool generally define the source of blood loss. In anemia associated with blood loss, the RBC size and structure are normal, and after a period of 3 to 5 days, the reticulocyte count increases appropriately. If hemorrhage has ceased, the hemoglobin level may be expected to gradually rise unless supervening factors, such as iron deficiency, exist. Severe hemorrhage associated with intravascular volume depletion warrants immediate intervention; RBC transfusions are necessary until hemorrhage has ceased. Less severe hemorrhage may not be associated with intravascular volume depletion and may merely manifest with moderate to severe anemia. Transfusions are necessary
when the oxygen-carrying capacity of the blood is diminished to the point of impending tissue hypoxia; the need for transfusion therapy is based on clinical parameters, including the presence of fatigue, lightheadedness, tachycardia, dyspnea, and heart failure. If hemorrhage has ceased, if intravascular volume is replete, and if the patient is not manifesting signs of cardiorespiratory compromise, transfusion therapy can often be avoided. In such instances, it is appropriate to supply therapeutic doses of iron to ensure adequacy of the reticulocyte response (see Table 48-10). Anemia Caused by Underproduction Anemia caused by underproduction (see Figs. 48-1 and 48-4) is characterized by a suboptimal bone marrow response (a corrected reticulocyte count of 1 yr age
Pure red blood cell defect; no anomalies, fetal hemoglobin, or i antigen; spontaneous recovery, normal MCV All cell lines involved; chloramphenicol, phenylbutazone, radiation
Transfusion for symptomatic anemia
All ages
Before 10 yr; mean, 8 yr
After 5 yr
Dyskeratosis congenita
Mean for skin, 10 yr; mean for anemia, 17 yr
Familial hemophagocytic lymphohistiocytosis
Before 2 yr
Epstein-Barr virus (EBV) Virus-associated hemophagocytic syndrome (CMV, HHV-6, EBV)
Treatment
Newborn–1 mo; 90% 5-10%)
Coombs' positive
Coombs' negative
Isoimmunization: Rh (D antigen) ABO, C, c, E, G Duffy, Kell Other minor group Drug-induced (PCN)
Blood smear
Obtain incubated osmotic fragility test
Blood cultures, obtain maternal serum for IgG, HIV, RPR/FTA RBC morphology
Obtain bone marrow Normal RBC morphology
Specific RBC dysmorphology Elliptocytes Poikylocytes Stomatocytes Fragmentation Basophilic stippling Spherocytes
Infections Bacterial infections Parvovirus B19 TORCH infections Syphylis Malaria HIV
Jaundice
Hypochromic Microcytic RBCs
No jaundice
Consider acute blood loss due to obstetric complications, external or internal hemorrhage, DIC/sepsis, bleeding dyscrasias
Congenital Enzymatic Defects G6PD Pyruvate kinase Hexokinase Glucose phosphate isomerase Others
Obtain specific enzyme assay
Chronic fetomaternal bleed Chronic twin-to-twin transfusion ATR-X and ATR-16 Alpha-thalassemia trait Gamma-thalassemia
Obtain hemoglobin electrophoresis, KB stain
Other Galactosemia Alpha or gamma chain hemoglobinopathies Acidosis Osteopetrosis Congenital leukemia Drugs (valproic acid, oxidizing agents)
Figure 48-9. Differential diagnosis of neonatal anemia. The physician first seeks information from the family, maternal, and labor and delivery histories and then obtains initial laboratory tests: hemoglobin, reticulocyte count, blood type, direct Coombs’ test, peripheral smear, red blood cell (RBC) indices, and bilirubin concentration. Results are used to navigate the diagnostic flow chart. ATR-16, α-thalassemia retardation syndrome, chromosome 16–linked; ATR-X, α-thalassemia retardation syndrome, X-linked; DIC, disseminated intravascular coagulation; FTA, fluorescent treponemal antibody test; G6PD, glocose6-phosphate dehydrogenase; HIV, human immunodeficiency virus; KB, Kleihauer-Betke; PCN, penicillin; RPR, rapid plasma reagin test; TORCH, toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex. (From Ohls RK: Evaluation and treatment of anemia in the neonate. In Christensen RD [ed]: Hematologic Problems of the Neonate. Philadelphia, WB Saunders, 2000, p 162.)
Table 48-21. Red Flags
Anemia Accompanied By Abnormal vital signs (tachycardia, hypotension, hypertension) Neutropenia and/or thrombocytopenia High MCV with normal RDW Blasts on the peripheral smear Firm adenopathy Bruising or bleeding Weight loss, failure to thrive Shortness of breath, fatigue Fever Hypoxia Organomegaly Edema Oliguria-anuria Bloody diarrhea Red urine (hemoglobinuria) Family history of anemia MCV, mean corpuscular volume; RDW, red blood cell distribution width.
Anemia may be a primary event reflecting intrinsic hematologic disease, or it may be a manifestation of a wide variety of disorders involving virtually any organ system. Anemia must always be fully evaluated, in view of the potential diagnostic and therapeutic implications. Patients who appear acutely ill should have a more thorough and prompt evaluation because acute blood loss must be treated quickly. If acute blood loss is not suspected, acute hemolysis or splenic sequestration of RBCs must be considered. Anemia is often a sign of underlying acute or chronic disease. In such cases, anemia is not usually an isolated finding. Therefore, symptoms such as shortness of breath, extreme pallor, weight loss, fevers, lethargy, and fatigue should prompt a thorough evaluation of the patient. On physical examination, the findings of abnormal vital signs, failure to thrive, bleeding or bruising, adenopathy, or organomegaly should lead the examiner to suspect that a potentially serious underlying disorder is present (Table 48-21). When a CBC is obtained, a low hemoglobin value accompanied by any abnormality of MCV, WBC, or platelet count should be taken seriously and should be more thoroughly investigated.
Section Eight Hematologic Disorders
894 REFERENCES
Krijanovski OI, Sieff CA: Diamond-Blackfan anemia. Hematol Oncol Clin North Am 1997;11:1061.
Workup of Anemia Bessman JD, Jilmer PR, Gardner FH: Classification of red cell disorders by MCV and RDW. Am J Clin Pathol 1983;80:322. Hermiston ML, Mentzer WC: A practical appproach to the evalution of the anemic child. Pediatr Clin North Am 2002;49:877. Hoffman R, Benz EJ, Shattil SJ, et al: Hematology: Basic Principles and Practice, 3rd ed. New York, Churchill Livingstone, 2000. Kline NE: A practical approach to the child with anemia. J Pediatr Health Care 1996;10:99. Kohli-Kumar M: Screening for anemia in children: AAP recommendations— a critique. Pediatrics 2001;108:E56. Nathan DG, Orkin SH, Ginsburg D, Look AT: Nathan and Oski’s Hematology of Infancy and Childhood, 6th ed. Philadelphia, Saunders, 2003. Novak RW: Red blood cell distribution within pediatric microcytic anemias. Pediatrics 1987;80:251. Segel GB, Hirsh MG, Feig SA: Managing anemia in a pediatric office practice: Part 1. Pediatr Rev 2002;23:75. Segel GB, Hirsh MG, Feig SA: Managing anemia in a pediatric office practice: Part 2. Pediatr Rev 2002;2:111. Walters MC, Abelson HT: Interpretation of the complete blood count. Pediatr Clin North Am 1996;43:599.
Iron Deficiency Abelson HT: Complexities in recognizing and treating iron deficiency anemia. Arch Pediatr Adolesc Med 2001;155:332. Alter BP: Bone marrow failure syndromes in children. Pediatr Clin North Am 2002;49:973. American Academy of Pediatrics Committee on Nutrition: Iron fortification of infant formulas. Pediatrics 1999;104:119. Bogen DL, Duggan AK, Dover GJ, et al: Screening for iron deficiency anemia by dietary history in a high-risk population. Pediatrics 2000;105:1254. Cheng TL: Iron deficiency anemia. Pediatr Rev 1998;19:321. Kwiatkowski JL, West TB, Heidary N, et al: Severe iron deficiency anemia in young children. J Pediatr 1999;135:514. Lozoff B, Wolf AW, Jimenez E: Iron-deficiency anemia and infant development: Effects of extended oral iron therapy. J Pediatr 1996;129:382. Walters T, Pino P, Pizarro F, Lozoff B: Prevention of iron deficiency anemia: Comparison of high and low iron formulas in healthy infants after six months of life. J Pediatr 1998;132:635. Wharton BA: Iron deficiency in children: Detection and prevention. Br J Haematol 1999;106:270. Sickle Cell Disease
Anemia with Acute and Chronic Disease Abshire TC: The anemia of inflammation. A common cause of childhood anemia. Pediatr Clin North Am 1996;43:623. Cowin HL, Krantz SB: Anemia of the critically ill: “Acute” anemia of chronic disease. Crit Care Med 2000;28:3098. Fitzsimons EJ, Brock JH: The anaemia of chronic disease. BMJ 2001;322:811. Means RT Jr: Advances in the anemia of chronic disease. Int J Hematol 1999;70:7. Hemolytic Anemia Beutler E: Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1991;324:169. Davidson RN, Wall RA: Prevention and management of infections in patients without a spleen. Clin Microbiol Infect 2001;7:657. Lynch AM, Kapila R: Overwhelming postsplenectomy infection. Infect Dis Clin North Am 1996;10:693. Sackey K: Hemolytic anemia: Part 1. Pediatr Rev 1999;20:152. Sackey K: Hemolytic anemia: Part 2. Pediatr Rev 1999;20:204. Trivedi DH, Bussel JB: Immunohematologic disorders. J Allergy Clin Immunol 2003:S669. Hypoplastic Anemia Cherrick I, Karayalcin G, Lanzkowsky P: Transient erythroblastopenia of childhood. Prospective study of fifty patients. Am J Pediatr Hematol Oncol 1994;16:320. DaCosta L, Thiebant-Noel W, Fixler J, et al: Diamond-Blackfan anemia. Curr Opin Pediatr 2001;13:10. Farhi DC, Luebbers EL, Rosenthal NS: Bone marrow biopsy findings in childhood anemia: Prevalence of transient erythroblastopenia of childhood. Arch Pathol Lab Med 1998;122:638.
Fixler J, Styles L: Sickle cell disease. Pediatr Clin North Am 2002;49:1193. Kinney TR, Sleeper LA, Wang WC, et al: Silent cerebral infarcts in sickle cell anemia: A risk factor analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics 1999;103:640. Quinn CT, Buchanan GR: The acute chest syndrome of sickle cell disease. J Pediatr 1999;135:416. Rucknagel DL: Progress and prospects for the acute chest syndrome of sickle cell anemia. J Pediatr 2001;138:160. Schatz J, Brown RT, Pascual JM, et al: Poor school and cognitive functioning with silent cerebral infarcts and sickle cell disease. Neurology 2001;56:1109. Section on Hematology/Oncology Committee on Genetics, American Academy of Pediatrics: Health supervision for children with sickle cell disease. Pediatrics 2002;109:526. Vichinsky EP, Neumayr LD, Earles AN, et al: Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. New Engl J Med 2000;342:1855. Walters MC, Storb R, Patience M, et al: Impact of bone marrow transplantation for symptomatic sickle cell disease: An interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood 2000;95:1998. Wang W, Enos L, Gallagher D, et al: Neuropsychologic performance in school-aged children with sickle cell disease: A report from the Cooperative Study of Sickle Cell Disease. J Pediatr 2001;139:391. Wethers DL: Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. Am Fam Physician 2000;62:1309. Woodard P, Lubin B, Walters CM: New approaches to hematopoietic cell transplantation for hematological diseases in children. Pediatr Clin North Am 2002;4:989. Yaster M, Kost-Byerly S, Maxwell LG: The management of pain in sickle cell disease. Pediatr Clin North Am 2000;47:699.
49
Neck Masses in Childhood
David J. Beste*
There are various paradigms for diagnosing neck masses. The dichotomous approaches are acquired versus congenital, inflammatory versus noninflammatory, and neoplastic versus nonneoplastic. Multifactorial approaches are based on anatomy, age at presentation, and historical and physical characteristics of the mass. Systemic features (fever, weight loss), airway compromise, recognizable clinical patterns of symptoms and signs, and the nature of progression of the mass also help determine a diagnosis. The presence of a new neck mass in a child is stressful for the parents, for a child old enough to understand the implications, and for the physician. After noting a cervical mass, parents worry about the possibilities of serious infection, surgery, or a diagnosis of cancer. The physician who understands and acknowledges these concerns can better care for the emotional needs of the family while evaluating and treating the child. Diagnosis of neck masses relies on pattern recognition. Important factors in pattern recognition of neck masses are (1) anatomic position (Table 49-1, Fig. 49-1), (2) presence of signs of inflammation, (3) associated symptoms (fever, night sweats, weight loss, upper airway symptoms), and (4) temporal development of the mass and symptoms.
Table 49-1. Childhood Neck Masses Associated with
Cervical Regions* Submental Lymphadenitis Viral Bacterial Thyroglossal duct cyst Submandibular Lymphadenopathy Viral Bacterial Atypical mycobacterial Lymphatic malformation Submandibular gland sialadenitis Kimura disease Jugulodigastric Lymphadenopathy, superficial cellulitis Viral Bacterial Abscess Lymphadenitis, deep cellulitis Viral Bacterial Abscess Hemangioma Cat-scratch disease (superficial or deep) First branchial anomaly Kimura disease Langerhans histiocytosis
HISTORY Most often, a child presenting with an inflammatory mass has an obvious explanation. If a cervical mass is inadvertently found on physical examination, a redirected history (such as a prior or current sore throat) is necessary to elicit the cause. The child’s age provides some evidence for origin of the cervical mass. The presence of a mass in the neonatal period is most likely of congenital origin. Fibromatosis colli, branchial cleft or pouch anomalies (especially if a sinus tract is present), vascular and lymphatic malformations, or dermoids may manifest early. In infants and toddlers, the most common masses are cellulitic or abscessed lymph nodes. Hemangiomas enter their rapid growth phase, and some branchial cleft anomalies, pilomatrixoma, and lymphatic and vascular malformations become evident in toddlers. The incidence of malignant neuroblastoma peaks among children younger than 1 year of age. Children have a high incidence of lymphadenitis, but a rare chronic lymphadenitis may be a childhood lymphoma, whose incidence peaks among children younger than 14 years. Branchial cleft anomalies and thyroglossal duct cysts occur throughout childhood. The incidences of some rare malignancies, such as salivary tumors, peak during adolescence. Localized lymphadenitis is rare in adolescents, but mononucleosis is common and may be accompanied by generalized lymphadenitis and systemic features (see Chapter 47).
Preauricular Lymphadenopathy Atypical mycobacterial Hemangioma First branchial cleft anomaly Parotid sialadenitis Parotid neoplasm Postauricular Dermoid Langerhans histiocytosis Hyoid Thyroglossal duct cyst Dermoid Lymphadenitis Viral Bacterial
*This chapter is an updated and edited version of the chapter by Robin E. Miller and Michael L. Nieder that appeared in the first edition.
Continued
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896
Section Eight Hematologic Disorders
Table 49-1. Childhood Neck Masses Associated with
Cervical Regions*—cont’d Suprasternal Lymphatic malformation Thyroid goiter Thyroid nodule Cystic Solid Papillary carcinoma Medullary carcinoma Hemangioma Neurofibromatosis Supraclavicular Lymphatic malformation Neuroblastoma Vascular malformation Posterior Cervical Triangle Lymphadenitis Viral Bacterial Abscess Lymphatic malformation Cat-scratch disease Neurofibromatosis Midsternocleidomastoid Second branchial cleft anomaly Fibromatosis colli Fourth branchial cleft anomaly
Figure 49-1. Regions of the head and neck. 1, submental; 2, submandibular; 3, jugulodigastric; 4, preauricular; 5, postauricular; 6, hyoid; 7, suprasternal; 8, supraclavicular; 9, posterior cervical triangle; 10, midsternocleidomastoid. (See Table 49-1 for neck masses associated with each region.)
*In decreasing frequency (see Fig. 49-1 for location of each region).
The character and duration of any prodromal illness is important because most childhood neck masses are usually inflammatory from local head and neck lesions, or they may be part of a more generalized illness. A history of localized pain, dysphagia, or swelling in the head and neck region and systemic manifestations of fever, cough, rash, or gastrointestinal symptoms need to be evaluated. Viral and bacterial upper aerodigestive diseases are a common source of cervical lymphadenopathy and lymphadenitis. Lymph node enlargement is the appropriate response to these infections, but a change in the size or character of the nodes, musculoskeletal symptoms, or new aerodigestive symptoms may signal a secondary complication involving the cervical nodes. The rapid onset of an inflammatory mass in an otherwise previously healthy child may result from the secondary infection of a preexisting congenital lesion. Sometimes there is a history of a fullness, dimple, or small mass; these signs may be subtle or nonexistent. Congenital lesions such as hemangioma, lymphatic and vascular malformations, and branchial cleft anomalies may not become evident until infected. The rapid progression is surprising and draws immediate attention to the area. A history of exposure to animals provides important information regarding tularemia, cat-scratch disease and some mycobacterial diseases. A history of travel to a developing nation may be suggestive of tuberculous cervical lymphadenitis. Ethnic heritage is important in the diagnosis of Kimura disease, and a family history of similar neck masses is invaluable for diagnosis of some syndromes. A history of high fever suggests an inflammatory (autoimmune, reactive lymphadenopathy) or infectious origin. Malignancy or a granulomatous process should be considered when fever is accompanied by constitutional symptoms such as night sweats and weight loss. In general, slowly enlarging lesions are more likely to be benign.
Masses that are painless and that enlarge very rapidly are suggestive of malignancy, whereas masses associated with infections are sometimes quite painful. Presence of the mass since birth, a prior lesion in a similar position, or a finding of chronic drainage from the region is indicative of congenital cysts or clefts. Recent upper respiratory illnesses (otitis, tonsillitis, pharyngitis) should be noted, as should any recent trauma or other infection in the head and neck region. A dental history can be particularly revealing because toothaches, bleeding gums, prior dental problems, and mouth trauma, with resultant odontogenic abscesses, are often associated with cervical lymphadenopathy. Information regarding all relevant exposures to illness, including tuberculosis contacts and travel history, must be sought. The patient and family should be queried about pertinent risk factors for human immunodeficiency virus such as intravenous drug abuse, high-risk sexual activity, and previous transfusions. Contact with cats, which serve as vectors for both cat-scratch disease and toxoplasmosis, should be identified. A history of pica could also be linked with toxoplasmosis. A detailed review of systems can be extremely helpful. Symptoms such as palpitations, heat intolerance, or weight loss should be noted, because hyperthyroidism can result not only in midline goiter but also in lymphadenopathy (Table 49-2). Similarly, manifestations of hypothyroidism should be noted (Table 49-3). The age-related causes of hypothyroidism are noted in Table 49-4. Symptoms associated with connective tissue disease (rashes, joint pain, and stiffness) are important to consider. Symptoms indicating extrinsic compression of the trachea, esophagus, or recurrent laryngeal nerve (vocal cord paralysis) must be identified, because progression of the mass could result in life-threatening airway compromise. In addition to pain, such symptoms might include dyspnea, orthopnea, dysphagia, or stridor. Other serious conditions associated with neck masses include the various types of immunodeficiency syndromes. It is important
Chapter 49 Neck Masses in Childhood
897
Table 49-2. Clinical Manifestations of Hyperthyroidism
Table 49-3. Symptoms and Signs of Hypothyroidism*
Increased catecholamine effects
Ectodermal
Hypermetabolism
Myopathy Miscellaneous
Nervousness Palpitations Tachycardia Atrial arrhythmias Systolic hypertension (wide pulse pressure) Tremor Brisk reflexes Hyperdynamic precordium Increased sweating Shiny, warm, smooth skin Heat intolerance Fatigue Weight loss with increased appetite Increased bowel movement (hyperdefecation) Weakness Periodic paralysis Cardiac failure, dyspnea Proptosis, stare, exophthalmos, lid lag Hair loss Inability to concentrate Personality change (emotional lability) Goiter Thyroid bruit Onycholysis Acute thyroid storm (hyperpyrexia, tachycardia, coma, high-output heart failure, shock)
From Styne DM, Sperling MA, Chernausek SP: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 632.
Circulatory
Neuromuscular
Metabolic
Poor growth Dull facies: thick pale lips, large tongue, depressed nasal bridge, periorbital edema Dry, scaly skin Sparse, brittle hair Diminished sweating Carotenemia Vitiligo Sinus bradycardia/heart block Cold extremities Cold intolerance Pallor ECG changes: low-voltage QRS complex Muscle weakness Hypotonia with constipation, potbelly Myxedema coma (CO2 narcosis, hypothermia) Pseudohypertrophy of muscles Myalgia Physical and mental lethargy Delayed relaxation of reflexes Paresthesia (nerve entrapment: carpal tunnel syndrome) Umbilical hernia Hearing loss Cerebellar ataxia Myxedema (tongue, face, extremities) Serous effusions (pleural, pericardial, ascites) Hoarse voice (cry) Weight gain (in adolescent) Menstrual irregularity Arthralgia Elevated CPK Macrocytosis (anemia)
From Styne DM, Sperling MA, Chernausek SP: Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders, 1994, p 631. *Other features in infants and children: delayed bone maturation; long bone growth delay and epiphyseal dysgenesis; delayed dentition; elevated cholesterol; elevated prolactin; and, occasionally, “precocious puberty.”
to obtain a history of recurrent infections (thrush, sinopulmonary infections, cellulitis, recurrent cutaneous abscesses). A mass that becomes more painful with eating (and with associated dry mouth [xerostomia]), although found not only in patients with immunodeficiencies or autoimmune disorders, could represent infection of a salivary gland.
infection of that tissue. In children, extension of a mass to adjacent structures occurs infrequently.
PHYSICAL EXAMINATION
DIAGNOSTIC TESTING
The majority of pediatric cervical adenopathies can be examined adequately by examination and palpation during the standard examination. If the physical examination is limited, full palpation and inspection may not be possible without sedation or a general anesthesia. Persistence or returning at another time can be successful with some uncooperative children. When a child is cooperative, there are two intraoral techniques that are useful for an improved delineation of cervical masses: inspection (and palpation) of Waldeyer’s ring and the bimanual palpation of the floor of the mouth. Anatomic location gives a great deal of useful information about the causes of masses (see Table 49-1 and Fig. 49-1). As a rule, masses arise from tissue that is native to their location. Rests of ectopic tissue or metastases are rare. Moreover, a mass firmly fixed to an organ or structure is most likely to result from a neoplasm or
For any unusual case, discussion with the radiologist before diagnostic imaging provides better information to answer the clinician’s questions. The radiologist can offer the best imaging modality for the patient’s clinical situation, as well as focus the imaging technique to the likely pathologic process and reduce the procedure’s duration. Computed tomographic (CT) scans are generally faster and thus less likely to require sedation for the child. CT scans are generally better in assessing bone involvement. Magnetic resonance imaging (MRI) is particularly good at assessing soft tissue involvement. However, MRI is more difficult because of the longer scanning duration, the physical constraints of the magnet, and the noise, all of which increase the apprehension of children. Experienced pediatric radiology and anesthesia staff can routinely overcome the obstacles associated with MRI.
CPK, creatine phosphokinase; ECG, electrocardiogram.
Section Eight Hematologic Disorders
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Table 49-4. Causes of Hypothyroidism in Infancy and Childhood Age
Manifestation
Newborn
No goiter Goiter
1-10 yr
No goiter Goiter
10-18 yr
No goiter Goiter
Cause
Thyroid gland dysgenesis,* panhypopituitarism, TSH deficiency, TSH unresponsiveness Inborn defect in hormone synthesis (iodine trapping defect, iodine organification defect [peroxidase deficiency: Pendred syndrome], iodotyrosine deiodination defect, thyroglobulin synthesis defect) Maternal goitrogens, including propylthiouracil, methimazole, iodides, amiodarone, radioiodine Severe iodide deficiency (endemic) Thyroid gland dysgenesis, TSH deficiency, TSH unresponsiveness Cystinosis Hypothalamic-pituitary insufficiency Inborn defect in hormone synthesis or effect Hashimoto thyroiditis: chronic lymphocytic thyroiditis* Goitrogenic drugs Endemic cretinism (iodine deficiency) Hypothalamic-pituitary disorders (neoplasms, eosinophilic granuloma, other granulomatous processes, therapeutic CNS irradiation, idiopathic) Hashimoto thyroiditis* Inborn defect in hormone synthesis or effect Goitrogenic drugs (lithium, amiodarone, foods) Surgical after thyrotoxicosis or thyroglossal duct cysts
*Most common for age group indicated. CNS, central nervous system; TSH, thyroid-stimulating hormone.
BENIGN NECK MASSES ACUTE INFLAMMATORY/ INFECTIOUS CERVICAL MASSES The most common benign neck mass is lymphadenopathy associated with a viral upper respiratory tract infection (see Chapter 47). Secondary bacterial lymphadenitis also commonly occurs after a viral infection. The area of primary infection determines which nodes are involved. The posterior cervical nodes are the primary nodes for the nose and nasopharynx. The oropharynx drains to the jugulodigastric nodes, medial and anterior to the superior sternocleidomastoid muscle. The posterior nasopharynx and oropharynx also drain to the retropharyngeal and parapharyngeal spaces. The anterior medial perioral area drains to the submental nodes, and the lateral perioral and intraoral areas drain to the submandibular spaces (see Table 49-1 and Fig. 49-1). The parapharyngeal space, the deep cervical fascial space, is the least understood site of cervical lymphadenopathy. Deeply situated in the neck, it is not easily examined by visual inspection or palpation. It contains multiple lymph nodes, important vascular structures (the internal carotid artery and internal jugular vein), and important nervous structures (vagus, glossopharyngeal and hypoglossal nerves, sympathetic chain). The parapharyngeal space drains lymph from the lateral skull base, from as far laterally as the external auditory canal and as far medially as the nasopharynx. Its medial wall drains from the adenoids superiorly to the tonsils inferiorly. Inflammatory or neoplastic processes may cause lymphadenopathy in this space. The tonsil on the affected side can be deviated medially by the mass effect in a parapharyngeal space. Manifesting with jugulodigastric nodes, fullness, or a mass in the region of the parotid tail, parapharyngeal space infections are usually rather extensive before they are identified. The retropharyngeal space is a potential outpouching of the parapharyngeal space, which may cause the posterior pharyngeal wall to bulge on the affected side. A swelling or an abscess in the retropharyngeal space cannot extend beyond the midline because of the median raphe. Moreover, the retropharyngeal space extends inferiorly to the mediastinum; therefore, infection in this space can progress to mediastinitis.
Viral and Bacterial Lymphadenitis In viral lymphadenitis, a concurrent upper respiratory illness is usually present. The nodes reliably enlarge in the jugulodigastric and posterior cervical locations. The lymphadenitis usually produces only mild local inflammatory signs and is treated with symptomatic support, observation, and parental reassurance. Bacterial lymphadenitis commonly occurs after a viral upper respiratory infection or a bacterial infection of the primary drainage site of these nodes. Bacterial lymphadenitis is recognized by the pronounced inflammation that it produces. Tenderness to palpation and severe overlying cellulitis are its hallmarks. The nodes are commonly in the superficial cervical fascial spaces. Early treatment with oral antibiotics during the cellulitic stage of lymphadenitis may prevent progression to severe cellulitis or abscess. Progressive local inflammation may signal abscess formation. Pointing—local skin erythema with fullness and subsequent necrosis with underlying softening and fluctuance—is a sign for incision and drainage of the involved nodes. Isolated superficial node abscess may still be treated on an outpatient basis after incision and drainage. An infection with multiple nodal sites involved, severe systemic signs of infection, or deep cervical involvement warrants hospitalization and treatment with intravenous antibiotics. The presence of severe systemic signs or generalized cervical inflammation calls for early imaging. If the child has respiratory distress, tracheal deviation, or submandibular fullness with tongue elevation, emergency airway management may be necessary. If severe symptoms are not present, a 24-hour trial of intravenous antibiotic is appropriate. If fever or systemic or local inflammatory signs do not respond within 24 hours, CT imaging with contrast material is useful for evaluating the extent of involvement and establishing the presence of abscesses. Early consultation with the pediatric head and neck surgeon is essential. Deep cervical infections and parapharyngeal space infections are relatively frequent but are not as easily identified on examination. Fullness and inflammation in the retromandibular area in association with jugulodigastric nodes and fullness of the affected tonsil without inflammation are signs of a parapharyngeal space infection. Torticollis or avoidance of neck rotation may be suggestive of isolated or combined retropharyngeal space involvement. CT imaging is not sensitive enough to distinguish between nodes with small abscesses
Chapter 49 Neck Masses in Childhood and nodes with cellulitis or necrosis. A pediatric head and neck surgeon may help prevent fruitless surgery in this instance. Mycobacterial Lymphadenitis The most common mycobacterial cervical lymphadenitis is the atypical tuberculosis, resulting from either Mycobacterium avium or Mycobacterium intracellulare infection. Atypical mycobacterial disease usually manifests as an asymptomatic unilateral mass located anywhere from the preauricular area extending through the tail of the parotid to the submaxillary space. This area overlies the facial nerve trunk and its branches. These nodes are usually painless, nontender, and without warmth. Systemic signs of inflammation are usually absent. The infection begins with an increase in the size of the superficial nodes, followed by pointing until they adhere to the overlying skin. The skin becomes erythematous, and painless necrosis results in a draining fistula. The fistula itself may drain for many months before the infection burns out. On occasion, several nodes may enlarge, sometimes in different nodal areas. Individual nodes may progress through the stages of inflammation, necrosis, and fistula at varying rates. Evaluation by imaging techniques is not generally useful, because the nodes are usually superficial and readily palpable. Imaging should be used if the masses do not follow the typical natural history or if other symptoms develop. Tuberculin skin testing is positive about 50% of the time. The diagnosis is usually made by biopsy, because cultures do not reliably demonstrate the organisms. Secondary infection by opportunist bacterial organisms may obfuscate the primary infectious cause. A mycobacterial RNA reverse transcriptase in situ polymerase chain reaction test to detect mycobacterial RNA in excised tissue may improve diagnosis when commercially available. Cervical tuberculous lymphadenitis is rare in the United States but is still seen in developing countries. Any bilateral chronic lymphadenitis should be evaluated for cervical tuberculous lymphadenitis with tuberculin skin testing and a chest radiograph. Cat-Scratch Disease The usual manifestation of cat-scratch disease is a nontender papule that occurs 3 to 10 days after inoculation of the pathogen. There may be a history of scratches by or exposure to flea-infested kittens, which are the major reservoir of Bartonella henselae. Two weeks later, the papule develops, and regional lymph nodes become enlarged. Available diagnostic testing includes indirect fluorescent antibody assay and enzyme immunoassay. Nodal aspiration specimens can be sent for polymerase chain reaction for B. henselae bacilli. Diagnostic imaging by CT scan or MRI may be useful for determining the extent of lymphadenopathy. Biopsies should be sent for Warthin-Starry staining. Although antibiotic treatment with macrolides is effective in immunocompromised patients, treatment is not thought to shorten the clinical course in immunocompetent children. However, surgical curettage of the necrotizing granulomas seems to shorten the duration of individual draining fistulas without the risks of extensive dissection in an inflamed neck. NECK MASSES IN PATIENTS UNDERGOING BONE MARROW TRANSPLANTATION OR CHEMOTHERAPY A new neck mass in a child undergoing chemotherapy or bone marrow transplantation is a major concern. Extension or recurrence of the primary malignancy, presence of an infection, or development of a lymphoproliferative disorder may alter the patient’s prognosis and therapy; early diagnosis is essential. Early imaging evaluation by CT scan or MRI is useful for determining the extent of the mass and/or the nodal involvement. In immunocompromised patients,
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infections may manifest without the usual inflammatory signs and symptoms. Bone marrow, lung, and visceral transplant recipients are at risk for Epstein-Barr virus infection, which causes post-transplantation lymphoproliferative disorder. This disorder has a high mortality rate, approaching 30% in some series. Cervical lymphadenopathy may be the presenting symptom, but tonsillar, adenoidal, and pharyngeal symptoms (i.e., sore throat, exudative tonsillitis, and airway obstruction) are uniformly present. Diagnosis is made by cervical node biopsy or tonsillectomy, with or without adenoidectomy. Adenotonsillectomy to relieve airway symptoms and discomfort can also provide a histologic diagnosis. Prompt recognition may enhance treatment with a combination of immunosuppression reduction, antiviral therapy, and, in resistant cases, chemotherapy. KIMURA DISEASE Asymptomatic, unilateral chronic cervical lymphadenopathy in Asian boys is suspect for Kimura disease. This benign condition is characterized by peripheral eosinophilia and elevated immunoglobulin E levels. Biopsies should be performed to rule out malignancy. Histologic specimens show a massive eosinophilic infiltration of the nodal architecture. This benign condition necessitates no therapy unless the adenopathy creates functional disability.
CONGENITAL MASSES THYROGLOSSAL DUCT CYSTS A midline neck mass between the submental area and the cricoid is suspect for a thyroglossal duct (TGD) cyst (Figs. 49-2 and 49-3). The incidence of TGD cysts is highest during the second decade of life, but they may appear from infancy to adulthood. These masses usually have a gradual onset with slow growth and rarely regress or resolve spontaneously. TGD cysts may also manifest with acute onset of infection or abscess. In these cases, drainage and culture for aerobic, anaerobic, and mycobacterial organisms are suggested. Empirical treatment for gram-positive skin pathogens is suggested until the culture results are available. A draining sinus often results from an infected TGD cyst. The differential diagnosis for midline neck masses includes anterior hyoid lymph nodes and dermoid cysts. Anterior hyoid lymph nodes frequently have a source of the inflammation that drains to those nodes (acne of the anterior chin). These lymph nodes resolve after the inciting infection or inflammatory process resolves. Dermoid cysts are uncommon and do not vary in size. Often the exact nature of the lesion is not known until the time of surgical excision. Diagnostic imaging is controversial. Thyroid scan or ultrasonography to document the existence of normal thyroid tissue is advocated by some authorities. Very rare instances of surgical excision of a TGD cyst have resulted in permanent hypothyroidism. Surgical excision is the treatment of choice. Excision of the TGD cyst prevents the risk of infection and eliminates the rare occurrence of thyroid malignancy with the cyst. Infected TGD cysts should be treated with appropriate antibiotics before excision. Preoperative infections are highly likely to recur, resulting in further scarring and making resection more difficult and extensive. Infrequent recurrences may complicate an appropriately performed excision. Repeated wide local resection is then advocated in this situation. BRANCHIAL CLEFT ANOMALIES Branchial cleft anomalies may appear at any age from the neonatal period to adulthood. These masses are usually in the area anterior and medial to the sternocleidomastoid muscles. Although these
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A B C D Figure 49-3. Thyroglossal duct cyst (arrow) located in the midline of the neck. (From Lusk RP: Neck masses. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 2nd ed, vol 2. Philadelphia, WB Saunders, 1990, p 1298.)
E
F Figure 49-2. Thyroglossal duct cysts. These cysts can be located anywhere from the base of the tongue to behind the sternum. A and B, lingual (rare); C and D, adjacent to hyoid bone (common); E and F, suprasternal fossa (rare). (From Welch K, Randolph JG, Ravitch MM, et al: Pediatric Surgery. Chicago, Year Book Medical Publishers, 1986, p 549.)
anomalies are usually unilateral, second branchial cleft sinus or cysts are occasionally bilateral (Fig. 49-4). First branchial cleft anomalies manifest with a sinus tract anterior or inferior to the lobule of the ear. Sometimes this tract extends as far anteriorly as the midportion of the mandible. These tracts usually end near the external auditory canal; they are thought to represent a duplication of the external auditory canal. They may have a fistulous opening in the cartilaginous canal or end blindly on the bony canal. A radiographic sinogram is not recommended as a routine evaluation because of the increased infection risk. Any sinus tract infection has the potential for facial nerve damage or paresis because the sinus tract is intimately intertwined with the facial nerve. Surgery is the treatment of choice. Second branchial cleft anomalies may manifest as asymptomatic pits, soft cysts, inflamed masses, or draining sinuses. Sinuses may drain small amounts of mucous with upper respiratory infections or may drain regularly. Once infected, recurrent infections of the mass or sinus are the rule, because sterilization of this space is unlikely to occur. When second branchial cleft anomalies are associated with familial hearing loss, preauricular pits, and ocular findings, a diagnosis of branchial-oto-renal syndrome is probable. This autosomal dominant disorder has variable penetrance; therefore, not all the syndrome components may be present in each family member. Genetic testing is available.
Second branchial cleft anomalies are uniformly located at the anterior border of the middle third of the sternocleidomastoid muscle (Fig. 49-5). The diagnosis is usually made on clinical grounds. The use of imaging modalities is rarely beneficial. Imaging can be very helpful when the anomaly is infected or is in an unusual anatomic location (Fig. 49-6). Sinograms are rarely beneficial and are invasive, and sedation or general anesthesia may be needed to obtain them. There is a risk of causing a new infection of the sinus tract, and dye may not reliably delineate the full extent of any tract. The natural history of these lesions is to remain or grow until they are surgically excised. Unless a lesion is symptomatic, surgical excision is best deferred until an infant is at least 6 months of age. Delaying treatment of asymptomatic stable branchial cleft anomalies is reasonable, but intermittent examinations are prudent. A child with a minimally draining sinus may defer treatment until 5 years of age. However, growing cystic lesions and previously infected lesions are best expeditiously excised. The occurrence of squamous cell carcinoma in branchial cleft anomalies is very controversial and is not thought to be grounds for immediate excision. Recurrence rates of second branchial cleft anomalies are very low when the anomalies are completely excised. In all cases, the cyst should be excised with the entire tract to reduce the risk of recurrence. Fourth branchial cleft anomalies are much less common. Manifesting occasionally as a lower cervical sinus, more often as a mass or cyst, and frequently as an acutely inflamed mass over the lateral thyroid, these lesions are more of a diagnostic challenge. Fourth branchial cleft anomalies have a high predilection for being left-sided. They may be confused with thyroid masses, lymphatic malformations, or second branchial cleft anomalies or confused with abscessed cervical nodes when infected. Involvement of the thyroid with abscess formation is very common and almost diagnostic. The natural history of these lesions is to persist; a draining sinus or recurrent inflammatory masses often develop until surgical excision is completed. Diagnostic imaging by ultrasonography, CT scan with contrast material, or MRI imaging can be very informative. A discussion with the radiologist before ordering imaging can provide the most efficient use of these procedures, but multiple imaging
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1st branchial groove 2nd branchial arch
Branchial arches 1 2 3 4
A
Pouch 1 Pouch 2 Pouch 3
2nd, cervical 3rd sinus and 4th branchial grooves B
Cervical sinus
Pouch 4 Pouch 5
Esophagus
Tonsillar fossa Sites of former openings of pharyngeal pouches Skin of neck
Tonsil
2 3
Internal branchial sinus
Pouch 2 Pouch 3
Pharynx Hyoid
External branchial sinus
Larynx
D C
Area where auricular pits are commonly found
Common carotid artery Tonsil
Internal opening
Pharynx Hyoid
E
Very rare type of internal branchial sinus
Figure 49-4. A, The head and neck region of a 5-week embryo. B, Horizontal section through the embryo illustrating the relationship of the cervical sinus to the branchial arches and pharyngeal pouches. C, The adult neck region, indicating the former sites of openings of the cervical sinus and the pharyngeal pouches. The broken lines indicate possible courses of branchial fistulas. D, The embryologic basis of various types of branchial sinuses. E, A branchial fistula resulting from persistence of parts of the second branchial cleft and the second pharyngeal pouch. F, Possible sites of branchial cysts and openings of branchial sinuses and fistulas. A branchial vestige is also illustrated. (From Moore KL: The Developing Human: Clinically Oriented Embryology. Philadelphia, WB Saunders, 1977.)
Sternocleidomastoid muscle Palatine tonsil Usual internal opening of fistula or sinus Branchial cyst Usual external opening of fistula clavicle or sinus
branchial vestige
F
techniques may be necessary. Direct laryngoscopy often reveals a sinus originating in the pyriform sinus and is diagnostic. VASCULAR LESIONS Vascular lesions are a common cause of pediatric head and neck masses. They manifest as soft to firm, nontender masses that may be present at birth or may evolve gradually. Expansion to adjacent sites or multiple sites is common; lesions may involve not just the deep cervical organs but also the head or thorax. Airway symptoms or dysphagia necessitates evaluation for extension to the oropharynx, hypopharynx, and larynx or for secondary lesions in those areas. Vascular lesions have been classified as vascular tumors (including hemangiomas) and vascular malformations such as capillary malformations, arterial and venous malformations, and lymphatic malformations. Vascular tumors are not present at birth but grow rapidly, whereas vascular malformations are present at birth and grow gradually at the same rate as the affected patient. Suspected vascular lesions can be evaluated with ultrasonography, which can distinguish
vascular tumors from vascular malformations and lymphatic malformations. Although ultrasonography is useful for determining the character of the lesions, CT scan is useful for determining the extent of the lesions before treatment. MRI and magnetic resonance angiography are additionally useful for determining extent of the lesion. Hemangioma Hemangiomas manifest as firm, doughy masses, most frequently in the parotid area. They are compressible, but slow, constant pressure may be necessary to compress them. Hemangiomas occur three times more frequently in girls than in boys and grow rapidly over the first several months of life. A quiescent period follows, sometimes for years, and then involution usually begins. About 30% of hemangiomas involute by 3 years of age; 50% by 5 years; and 80% to 90% by 10 years. Some residual evidence of the lesion, such as thinning of the skin or subcutaneous fat, hypopigmentation, or scarring, usually remains. Severe or “malignant” hemangiomas, which threaten life or organ function, rarely occur as isolated cervical masses but appear more
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commonly in the face. Recurrent bleeding may occur with ulceration of a superficial cervical hemangioma. Corticosteroid therapy (prednisone) in the dose range of 2 to 3 mg/kg/day may be remedial for these lesions. Symptomatic cervical hemangiomas that fail to involute may be surgically excised, sometimes preceded by embolization. Additional therapies such as recombinant interferons alfa-2a and alfa-2b and interstitial neodymium:yttrium-aluminumgarnet photocoagulation are in the early stages of investigation. Flashlamp-pulsed dye lasers are effective for superficial cutaneous vascular lesions. Stridor may signal another site of hemangioma, particularly of the subglottis. Evaluation by lateral soft tissue radiograph or by laryngoscopy is diagnostic. Vascular Malformations Vascular malformations may be categorized as low-flow lesions, such as venous and capillary lesions, and high-flow lesions, such as arteriovenous and arterial malformation. Treatment for high-flow lesions is usually embolization and excision. Low-flow malformations may be sclerosed, and subsequent excision may be necessary. Superficial cutaneous lesions and capillary malformations such as port wine stains respond well to flashlamp-pulsed dye laser therapy. Lymphatic Malformations Lymphatic malformations manifest as soft masses anywhere in the neck but most frequently in the submandibular triangle. These lesions are not usually tender but can be very painful when inflamed. The extent of cervical involvement varies greatly. Transillumination of the mass, although not diagnostic, sometimes provides differentiation
Figure 49-5. Branchial cleft cyst (arrow) along the anterior border of the sternocleidomastoid muscle. (From Lusk RP: Neck masses. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 2nd ed, vol 2. Philadelphia, WB Saunders, 1990, p 1298.)
A
B
Figure 49-6. A, The longitudinal coronal sonogram of a 2-week-old boy with a nontender left-sided neck mass (arrows) that is uniformly hypoechoic with good through transmission. B, The computed tomographic scan reveals low attenuation of the mass anteromedial to the carotid (arrowhead) sheath. The trachea and the esophagus are displaced to the right. The epicenter of this branchial cleft cyst is inferior to the left lobe of the thyroid gland (arrow), which is elevated and displaced to the right. (From Lima JA, Graviss ER: Methods of examination. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 2nd ed, vol 2. Philadelphia, WB Saunders, 1990, p 1290.)
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Figure 49-7. Lymphangioma of neck in a 2-week-old patient. (From Clary RA, Lusk RP: Neck masses. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 3rd ed, vol 2. Philadelphia, WB Saunders, 1996, p 1494.)
from other vascular masses. Transillumination involves placing a light source on the mass in a darkened room; when positive, the entire mass seems to glow. Lymphatic malformations do not have readily discernible margins because they are extensions of the normal lymphatic vessel anatomy (Fig. 49-7). The lymph vessels extend from muscles, organs, and nerves that form the lymphatic mass. Currently, these lymphatic malformations are described as macrocystic if individual cystic spaces are larger than 1 cm in diameter or as microcystic if the spaces are smaller than 1 cm. Cervical lymphatic malformations with very large cystic spaces are sometimes called cystic hygromas. MRI is the best imaging method for determining the type and extent of malformations (Fig. 49-8). The natural history of lymphatic malformations is to grow slowly at the same rate as the surrounding tissues. Spontaneous regression is very rare. Infections may cause a previously asymptomatic cervical malformation to rapidly increase in size, causing severe airway compromise or dysphagia. Antibiotic coverage for the infection, corticosteroids, and careful observation in a critical care unit may be necessary, especially for neonates. Benefits of surgical excision or sclerosis must be weighed against the risks of injury to the surrounding tissues. The resulting functional deficit may outweigh the benefits of surgical excision. Even after a successful surgical excision, surrounding smaller but abnormal and unrecognized lymphatic vessels can expand because of rerouting in the lymphatic flow. Within hours after near complete excision, the malformation can permanently or temporarily blossom to presurgical magnitude. A staging system by de Serres and colleagues based on anatomic infrahyoid or suprahyoid disease was found to correlate with efficacy of excision and complications. Rates of complications, including cranial nerve injury, wound infection, seroma formation, malocclusion, speech delay, cosmetic deformity, and persistent disease, ranged from 17% in stage I disease to 100% in stage V disease. OK432, a lyophilized low-virulence Su strain of group A Streptococcus, offers an improvement in sclerosis therapy with little damage to surrounding tissues. It is less effective with microcystic lesions, with lesions with massive craniofacial involvement, and in cases with previous surgery. Therapeutic trials are currently under way and seem promising.
Figure 49-8. Magnetic resonance imaging clearly delineates the extent of the lymphangioma of the patient in Figure 49-7. Arrows mark the borders of the lymphangioma. (From Clary RA, Lusk RP: Neck masses. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 3rd ed, vol 2. Philadelphia, WB Saunders, 1996, p 1494.)
SALIVARY MASSES Inflammatory Acute sialadenitis is rarely seen today because of mumps vaccination. When it is seen, it usually manifests with severe pain and inflammation of the parotid or submandibular glands. Acute bacterial sialadenitis (acute suppurative parotitis) is usually a complication of dehydration caused by another illness. Clinical diagnosis can be made from the localized inflammation, but bacterial culture from the affected salivary duct is confirmatory. Milking the tender affected gland can express purulent drainage for intraoral collection. Staphylococcus aureus is the most common pathogen. Treatment involves hydration, antibiotics, and sialagogues to increase salivary flow. Chronic and recurrent sialadenitis in children is now more common than acute sialadenitis. The parotid gland is the most common site, and the disorder manifests with minimal inflammation and diffuse or localized parotid gland enlargement. Imaging by sialography is not necessary for diagnosis and increases the risk of an acute infection. Culture-directed intravenous antibiotic therapy has been effective against both chronic and recurrent parotitis. If the condition is chronically symptomatic with acute exacerbations, a superficial parotidectomy may be necessary. Noninflammatory Ranulas are mucoceles of the sublingual salivary gland. Appearing in the anterior submandibular space, the mass has ill-defined edges and is best evaluated by intraoral inspection and bimanual palpation. The clinician does this with one hand palpating the floor of the patient’s mouth while simultaneously the other hand palpates the patient’s
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submandibular space. Imaging with CT scan or MRI can be helpful, but differentiating a ranula from macrocystic lymphatic malformations can still be difficult. Bilateral submandibular gland enlargement may result from cystic fibrosis or Sjögren’s syndrome. Unilateral enlargement always raises the possibility of a neoplasm. A salivary mass is more likely to be a carcinoma in a child than in an adult. Fifty-nine percent of salivary masses are hemangiomas, 28% are lymphangioma, and 13% are salivary neoplasms. The incidence of salivary neoplasm is increased by childhood radiation treatment for adenotonsillar hypertrophy. If the presence of hemangioma or lymphatic malformation is unclear, ultrasonography is the most efficient method of differentiating these lesions. Other imaging modalities can be useful if delineation of the lesion’s magnitude is of concern. If a malignancy is suspected, fine-needle aspiration may be performed during a CT scan. A questionable or negative result of fine-needle aspiration does not preclude surgical biopsy. The presence of an asymptomatic solid solitary mass in any of the major or minor salivary glands is very suspect for malignancy. Most of these malignancies occur in later childhood or adolescence, and the parotid gland is the most common site. The most common manifestation of a salivary neoplasm is a rapidly growing mass in the preauricular or infra-auricular area. If a parotid salivary neoplasm is suspected, the biopsy of choice is a superficial parotidectomy with facial nerve dissection. This provides an appropriate excisional specimen with margins that carries less risk for facial nerve paralysis. MYOFIBROMATOSIS Fibromatosis colli is common in neonates. Manifesting as smooth, oval, and nontender masses, they involve the middle third of the sternocleidomastoid muscle. The fibrosis can shorten the sternocleidomastoid muscle and cause torticollis. In rare cases, fibromatosis colli is associated with plagiocephaly or craniofacial anomalies. Therapy consists of passive range-of-motion exercises stretching the sternocleidomastoid muscle. Parents can often perform the therapy; a physical therapist may be necessary in severe cases. Imaging with ultrasonography or with CT scan may be diagnostic but is rarely necessary. Consultation with a surgeon is warranted if the mass is not limited to the sternocleidomastoid muscle, is enlarging, or is inflamed. PILOMATRIXOMA Pilomatrixoma, formerly called calcifying epithelium of Malherbe, occurs most commonly in the head and neck of children younger than 2 years. It is a benign growth of the hair cortex cells or the hair follicle of the sebaceous glands, and it manifests as a hard mass attached to the skin, the bulk of the mass being subcutaneous. Usually it is a solitary lesion, but there may be other noncontiguous or secondary lesions. The subcutaneous portion of the mass is mobile and is blue or blue-black mixed with white areas. The mass is frequently misidentified as a hemangioma because of its blue color. It grows slowly until excised. If infected, it drains, and recurrent infections commonly develop until it is excised. Surgical excision with conservation of the surrounding tissue is the treatment of choice, and recurrences are infrequent. THYROID MASSES For a patient with a thyroid mass, the clinician must ask questions regarding symptoms of hypothyroidism or hyperthyroidism (see Tables 49-2 and 49-3). If there is a history of radiotherapy to the neck or a family history of endocrine tumors, a solitary mass is highly suspect for carcinoma. Multiple endocrine neoplasia type 2 is an autosomal dominant or, in rare cases, a sporadic disease in which patients develop medullary carcinoma of the thyroid. A careful
Figure 49-9. Palpation of the thyroid gland. The examiner stands behind the patient. A slight retraction of the sternocleidomastoid muscle away from the midline with one of the examiner’s hands permits the examiner’s other hand to outline the surface of the lobe. (From Lima JA, Graviss ER: Methods of examination. In Bluestone CD, Stool SE [eds]: Pediatric Otolaryngology, 2nd ed, vol 2. Philadelphia, WB Saunders, 1990, p 1284.)
family history of primary hyperparathyroidism can delineate the autosomal dominant or recessive types and is important for determining prognosis. In a careful physical examination, the clinician attempts to differentiate diffuse goiter from solitary or multiple nodules (Fig. 49-9). Thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone are tested to evaluate thyroid function in patients with diffuse goiters (Table 49-5). Results of these tests are routinely normal in thyroid malignancies. If a solitary mass is present, then ultrasound evaluation determines whether the lesion is cystic or solid. Cystic masses can be aspirated during the ultrasound study and sent for cytologic evaluation. Radionucleotide scanning determines the presence of hyperfunctioning (“hot”) nodules or hypofunctioning (“cold”) nodules. Cold nodules are very suspect for malignancy. The prevalence of carcinoma in solitary thyroid nodules is 15% to 40%; therefore, biopsy must be definitive. The use of surgical biopsy, by hemithyroidectomy, is generally recommended over fine-needle aspiration biopsy.
MALIGNANT NECK MASSES Approximately 25% of pediatric malignancies involve the head and neck. However, unlike adult cervical malignancies, the majority of these do not originate in the head or neck. Mesenchymal derivatives make up 90% of pediatric cervical malignancies. LYMPHOMA Lymphomas are the third most common pediatric malignancy, constituting 12% of new pediatric tumors annually. The manifestation is typically that of a chronic lymphadenopathy with minimal local symptoms. Hodgkin lymphomas in children most typically manifest as asymptomatic masses involving the cervical or supraclavicular nodes. Less frequently, axillary or inguinal nodes are the presenting symptom; subdiaphragmatic disease is rare. Biopsy of the mass is suggested. Staging is also modified by the presence of preoperative fevers, night sweats, and weight loss. The presence of these symptoms significantly worsens the prognosis.
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Table 49-5. Laboratory Test Results in Various Types of Thyroid Function Abnormalities in Children Serum Total T4
Free T4
Serum TSH
↓
↓
↑
↓
N
↓
↓
N
↓
N
↓
↓
N
↓
N
↓ ↑
N Ν
N Ν
↑ ↓
↓ ↑
Primary hypothyroidism Hypothalamic (TRH) hypothyroidism Pituitary (TSH) hypothyroidism TBG deficiency TBG excess
Serum T3 Resin Uptake
Serum TBG
From Endocrine disorders. In Behrman RE, Kliegman RM (eds): Nelson Essentials of Pediatrics, 2nd ed. Philadelphia, WB Saunders. 1994, p 629. T3, triiodothyronine; T4, thyroxine; TBG, thyroxine-binding globulin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. ↓, decreased; ↑, increased; N = normal.
Pediatric non-Hodgkin lymphomas are diffuse, aggressive, and frequently widespread at initial diagnosis. Non-Hodgkin lymphomas make up 60% of pediatric lymphomas and generally occur as abdominal or thoracic masses. In Africa and the Middle East, Burkitt lymphomas are most frequent and seem to have a different natural history than in the United States and Europe. Endemic lymphomas frequently occur in the mandibular or oropharyngeal lymph nodes. Staging of the lymphomas requires open biopsy of the affected nodes. Molecular studies, immunophenotypic cell markers, and karyotypic cell markers can then be identified. RHABDOMYOSARCOMA Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Within the head and neck, this lesion originates in the nasopharynx (chronic sinusitis, nasal discharge), ear, or orbit (proptosis) and may manifest with serosanguineous drainage from the nose or ear that is refractory to medical therapy. Typically, it is accompanied by painless enlargement of cervical nodes. Therefore, a thorough examination of the nasopharynx is warranted in patients with cervical adenopathy. The median age at diagnosis is approximately 6 years. Rhabdomyosarcoma is a very aggressive tumor, and treatment involves a combination of modalities, including surgery, chemotherapy, and radiation. Because total excision is an extremely important factor in determining prognosis, early diagnosis is very important. NEUROBLASTOMA Neuroblastomas arise from postganglionic sympathetic cells. In the neck, the cervical sympathetic chain is the site of origin. These tumors manifest as firm masses in the lower neck lateral to the trachea in infants younger than 1 year. Horner syndrome (unilateral ptosis, miosis, and ipsilateral facial anhydrosis) may develop as a result of cervical or thoracic sympathetic chain neuroblastoma. In 35% of affected children, regional metastasis is detected at presentation. As expected, children with isolated distant nodal involvement have a better prognosis than do those with disseminated metastatic involvement. Treatment is multimodal; surgery is usually required in all patients. Subsequent radiotherapy or chemotherapy is based on clinical and biologic features.
DIAGNOSTIC APPROACH The clinician should first try to establish the most likely broad diagnostic category by history and physical examination. Only when a diagnosis is suspected should the clinician attempt to narrow the
differential by using the appropriate diagnostic testing. It is particularly important to decide which patients can be observed or managed medically by the primary care physician and which should be referred to a hematologist/oncologist, otolaryngologist, or pediatric surgeon. The physical examination is often the most valuable diagnostic tool. A general approach to the patient with a neck mass is presented in Figure 49-10. First, the clinician must decide whether the history and physical findings are suggestive of a congenital lesion. If they are, then after initiating treatment of any associated infection, the patient should be referred to a surgical specialist immediately. If the lesion is not congenital, the next step should be to determine whether the lesion appears inflamed or infected. If it is inflamed or infected, associated systemic infections (upper respiratory) or local infections (dental abscess, scalp lesion) should be sought. If pharyngitis is present, a throat culture should be considered to rule out group A streptococcal infection. If the culture result is negative and symptoms persist, the physician should consider a viral infection with Epstein-Barr virus or cytomegalovirus (CMV), and appropriate serologic testing may be done. Toxoplasmosis or cat-scratch disease can be contemplated as well. A complete blood cell count with differential may be helpful at this point, because Epstein-Barr virus is often associated with an atypical lymphocytosis. If the inflamed lesion becomes fluctuant, referral should be made for incision and drainage. The diagnosis of Kawasaki disease should be considered in any patient with an inflammatory node that does not suppurate and for which there is not an immediate explanation (see Chapter 55). For patients whose signs and symptoms do not fit these criteria, other systemic disorders should be considered. The patient and family should be questioned for human immunodeficiency virus risk factors and tested if appropriate. Signs and symptoms of connective tissue disease should be sought and a chest radiograph obtained. If the patient is found to have a history remarkable for recurrent infections, further workup for immunodeficiencies should be considered (see Chapter 51). If after all of these steps are taken the diagnosis remains unknown, the lesion may be monitored expectantly for 2 to 3 weeks. If regression of the mass has not occurred by the time of follow-up, further evaluation should be pursued. If on examination the mass does not appear to be inflammatory, and if it is located in the supraclavicular or posterior cervical region, a complete blood cell count should be performed and a chest radiograph obtained. Because of the high incidence of malignancy associated with these findings, an immediate referral should be made for incisional biopsy. If the lesion is overlying the thyroid, and if the manifestation is not consistent with thyroglossal duct cyst, thyroid function tests and a thyroid scan should be performed, and referral for fine-needle aspiration or excisional biopsy should be made.
Figure 49-10. Diagnostic decision tree for childhood neck masses. CBC, complete blood count; CXR, chest radiograph; EBV, Epstein-Barr virus; ECHO, echocardiogram; HIV, human immunodeficiency virus; IVIG, intravenous immune globin; PPD, purified protein derivative; TB, tuberculosis; URI, upper respiratory infection.
906 Section Eight Hematologic Disorders
Chapter 49 Neck Masses in Childhood For lesions lying outside of these regions, a purified protein derivative test should be part of the initial workup. In patients whose skin tests yield positive results, with more than 5 to 15 mm of induration (depending on risk group), tuberculosis is the most likely diagnosis (see Chapter 2). If the patient is at low risk for tuberculosis and the skin test yields a “positive” reaction with less than 15 mm of induration, infection with atypical mycobacteria should be suspected. These cases should be referred for excisional biopsy or curettage, and the material should be obtained for culture of acid-fast bacteria. If the patient is found to be anergic, immunodeficiencies and malignancies should be suspected. If the purified protein derivative test does not yield a reaction, the diagnosis of cat-scratch disease may be entertained. Patients with a history of cat exposure and physical findings consistent with this diagnosis may be observed for a period of 2 to 3 weeks. If the nodes continue to enlarge, excisional biopsy with Warthin-Starry staining of the biopsy specimen is appropriate. In patients with noninflammatory nodes, especially with a history of cat exposure, toxoplasmosis should also be considered, and titers may be obtained. In the patient whose clinical picture is not consistent with cat-scratch disease and whose diagnosis has not been established during the evaluation just described, the possibility of malignancy must be strongly considered. The clinician should consider several questions that indicate red flags: ● ● ●
Are the nodes firm, matted, or fixed to underlying tissue? Are there associated constitutional symptoms? Are there abnormalities on the complete blood count that would suggest malignancy or on the chest radiograph that would suggest mediastinal adenopathy or mass?
If the answer to any of these questions is yes, immediate referral should be made for excisional biopsy. If none of the answers is yes, the mass may again be monitored with serial measurements for 2 to 3 more weeks. Masses that continue to increase in size and those that do not regress over the next several weeks should be examined through biopsy.
SUMMARY AND RED FLAGS Diagnosis of childhood cervical masses is challenging and satisfying. The basic clinical history and physical examination skills are reliably successful in this area. The differential diagnosis can be limited on the basis of anatomic, inflammatory, and historical information. The likelihood of successful treatment is high in children. Red flags include signs of airway compromise; dysphagia; supraclavicular adenopathy; a solid, solitary mass in a salivary gland; a cold thyroid nodule; matted or fixed nodes; and fever, night sweats, or weight loss associated with a neck mass (Table 49-6).
Table 49-6. “Red Flags”: Signs and Symptoms Suspect
for Malignancy or Decompensation Supraclavicular adenopathy Adenopathy in posterior triangle without evidence of scalp inflammation Nodes fixed to underlying tissue Size > 3 cm Matting of nodes into single indistinct mass Slow, steadily progressive painless enlargement Signs of airway obstruction Constitutional symptoms in association with above: Fever Weight loss Night sweats
907 REFERENCES Bacterial Lymphadenitis
Sichel JY, Gomori JM, Saah D, Elidan J: Parapharyngeal abscess in children: The role of CT for diagnosis and treatment. Int J Pediatr Otorhinolaryngol 1996;35:213-222. Mycobacterium Lymphadenitis April MM, Garelick JM, Nuovo GJ: Reverse transcriptase in situ polymerase chain reaction in atypical mycobacterial adenitis. Arch Otolaryngol Head Neck Surg 1996;122:1214-1218. Cat-Scratch Disease Kacker A, Kuhel WI, Hoda RS: Quiz Case 2: Cat-scratch disease. Arch Otolaryngol Head Neck Surg 2000;126:677-682. Neck Masses in Patients Undergoing Bone Marrow Transplantation or Chemotherapy Posey LA, Kerschner JE, Conley SF: Posttransplantation lymphoproliferative disease in children: Otolaryngologic manifestations and management. South Med J 1999;92:1079-1082. Kimura Disease Chusid MJ, Rock AL, Sty JR, et al: Kimura’s disease: An unusual cause of cervical tumor. Arch Dis Child 1997;77:153-154. Thyroglossal Duct Cysts Buchino JJ, Fallat ME, Montgomery VL: Pathological case of the month. Papillary carcinoma of the thyroid in a thyroglossal duct remnant. Arch Pediatr Adolesc Med 1999;153:999-1000. Sullivan DP, Liberatroe LA, April MM, et al: Epidermal inclusion cyst versus thyroglossal duct: Sistrunk or not? Ann Otol Rhinol Laryngol 2001; 110:340-344. Branchial Cleft Cyst, Sinus, Vestige Milbrath MM, Beste DJ, Sty JR: Comparative imaging: Thyroid abscess. Clin Nucl Med 1990;15:197. Vascular Lesions Clymer MA, Fortune D, Reinisch L, et al: Interstitial Nd: YAG photocoagulation for vascular malformations and hemangiomas in childhood. Arch Otolaryngol Head Neck Surg 1998;124:431-436. Fishman SJ. Mulliken JB: Vascular anomalies. A primer for pediatricians. Pediatr Clin North Am 1998;45:1455-1477. Jackson IT, Careno R, Potparic Z, Hussain K: Hemangiomas, vascular malformations and lymphovenous malformations: Classification and methods of treatment. Plast Reconstr Surg 1993;91:1216-1230. Mulliken JB, Glowacki J: Hemangiomas and vascular malformations in children: A classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:412-422. Lymphatic Malformations de Serres LM, Sie KC, Richardson MA: Lymphatic malformations of the head and neck. A proposal for staging. Arch Otolaryngol Head Neck Surg 1995;121:577-582. Salivary Masses Bentz BG, Hughes CA, Ludemann JP, et al: Masses of the salivary gland region in children. Arch Otolaryngol Head Neck Surg 2000;126: 1435-1439. Pershall KE, Koopmann CF Jr, Coulthard SW: Sialadenitis in children. Int J Pediatr Otorhinolaryngol 1986;11:199-203.
Section Eight Hematologic Disorders
908 Myofibromatosis
Rhabdomyosarcoma
Jaber M, Goldsmith AJ: Sternocleidomastoid tumor of infancy: Two cases of an interesting entity. Int J Pediatr Otorhinolaryngol 1999;47:269-274.
Blatt J, Snyderman C, Wollman MR, et al: Delayed resection in the management of non-orbital rhabdomyosarcoma of the head and neck in childhood. Med Pediatr Oncol 1997;28:294-298. Coene IJ, Schouwenburg PF, Voute PA, et al: Rhabdomyosarcoma of the head and neck in children. Clin Otolaryngol Allied Sci 1992;17:291-296. Raney RB, Asmar L, Vassilopoulou-Sellin R, et al: Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)–II and –III. IRS Group of the Children’s Cancer Group and the Pediatric Oncology Group. Med Pediatr Oncol 1999;33:362-371.
Pilomatrixoma Duflo S, Nicollas R, Roman S, et al: Pilomatrixoma of the head and neck in children: A study of 38 cases and a review of the literature. Arch Otolaryngol Head Neck Surg 1998;124:1239-1242. Thyroid Masses Alter CA. Moshang T Jr: Diagnostic dilemma. The goiter. Pediatr Clin North Am 1991;38;567-578. Lymphoma Hudson MM, Donaldson SS: Hodgkin’s disease. Pediatr Clin North Am 1997;44:891-906. Shad A, Magrath I: Non-Hodgkin’s lymphoma. Pediatr Clin North Am 1997;44:863-890.
Neuroblastoma Castleberry RP: Biology and treatment of neuroblastoma. Pediatr Clin North Am 997;44:919-935.
50
Bleeding and Thrombosis
J. Paul Scott
Hemostasis is a process that maintains normal blood flow through healthy vessels but, when a vessel is damaged, rapidly generates a clot at the site of vascular injury. In addition to flow, the major components of the hemostatic mechanism are the platelets, the anticoagulant proteins, the procoagulant proteins, and various components of the vascular wall. Normal hemostasis is an interactive process in which each element cooperates closely to generate a rapid, cohesive, focused reaction. An abnormality of one element destabilizes the system, but significant clinical symptoms often manifest only when two components are affected. Typical examples include the patient with hemophilia who bleeds after sustaining trauma and the antithrombin III-deficient woman in whom thrombosis develops during pregnancy. The astute clinician is aware of situations that may exacerbate preexisting conditions. Pretreatment of known predisposing conditions can prevent complications, as exemplified by infusion of factor VIII concentrate before and after surgery to a patient with hemophilia A to prevent excessive bleeding. Table 50-1 shows common bleeding symptoms and the most common disorders that trigger these symptoms.
COAGULATION INHIBITORS Four key systems interact to inhibit the coagulation mechanism: ● ● ● ●
antithrombin (AT) protein C/S system fibrinolytic system tissue factor pathway inhibitor (TFPI) ANTITHROMBIN
AT is a member of the serine protease inhibitor family (serpins) that inhibits thrombin, factor Xa, and, less efficiently, factors IXa and XIa. When AT is bound to heparin, this reaction is accelerated 1000fold. AT is the active anticoagulant operative during heparin therapy; if AT is deficient, heparin therapy may fail. Heparin-like molecules are synthesized by endothelial cells and interact with AT on the vessel wall to inhibit coagulation. Both congenital and acquired AT deficiencies are associated with a predisposition toward thrombosis. AT is consumed during clotting.
THE COAGULATION CASCADE Two opposing systems generate local clots but limit the clot to the area of vascular damage. Figure 50-1 shows the sequence of activation of coagulation. The cascade is capable of rapid response because generation of a small number of activated factors at the “top” of the cascade leads to thousands of molecules of thrombin. Deficiencies of proteins at or below factors XI or VII in the coagulation cascade sequence result in clinical bleeding symptoms, whereas deficiencies of factor XII, prekallikrein, and high-molecularweight kininogen do not. The coagulation mechanism is continuously generating a small amount of thrombin, probably through autocatalysis of factor VII to factor VIIa. If there is trauma, tissue factor and factor VII combine to activate factor X to factor Xa both directly and indirectly via factor IX. Factor Xa then forms a complex on a membrane surface (provided by the activated platelet) with factor V and calcium, which results in more thrombin generation. Platelets stick to areas of vessel injury, thus restricting thrombin generation and clot formation to the area of damage. Thrombin exerts positive feedback on the system by acting on factor XI to trigger the intrinsic system, cleaving factors V and VIII to activate them, further accelerating thrombin generation, aggregating platelets, and activating factor XIII. In this model, coagulation is always “turned on” and, therefore, reacts faster than if it were static and suddenly had to initiate a series of reactions to trigger clot formation. This dynamic concept underscores the impact of deficiencies in anticoagulant proteins, inasmuch as the system is continuously generating thrombin. A deficiency of an inhibitory enzyme or a cofactor removes part of the “brakes” on the system and causes increased thrombin generation.
Table 50-1. Common Causes of Clinical Bleeding
Symptoms Mucocutaneous Bleeding Acute Immune thrombocytopenic purpura Child abuse Trauma Poisoning with anticoagulants (rat poison) Chronic/insidious von Willebrand disease Platelet function defect Marrow infiltration/aplasia Deep/Surgical Bleeding Hemophilia Vitamin K deficiency von Willebrand disease Generalized Bleeding Disseminated intravascular coagulation Vitamin K deficiency Liver disease Uremia 909
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910
Procoagulants F XI
T
XIa
F IX
VIIa
IXa VIIIa
T von Willebrand factor
VII
F VIII
PL Ca++
TF
FX
Xa T
FV
PL Ca++ Va Prothrombin (F II)
Thrombin (IIa)
Fibrinogen (I)
F XIII T
Fibrin
Figure 50-1. The coagulation cascade and the critical positive feedback role of factor IIa (thrombin) (T) on multiple aspects of the coagulation cascade. In addition, thrombin aggregates platelets and thereby contributes to platelet plug formation. The dotted line connecting factor VIIa with factor IX depicts the physiologic pathway of factor IX activation in vivo. Factor VIII circulates bound to von Willebrand factor. After activation by thrombin, factor VIIIa can participate with factor IXa in the activation of factor X. Factor XIIIa cross-links fibrin and stabilizes the fibrin clot. Ca2+, calcium; PL, platelet phospholipid surface; TF, tissue factor. (Modified from Montgomery RR, Scott JP: Hemorrhage and thrombotic diseases. In Behrman RE, Kliegman RM, Jenson HB [eds]: Nelson Textbook of Pediatrics, 16th ed. Orlando, Fla, WB Saunders, 1999, p 1505.)
F XIIIa Clot In addition, APC may also promote fibrinolysis. In such a manner, thrombin itself is inactivated when bound to thrombomodulin and simultaneously augments the anticoagulant response by generating APC. APC limits the amount of thrombin that can be generated subsequently. ATIII, protein C, and protein S are important inhibitors of clotting because deficiencies of each of these proteins, either inherited or acquired, are associated with an increased risk of thrombosis. A mutation in factor V (factor V Leiden) that makes it less susceptible to proteolysis by APC (resistance to APC) is the most common hereditary predisposition to thrombosis.
PROTEIN C/PROTEIN S SYSTEM The protein C/protein S system is complex and limits clot extension by inactivating the rate-limiting coenzymes of the coagulation cascade, factors VIII and V. To prevent extension of the clot, the anticoagulant mechanism must limit thrombin formation to areas of vascular damage. The protein C/protein S system accomplishes this goal. As a first step, thrombin binds to the protein thrombomodulin on intact endothelial cells. Thrombomodulin-bound thrombin then converts protein C into its activated form, activated protein C (APC). APC then combines with protein S to inactivate factors VIII and V.
Procoagulants F XI
XIa
F IX
IXa
VII
VIIIa von Willebrand factor
F VIII
Anticoagulants
PL Ca++
VIIa
TF
FX
TFPI
P-C/S Xa FV
AT-III
PL Ca++ Prothrombin (F II) Fibrinogen (I)
Va
P-C/S Thrombin (IIa)
Fibrin F XIII Clot
AT
Figure 50-2. The major sites of action of the physiologic anticoagulants. Antithrombin (AT) irreversibly binds and inactivates factor Xa and thrombin. Thrombin binds to endothelial thrombomodulin and activates protein C. The activated protein C/protein S complex (P- C/S) proteolyses and inactivates factors Va and VIIIa. The tissue factor pathway inhibitor (TFPI) binds to the complexes of factor VIIa–tissue factor–factor Xa and inactivates factor VIIa. Ca2+, calcium; PL, platelet phospholipid surface; TF, tissue factor. (Modified from Montgomery RR, Scott JP: Hemorrhage and thrombotic diseases. In Behrman RE, Kliegman RM, Jenson HB [eds]: Nelson Textbook of Pediatrics, 16th ed. Orlando, Fla, WB Saunders, 1999, p 1505.)
Chapter 50 Bleeding and Thrombosis TFPI is an inhibitor of factor VIIa. Because a pathologic deficiency state of TFPI has not been discovered, the role of TFPI as a physiologic inhibitor of coagulation is unclear at present (Fig. 50-2). FIBRINOLYTIC SYSTEM The fibrinolytic system dissolves and removes clots from the vascular system so that normal flow through vessels can be restored. Endothelial cells synthesize two activators of plasminogen: tissuetype plasminogen activator (TPA) and urokinase, both of which convert plasminogen to plasmin, the enzyme that degrades fibrin. Normally, plasminogen activator and its inhibitor, plasminogen activator inhibitor, are synthesized in equimolar amounts and are released from endothelial cells in parallel, leading to minimal amounts of active fibrinolysis. Increased activation or damage to the vascular system can alter this balance and result in increased TPA release, thus generating plasmin and lysing local clots. When fibrin is degraded by plasmin, fibrin degradation products (FDPs) are formed. These can be measured in the clinical laboratory by immunologic assays that detect the presence of proteolysed fibrin(ogen) (FDPs) or that measure the breakdown products of plasmin action on cross-linked fibrin (D-dimer). Plasminogen activator has been synthesized in a recombinant form (rTPA) and is an effective pharmacologic fibrinolytic agent in vivo.
THE PLATELET-ENDOTHELIAL CELLS AXIS Clotting is initiated when platelets adhere to damaged endothelium (Fig. 50-3). In areas of vascular damage, the adhesive protein, von Willebrand factor (vWF), binds to the exposed subendothelial collagen matrix and undergoes a conformational change. vWF then binds to its platelet receptor, glycoprotein Ib, and activates platelets. Activated platelets secrete adenosine diphosphate (ADP), which
911
induces nearby circulating platelets to aggregate. Platelet-to-platelet cohesion is mediated by the binding of fibrinogen to its platelet receptor, glycoprotein IIb/IIIa. Therefore, both vWF and fibrinogen play essential roles in normal platelet function in vivo. Simultaneously with the platelet adhesion-aggregation response, coagulation is being activated. The platelet membrane brings the reactants of the cascade into close proximity, promoting rapid, effective factor catalysis and accelerating the reactions 1000-fold faster than would occur in the absence of the appropriate surface. Normally, endothelial cells provide an antithrombotic surface through which blood flows without interruption. Nevertheless, the endothelial cell is capable of a rapid change in function and character so that it can augment coagulation after stimulation with a variety of modulating agents, including lymphokines and cytokines, as well as noxious agents such as endotoxin and infectious viruses (Fig. 50-4). Widespread alteration of endothelial cell function can shift and dysregulate the hemostatic response and promote activation of clotting. This is probably the mechanism by which sepsis induces the clinical syndrome of disseminated intravascular coagulation (DIC).
DEVELOPMENTAL HEMOSTASIS Hemostatic disorders in newborns are common, more so than at any other pediatric age. The neonate is relatively deficient in most procoagulant and anticoagulant proteins. Platelet function may also be impaired. Blood flow characteristics in the newborn are unique because of the high hematocrit, small-caliber vessels, low blood pressure, and special areas of vascular fragility. Table 50-2 presents the normal values for coagulation screening tests and procoagulant proteins in preterm and full-term infants, as well as in older children. Table 50-3 presents age-specific values for the anticoagulant and fibrinolytic proteins. Levels of factors V and VIII, fibrinogen, vWF, and platelets become normal by 28 weeks of gestation. Protein S levels are also
Figure 50-3. The endothelial cell–platelet–von Willebrand factor (vWF) interaction that results in initiation of the normal platelet plug by the adhesion of platelets to damaged endothelium, mediated by vWF with subsequent formation of the platelet plug and fibrin clot. (Courtesy of R. R. Montgomery.)
Section Eight Hematologic Disorders
912 Antithrombotic
Prothrombotic {endotoxin} {cytokines} {viral agents}
Thrombomodulin Heparin Surface charge ADP'ase Tissue plasminogen activator Prostacyclin generation Nitric oxide (NO)
Tissue factor generation Synthesis of clotting factors and von Willebrand factor Reaction surface Plasminogen activator inhibitor Platelet activating factor
Figure 50-4. Endothelial balance. The pivotal role of the endothelium in maintaining a balance between antithrombotic and prothrombotic activities, as influenced by endotoxins, viruses, and immunomodulatory cytokines. ADPase, adenosine diphosphatase; NO, nitric oxide.
normal at birth, but levels of other anticoagulant proteins, especially protein C, ATIII, and plasminogen, are low in full-term infants and are even lower in premature neonates. The levels of most procoagulant and anticoagulant proteins increase throughout gestation; therefore, the most immature infant has the lowest levels of these proteins and is at the highest risk of either bleeding or thrombotic complications. The hemostatic balance of neonates, especially premature neonates, is precarious and easily shifted toward bleeding, thrombosis, or both. Vitamin K deficiency is a particular problem of the newborn. Vitamin K is a fat-soluble vitamin that induces the post-translational γ-carboxylation of the vitamin K–dependent substances (factors II, VII, IX, and X; protein C; and protein S). This carboxylation step occurs after the protein is synthesized in the liver and must occur for the vitamin K–dependent coagulation factor to bind calcium, the bridge to the membrane surface on which these proteins form complexes with other members of the clotting cascade and catalyze subsequent reactions. Vitamin K deficiency effectively renders these proteins unable to bind to a surface. Most of the vitamin K in adults originates from the diet and from bacterial production in the intestine. The breast-fed neonate is at high risk for vitamin K deficiency because human milk is relatively deficient in vitamin K, the neonatal liver itself is immature, and the newborn’s gut requires several days to develop normal bacterial flora. Severe vitamin K deficiency in neonates, hemorrhagic disease of the newborn (HDN), occurs in breast-fed infants who have not received intramuscular vitamin K prophylaxis. Such infants may experience diffuse bleeding and even central nervous system hemorrhage at 3 to 5 days of life. HDN is an extraordinarily rare event in the United States because of nearly universal neonatal administration of vitamin K. In the evaluation of bleeding in a newborn, the clinician should confirm that vitamin K has been administered. Patients with disorders of the gastrointestinal tract, those taking broad-spectrum antibiotics, those born of mothers who received phenobarbital or phenytoin during pregnancy (very-early-onset HDN), and those with cholestasis and malabsorption (late-onset HDN) are at higher risk for vitamin K deficiency.
CLUES FROM THE HISTORY AND PHYSICAL EXAMINATION HISTORY Table 50-4 is an outline of historical questions that are important for the diagnosis of bleeding disorders. To obtain a meaningful history, it is critical to obtain quantifiable, precise information: a documented need for postsurgery transfusion because of excessive bleeding, nosebleeds that necessitate cautery, and large (>2 inches in diameter) or raised bruises in areas not usually associated with trauma. Although
easy bruising and nosebleeds are common in children, the presence of large bruises at multiple sites, prolonged nosebleeds, and hematoma formation are rare in otherwise well children, but are seen in 20% to 38.5% of children with a bleeding disorder. Evaluation of children with an isolated history of easy bruising in a commonly traumatized area yields few findings of disease, whereas there is a much higher likelihood of pathologic processes with a history of large bruises at multiple sites. Epistaxis that is prolonged (>15 to 30 minutes), especially without trauma or a history of allergy or infection, that requires cautery or packing, or that results in iron deficiency is more likely to be caused by a hemostatic deficiency or an anatomic problem. Some helpful questions include “What was the biggest bruise you ever had, and what caused it?”; “Which finger do you pick your nose with?”; and “Have you ever noted little red dots [petechiae] on your skin?” A personal or family history of gynecologic bleeding is often valuable. Menorrhagia causing iron deficiency anemia, bleeding after childbirth, or need for transfusion or early hysterectomy because of bleeding is often inappropriately assumed to have anatomic causes (“dysfunctional uterine bleeding”). The clinician must ascertain the number of pads used per day, in addition to the length and the frequency of each menstrual cycle (see Chapter 30). If the majority of women in a family have an underlying bleeding disorder, then that family’s “normal menstrual periods” may be quite abnormal. Many adolescent girls with menorrhagia caused by an underlying bleeding disorder respond to oral contraceptive agents; therefore, improvement in bleeding symptoms after starting oral contraceptive agents does not rule out a bleeding disorder. Historical information is equally important in deciding who requires evaluation for a predisposition to thrombosis. Virtually all pediatric patients in whom a blood clot develops in the absence of major vascular instrumentation need careful laboratory screening for a prothrombotic state (a hereditary or acquired disorder that predisposes to clotting). The only patients for whom there is insufficient evidence to judge whether studies need to be performed are neonates with catheters in place in whom venous or arterial thrombi develop in association with the catheter. Even in these situations, a detailed family history should be documented for early-onset stroke; early myocardial infarction; and blood clots in the veins, arteries, or lungs.
PHYSICAL EXAMINATION The most important determination is whether the patient appears acutely or chronically ill, including vital signs and growth parameters. The nose should be examined for ulcers or anatomic bleeding sites, and the heart should be examined for the presence of murmurs (as occur in anemia and endocarditis). Joints should be examined for chronic arthropathy (as occurs in hemophilia) or joint laxity (as occurs in Ehlers-Danlos syndrome), and the extremities are examined for thumb or radial anomalies (thrombocytopenia–absent radius syndrome, which occurs in Fanconi anemia). The abdomen and lymph nodes should be examined for the presence of hepatosplenomegaly and adenopathy. The examination of the skin should include a search for pallor, hematomas, petechiae, ecchymoses, telangiectasias, poor wound healing (large or abnormal scars), lax (loose) skin, and varicose veins (possible deep venous thrombosis). Petechiae are pinpoint, flat, dark red lesions caused by capillary bleeding into the skin. Ecchymoses are larger lesions (bruises) that are flat and usually not palpable. Hematomas are accumulations of blood in the skin or deeper tissues; in the skin, hematomas are raised and palpable. Bruises should be described in detail, including whether hematomas are associated with bruises and whether petechiae are present. Petechiae and ecchymoses are usually painless. Purpura refers to any group of disorders characterized by the presence of dark-red, purplish, or brown lesions of the skin and mucous membranes. The discoloration is caused by the leakage of red blood
15.4 (14.6-16.9) — 108 (80-168) 2.56 (1.60-5.50) — 0.31 (0.19-0.54) 0.65 (0.43-0.80) 0.37 (0.24-0.76) 0.79 (0.37-1.26) 1.41 (0.83-2.23) 0.18 (0.17-0.20) 0.36 (0.25-0.64) 0.23 (0.11-0.33) 0.25 (0.05-0.35) 0.26 (0.15-0.32) 0.32 (0.19-0.52) — —
0.12 (±0.02) 0.41 (±0.10) 0.28 (±0.04) 0.39 (±0.14)
0.64 (±0.13) 0.10 (±0.01) 0.21 (±0.03) — 0.22 (±0.03) — — — —
28-31 Weeks’ Gestation†
— — — 1.00 (±0.43) —
19-27 Weeks’ Gestation†
1.53 (0.50-2.87) 0.53 (0.15-0.91)†‡ 0.40 (0.12-0.68)‡ 0.38 (0.40-0.66)‡ 0.53 (0.13-0.93)‡ 0.37 (0.18-0.69)‡ 0.54 (0.06-1.02)‡ 0.79 (0.27-1.31)‡ 0.76 (0.30-1.22)‡
0.48 (0.26-0.70)‡ 0.72 (0.34-1.08)‡ 0.66 (0.28-1.04)‡ 1.00 (0.50-1.78)
0.45 (0.20-0.77)‡ 0.88 (0.41-1.44)§ 0.67 (0.21-1.13)‡ 1.11 (0.5-2.13) 1.36 (0.78-2.10) 0.35 (0.19-0.65)‡§ 0.41 (0.11-0.71)‡ 0.30 (0.08-5.2)‡§ 0.38 (0.10-0.66)‡§ 0.33 (0.09-0.89)‡ 0.49 (0.09-0.89)‡ 0.70 (0.32-1.08)‡ 0.81 (0.35-1.27)‡
13.0 (10.1-15.9) 1.00 (0.53-1.62)‡ 42.9 (31.3-54.3)‡ 2.83 (1.67-3.99) —
Full Term
13.0 (10.6-16.2) 1.0 (0.61-1.7) 53.6 (27.5-79.4)‡§ 2.43 (1.50-3.73)‡§ —
30-36 Weeks’ Gestation
0.82 (0.60-1.20) 0.73 (0.47-1.04)‡ 0.88 (0.58-1.16)‡ 0.30 (0.08-0.52)‡§ 0.93 (0.64-1.29) 0.95 (0.65-1.30) 0.98 (0.64-1.32) 1.08 (0.72-1.43) 1.13 (0.69-1.56)‡
0.94 (0.71-1.16)‡ 1.03 (0.79-1.27) 0.82 (0.55-1.16)‡ 0.90 (0.59-1.42)
11 (10.6-11.4) 1.0 (0.96-1.04) 30 (24-36) 2.76 (1.70-4.05) 6 (2.5-10)‡
1-5 Years
0.95 (0.44-1.44) 0.75 (0.63-0.89)‡ 0.75 (0.55-1.01)‡ 0.38 (1.10-0.66) 0.92 (0.60-1.40) 0.99 (0.66-1.31) 0.93 (0.60-1.30) 1.09 (0.65-1.51) 1.16 (0.77-1.54)‡
0.88 (0.67-1.07)‡ 0.90 (0.63-1.16)‡ 0.86 (0.52-1.20)‡ 0.95 (0.58-1.32)
11.1 (10.1-12.0) 1.01 (0.91-1.11) 31 (26-36) 2.79 (1.57-4.0) 7 (2.5-13)‡
6-10 Years
1.00 (0.46-1.53) 0.82 (0.59-1.22)‡ 0.79 (0.50-1.17) 0.74 (0.50-0.97)‡ 0.81 (0.34-1.37)‡ 0.99 (0.53-1.45) 0.91 (0.63-1.19) 0.99 (0.57-1.40) 1.02 (0.60-1.43)
0.83 (0.61-1.04)‡ 0.77 (0.55-0.99)‡ 0.83 (0.58-1.15)‡ 0.92 (0.53-1.31)
11.2 (10.2-12.0) 1.02 (0.93-1.10) 32 (26-37) 3.0 (1.54-4.48) 5 (3.8)‡
11-18 Years
0.92 (0.50-1.58) 1.09 (0.55-1.63) 1.06 (0.70-1.52) 0.97 (0.56-1.50) 1.08 (0.52-1.64) 1.12 (0.62-1.62) 0.92 (0.50-1.36) 1.05 (0.55-1.55) 0.98 (0.57-1.37)
1.08 (0.70-1.46) 1.06 (0.62-1.50) 1.05 (0.67-1.43) 0.99 (0.50-1.49)
12 (11.0-14.0) 1.10 (1.0-1.3) 33 (27-40) 2.78 (1.56-4.0) 4 (1-7)
Adult
Values are significantly different from those of full-term infants.
APTT, activated partial thromboplastin time; HMWK, high-molecular-weight kininogen; INR, international normalized ratio; PK, prekallikrein; PT, prothrombin time; vWf, von Willebrand factor.
§
Values are significantly different from those of adults.
Levels for 19-27 weeks and 28-31 weeks are from multiple sources and cannot be analyzed statistically.
‡
†
*All factors except fibrinogen are presented as units/mL (fibrinogen in mg/mL), where pooled normal plasma contains 1 unit/mL. All data are expressed as the mean followed by the upper and lower boundaries encompassing 95% of the normal population.
Data from Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990;12:95–104; and Andrew M, Vegh P, Johnston M, et al: Maturation of the hemostatic system during childhood. Blood 1992;80:1998–2005.
PT (sec) INR APTT (sec) Fibrinogen Bleeding time (min) Factor II Factor V Factor VII Factor VIII procoagulant vWf Factor IX Factor X Factor XI Factor XII PK HMWK Factor XIIIa Factor XIIIb
Test
Table 50-2. Reference Values for Coagulation Tests in Healthy Children*
Chapter 50 Bleeding and Thrombosis
913
19-27 Weeks’ Gestation†
0.38 (0.14-0.62)‡§ 0.28 (0.12-0.44)‡§ — 0.26 (0.14-0.38)‡§ — 1.70 (1.12-2.48)‡ 8.48 (3.00-16.70) 0.78 (0.40-1.16) 5.4 (0.0-12.2)‡
— — —
30-36 Weeks’ Gestation
0.28 (0.20-0.38)‡ — — — — —
28-31 Weeks’ Gestation†
9.6 (5.0-18.9) 0.85 (0.55-1.15) 6.4 (2.0-15.1)
0.63 (0.39-0.87)‡ 0.35 (0.17-0.53)‡ — 0.36 (0.12-0.60)‡ — 1.95 (1.25-2.65)‡
Full Term
1.11 (0.90-1.31) 0.69 (0.45-0.93)‡ — 0.78 (0.41-1.14) 0.42 (0.22-0.62) 0.92 (0.75-1.08) 2.42 (1.0-5.0)‡ 0.99 (0.89-1.10) 6.79 (2.0-12.0)‡
2.15 (1.0-4.5)‡ 1.05 (0.93-1.17) 5.42 (1.0-10.0)
6-10 Years
1.11 (0.82-1.39) 0.66 (0.40-0.92)‡ — 0.86 (0.54-1.18) 0.45 (0.21-0.69) 0.98 (0.78-1.18)
1-5 Years
2.16 (1.0-4.0)‡ 0.98 (0.78-1.18) 6.07 (2.0-10.0)‡
1.06 (0.77-1.32) 0.83 (0.55-1.11)‡ — 0.72 (0.52-0.92) 0.38 (0.26-0.55) 0.86 (0.68-1.03)
11-18 Years
1.02 (0.68-1.36) 1.02 (0.68-1.36) 3.60 (0-11.0)
1.0 (0.74-1.26) 0.96 (0.64-1.28) — 0.81 (0.61-1.13) 0.45 (0.27-0.61) 0.99 (0.77-1.22)
Adult
Values are significantly different from those of full-term infants.
α2AP, α2-antiplasmin; ATIII, antithrombin-III; PAI-1, plasminogen activator inhibitor type 1; TPA, tissue plasminogen activator.
§
Values are significantly different from those of adults.
Levels for 19-27 weeks and 28-31 weeks are from multiple sources and cannot be analyzed statistically.
‡
†
*All values are expressed in units/mL, where pooled plasma contains 1 unit/mL, with the exception of free protein S, which contains a mean of 0.4 unit/mL. All values presented as the mean by the upper and lower boundaries encompassing 95% of the population.
Data from Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990;12:95-104; and Andrew M, Vegh P, Johnston M, et al: Maturation of the hemostatic system during childhood. Blood 1992;80:1998-2005.
ATII 0.24 (±0.03)‡ Protein C 0.11 (±0.03)‡ Protein S — Total (U/mL) — Free (U/mL) — Plasminogen — (U/mL) TPA (ng/mL) — α2AP (U/mL) — PAI-1 —
Inhibitor
Table 50-3. Reference Values for the Inhibitors of Coagulation in Healthy Children in Comparison with Adults*
914 Section Eight Hematologic Disorders
Chapter 50 Bleeding and Thrombosis
915
Table 50-4. History of a Bleeding Disorder
I. History of Disorder A. Onset of symptoms 1. Age 2. Acute versus lifelong 3. Triggering event 4. Timing of bleeding after injury: immediate versus delayed B. Sites of bleeding 1. Mucocutaneous* a. Epistaxis (1) Duration, frequency, seasonal tendency (2) Associated trauma (nose picking, allergy, infection) (3) Resultant anemia, emergency department evaluation, cautery b. Oral (gingiva, frenulum, tongue lacerations, bleeding after tooth brushing, after dental extractions requiring sutures/packing) c. Bruising (number, sites, size, raised [other than extremities], spontaneous versus trauma, knots within center, skin scarring) d. Gastrointestinal bleeding 2. Deep a. Musculoskeletal (1) Hemarthroses, unexplained arthropathy (2) Intramuscular hematomas b. Central nervous system hemorrhage c. Genitourinary tract 3. Surgical a. Minor (sutures, lacerations, poor or delayed wound healing) b. Major (1) Tonsillectomy and adenoidectomy (2) Abdominal surgery
C. Perinatal history a. Superficial (bruising, petechiae) b. Deep (1) Circumcision (2) Central nervous system bleeding (3) Gastrointestinal bleeding (4) Cephalohematoma (5) Unexplained anemia or hyperbilirubinemia (6) Delayed cord separation, bleeding after cord separation c. Vitamin K administration d. Maternal drugs D. Obstetric/gynecologic bleeding 1. Menorrhagia (1) Onset, duration, amount (number of pads), frequency, persistence after childbirth (2) Resultant anemia, iron deficiency 2. Bleeding at childbirth (onset, duration, transfusion requirement, history of traumatic delivery, recurrences with subsequent pregnancies, spontaneous abortions) E. Medications a. Aspirin and nonsteroidal antiinflammatory drugs b. Anticoagulants c. Antibiotics d. Anticonvulsants F. Diet a. Vitamin K b. Vitamin C II. Family History Draw family tree. The items just listed should be applied to immediate family members, especially a history of easy bruising, epistaxis, excessive bleeding after surgery, menorrhagia, excessive bleeding after childbirth, or a family history of others with diagnosed or suspect bleeding disorders. Attempt to deduce inheritance pattern.
*Significant historical information is presented in boldface type.
cells from affected vessels. Purpuric lesions can be caused by abnormalities of the platelets, of coagulation proteins, or of vessel walls.
● ●
bleeding time vWF function (ristocetin cofactor activity)
There are no satisfactory tests to screen for a thrombotic tendency.
COAGULATION SCREENING TESTS After obtaining a history and performing a physical examination, the clinician must determine the need for a hemostatic evaluation. The presence of significant symptoms should warrant such an evaluation. The history is likely to be the most sensitive screening tool for a significant bleeding disorder, although the history is often nonspecific. Its use in a very young child, especially before toddler age, is limited, and attention must shift to the perinatal history and the family history. For patients who are to be evaluated for a bleeding disorder because of clinical clues or planned surgery, the initial screening studies should assess the clotting factors and platelet and vessel wall interaction, including vWF function. No set of screening tests is complete and capable of detecting the panorama of hemorrhagic disorders, but the screen should include ● ● ● ●
prothrombin time (PT) partial thromboplastin time (PTT) functional fibrinogen level or thrombin time platelet count
PROTHROMBIN TIME AND PARTIAL THROMBOPLASTIN TIME The PT and PTT (Fig. 50-5) are measures of all the coagulation factors except factor XIII. Fibrinogen function should be measured as fibrinogen activity or thrombin time. The bleeding time provides an indirect measure of platelet number, platelet function, and the platelet–vessel wall interaction. The PTT is the screening test that checks for deficiency of all clotting factors except factors VII and XIII. The PTT can be prolonged either by a deficiency of a clotting factor or by the presence of an agent in the plasma that delays the clotting time (an inhibitor). The PT is especially sensitive to deficiencies of factor VII. To test for an inhibitor, one part of the patient’s plasma is mixed with one part of pooled normal plasma obtained from 20 to 50 healthy adults. Pooled normal plasma provides a 100% level of each clotting factor. If mixed 1:1 with plasma that is deficient in one or several factors, the mixture should possess at least a 50% level of each factor and the PTT should correct to the normal range. If an inhibitor is present, the PTT usually does not correct to normal. The
Section Eight Hematologic Disorders
916 PTT Kallikrein F XII
HMWK
XIIa PT
Prekallikrein
F XI
XIa
F IX
IXa
F VIII
Figure 50-5. Elements of the coagulation cascade measured by the prothrombin time (PT) and the partial thromboplastin time (PTT). Note that prekallikrein (PK), high-molecular-weight kininogen (HMWK), and factor XII are shown in this figure and not in the depiction of the coagulation cascade in Figure 50-1, because a deficiency of PK, HMWK, or factor XII can cause a prolongation of the PTT. However, a deficiency of any of these proteins alone is not associated with a clinical bleeding disorder. Ca2+, calcium; PL, platelet phospholipid surface; TF, tissue factor. (Modified from Montgomery RR, Scott JP: Hemorrhage and thrombotic diseases. In Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics, 16th ed. Orlando, Fla, WB Saunders, 1999, p 1505.)
VIIa
PL VIIIa
T von Willebrand factor
VII
TF Ca++
FX
Xa T
FV
PL Ca++ Va Prothrombin (F II) Fibrinogen (I)
Thrombin (IIa) Fibrin F XIII Clot
most common types of inhibitors include anticoagulants, such as heparin, and autoantibodies directed against either specific clotting factors (factor VIII inhibitors) or the phospholipid substances used in the PTT (lupus-type anticoagulants). The PTT is especially sensitive to deficiencies of factors VIII, IX, and XI (hemophilia A, B, and C, respectively). A prolonged PTT in an asymptomatic child is most commonly caused by factor XII deficiency or by a lupus-type anticoagulant. The PTT can yield a false result 1. when poor venipuncture technique, by adding tissue factor to the blood, activates clotting and artifactually shortens the PTT 2. when insensitive laboratory reagents fail to detect clinically significant deficiencies (commonly in factor IX) 3. when the citrate concentration is not corrected for blood with a high hematocrit (in neonates and in patients with cyanotic congenital heart disease), leading to a prolonged PTT
and mild or moderate platelet function deficits. Figures 50-6 to 50-8 provide an approach to evaluate the patient with an isolated prolongation of the PT, PTT, or bleeding time, respectively. THROMBIN TIME AND REPTILASE TIME The thrombin time and reptilase time are tests that measure the conversion of fibrinogen to fibrin. The thrombin time is sensitive to heparin effect, whereas the snake venom reptilase time remains normal in the presence of heparin. Both the thrombin time and the reptilase time are prolonged by uremia, by dysfibrinogenemia, by
Protime Normal
Retest off medications
BLEEDING TIME
STOP
Prolonged
The bleeding time is measured by placing a blood pressure cuff on the patient’s arm and inflating it to 40 mm Hg; lower pressures have been used for infants. An incision of predetermined length and depth is made on the volar surface of the arm below the antecubital fossa using a standardized automated device. The wound is blotted with filter paper, and the time until the blood stops oozing is measured with a stopwatch. The bleeding time is an indirect measure of platelet number and a more direct measure of platelet function, vascular integrity, and platelet interaction with the vascular subendothelium. As such, the bleeding time should be abnormal in patients with thrombocytopenia, platelet function abnormalities, abnormal collagen (Ehlers-Danlos syndrome), and von Willebrand disease. Unfortunately, because of its insensitivity and high level of variability, the bleeding time is a relatively poor tool for detecting the milder forms of these hemostatic disorders and cannot be used to rule out von Willebrand disease
Perform 1:1 mix, repeat PT Mix corrects
Trial vitamin K, repeat PT Prolonged
Prolonged
Test for factor inhibitor and lupus anticoagulant
Assay factor VII Normal
Assay factors II, V, and X Figure 50-6. Flow diagram for the evaluation of an isolated prolongation of the prothrombin time (PT).
Chapter 50 Bleeding and Thrombosis
PTT Normal
Retest off medications
STOP
Prolonged
Perform 1:1 mix, repeat PTT Mix corrects
Prolonged
Assay factors VIII, IX, XI, XII, and vWF
Negative
Test for lupus anticoagulant; rule out heparin
Figure 50-7. Flow diagram for the evaluation of a patient with a prolonged partial thromboplastin time (PTT). To rule out heparin effect, the thrombin time is compared with the reptilase time. If the thrombin time is significantly longer than the reptilase time, heparin is present in the sample. vWF, von Willebrand factor.
low fibrinogen levels ( Age 5 Years and Adults Progressive dermatomyositis with chronic ECHO virus encephalitis Sinopulmonary infections, neurologic deterioration, telangiectasis Recurrent Neisseria meningitis Sinopulmonary infections, malabsorption, splenomegaly, autoimmunity
Diagnosis
DiGeorge syndrome Congenital asplenia Leukocyte adhesion deficiency syndrome Severe combined immunodeficiency Severe combined immunodeficiency with graft-versus-host disease Wiskott-Aldrich syndrome Chédiak-Higashi syndrome Rac-2 deficiency C3 deficiency Severe congenital neutropenia Immunodeficiency with hyper-IgM syndrome
X-linked lymphoproliferative syndrome (Duncan disease) X-linked agammaglobulinemia Hyperimmunoglobulin E syndrome Chronic mucocutaneous candidiasis Specific granule deficiency Chronic granulomatous disease Cartilage hair hypoplasia with short-limbed dwarfism X-linked agammaglobulinemia Ataxia-telangiectasia C5, C6, C7, and C8 deficiency Common variable immunodeficiency
Modified from Conley ME, Stiehm ER: Immunodeficiency disorders: General consideration. In Stiehm ER (ed): Immunologic Disorders in Infants and Children, 4th ed. Philadelphia, WB Saunders, 1996, p 212. ECHO, enteric cytopathogenic human orphan virus; IgM, immunoglobulin M.
patient. A neutrophil count below 500/mm3 might indicate severe congenital neutropenia, cyclic neutropenia, idiopathic neutropenia, marrow failure, or replacement of marrow by leukemia or a tumor if other hematopoietic cell lines are affected. Once initial immunoglobulin level screening is completed, other tests may include specific antibody responses to vaccines (tetanus, rubella, pneumococcal); immunoglobulin G (IgG) subclass levels for IgG1, IgG2, IgG3, and IgG4; and delayed hypersensitivity skin tests. Table 51-6 presents the characteristic clinical features of some of the primary immunodeficiencies.
benign infectious agents, or they develop infections with unusual organisms. Pneumocystis carinii, cytomegalovirus, measles, and varicella often cause fatal pneumonitis in these patients. Pneumonitis occurring with any of these agents should alert the clinician to a potential immunodeficiency. Affected children also have a higher incidence of malignancy and autoimmune disorders. A partial list of primary disorders of lymphocyte function is shown in Table 51-7; their evaluation is described in Figure 51-1.
DISORDERS OF ANTIBODY PRODUCTION LYMPHOCYTE DISORDERS Lymphocyte disorders are a heterogeneous group of primary disorders involving both cell-mediated and humoral immunity. Disorders affecting T cell function (cell-mediated immunity) tend to be more severe than primary B cell disorders; combined deficits carry the poorest prognosis. Children with altered T lymphocyte function have recurrent infections (see Tables 51-1 and 51-7) or unusual responses to usually
X-LINKED AGAMMAGLOBULINEMIA Bruton agammaglobulinemia, an X-linked recessive disorder characterized by an arrest in B cell differentiation, leaves affected children severely deficient in serum immunoglobulins and at serious risk for recurrent life-threatening infections. The affected gene product encoded at chromosome Xq22 is a cytoplasmic protein tyrosine kinase (Bruton tyrosine kinase [BTK]), which is essential for pre–B cell growth into mature B cells; its mutation accounts for the absence
Not known AR (14q32.3) X-linked (Xq26.3q27.1) AR (12p13)
IgG subclass deficiency
Immunodeficiency with increased IgM
1-3 months
1-3 months
1-3 months
1-3 months
X-linked (Xq13.1q21.1) AR (5p13)
AR (1q31-q32)
AR (11q23)
Severe combined immunodeficiency (SCID)
Birth
AR (9p13)
Cartilage-hair hypoplasia (short-limbed dwarf)
2-5 years
Early infancy
Early infancy
AR (11q22.3)
Not hereditary microdeletion (22 q11.2) X-linked (Xp11.22)
2-3 years
2-3 years
Variable
Second to third decade Infancy (4-9 months) Variable
Infancy (6-9 months)
Onset
Ataxia-telangiectasia
Wiskott-Aldrich syndrome
DiGeorge anomaly
Immunodeficiency with increased IgM
Not known
Common variable immunodeficiency Transient hypogammaglobulinemia of infancy IgA deficiency Not known
X-linked (Xq21.3-q22)
Genetics
Bruton agammaglobulinemia
Disorder
Table 51-7. Disorders of Lymphocyte Function
Same as previous entry
Same as previous entry
Same as previous entry
Candidiasis, all types of infections (bacterial, viral, fungal, protozoal)
Variable infections
Recurrent otitis media, pneumonia, meningitis with encapsulated organisms Sinopulmonary infections
Recurrent high-grade infections, sinusitis, pneumonia, meningitis Sinusitis, bronchitis, pneumonia, chronic diarrhea Recurrent viral and pyogenic infections Sinopulmonary infections; Gastrointestinal infections; may be unaffected Variable (unaffected to recurrent sinopulmonary infections and gastrointestinal infections) Recurrent pyogenic infections (otitis media, sinusitis, tonsillitis, pneumonia) Recurrent pyogenic infections (otitis media, sinusitis, tonsillitis, pneumonia) Variable
Manifestations
Mutation in the RMRP gene disrupting RNAse MRP RNA affecting multiple organs IL-2Rγ depletion (severe T cell depletion), T cell negative, B cell positive, natural killer cell negative T cell–negative, B cell–positive, natural killer cell–positive, SCID secondary to IL-7 receptor α-chain mutation on 5p13 T cell–negative, B cell–positive, natural killer cell–positive, SCID secondary to mutant CD45 phosphatase (which encodes for tyrosine kinase signaling protein, known as CD45 deficiency T cell–negative, B cell–positive, natural killer cell–positive, SCID secondary to mutations in CD 3 genes
Defect in DNA repair and control of cell cycle
Control of assembly of actin filaments
Defect in isotype IgG production secondary to mutation of genes encoding the μ chain on 14q32.3 Defect in IgG and IgA synthesis secondary to abnormal gene encoding CD40 ligand on T cells Mutation of activation-induced cytidine deaminase gene that controls signaling in B cells Hypoplasia of third and fourth pharyngeal pouch
Arrest in B cell to plasma cell differentiation Delayed development of plasma cell maturation Failure of IgA expressing B cell differentiation
Arrest in B cell differentiation (pre-B–B level; initiation of BTK)
Pathogenesis
Same as previous entry
Same as previous entry
Graft-versus-host disease from blood transfusions
Continued
Severe graft-versus-host disease from maternal fetal transfusions
Hypoparathyroidism, micrognathia, hypertelorism, congenital heart disease Recurrent infections, atopic dermatitis, platelet dysfunction, thrombocytopenia Neurologic and endocrine dysfunction, malignancy, telangiectasias Metaphyseal dysplasia, short extremities, neutropenia
Hematologic autoimmune disease
Hematologic autoimmune disease
Autoimmune disease, RA, SLE, Graves disease, ITP, malignancy Frequent in families with immunodeficiencies IgG subclass deficiency, common variable immunodeficiency, autoimmune diseases IgA deficiency
Lymphoid hypoplasia
Associated Features
Chapter 51 Recurrent Infection
939
AR (2q12)
CD8 lymphopenia
Early infancy
1-3 months
Infections similar to those in SCID
Similar to MHC class II deficiency
Persistent diarrhea secondary to cryptosporidiosis, bacterial pneumonia, P. carinii pneumonia, septicemia, viral and candida infections; patients are not at risk for graft-versushost disease
Defective maturation of common stem cell affecting myeloid and lymphoid cells Three mutations affect subunits of RFX, a multiprotein transcription factor complex that binds the X-box motif of the MHC class II promoter, which controls expression of MHC class II molecules; a fourth mutation involves MHC class II transactivator (CIITA), which is a molecule that controls the inducibility of expression of class II MHC genes Mutations affecting either TAP1 or TAP2 genes within MHC locus on chromosome 6 that encodes the peptide-transporter proteins called transporters associated with antigen processing (TAPs); TAPs transport peptide antigens from the cytoplasm to join the α chain of MHC class I molecules and β2 microglobulin; if the complex cannot be completed because of a lack of peptide antigens, MHC class I complex is destroyed in the cytoplasm Mutations in gene encoding ζ-associated protein 70 (ZAP-70), a tyrosine kinase important in T cell signaling
Enzyme deficiency results in dGTP-induced T cell toxicity
T cell–negative, B cell–positive, natural killer cell–negative, SCID secondary to mutant Janusassociated kinase 3 gene on 19p13.1 T cell–negative, B cell–negative, natural killer cell–positive, SCID associated with deficiencies of recombinase-activating gene proteins secondary to RAG1 or RAG2 gene on 6q21.3 Enzyme deficiency results in dATP-induced T cell toxicity
Pathogenesis
Normal or elevated CD4+ T cells, no CD8+ T cells, normal natural killer cells, normal B cells, normal immunoglobulin levels
Deficiency of CD8+ T cells, normal number of CD4+ cells
Few CD4+ T cells normal or CD8+ T cells elevated MHC class II antigens are lacking on B cells and monocytes Immune responses are impaired
Neurologic disorders, severe graft-versus-host disease from blood transfusions Agammaglobulinemia, alymphocytosis, agranulocytosis
Multiple skeletal abnormalities, chondroosseous dysplasia
Same as previous entry
Same as previous entry
Associated Features
ADA, adenosine deaminase; AR, autosomal recessive; BTK, Bruton tyrosine kinase; dATP, deoxyadenosine triphosphate; dGTP, deoxyguanosine triphosphate; IgA, IgG, and IgM, immunoglobulins A, G, and M; IL-2Rγ, interleukin-2 receptor γ chain; IL-7, interleukin-7; ITP, idiopathic thrombocytopenic purpura; MHC, major histocompatibility complex; PNP, purine nucleoside phosphorylase; RA, rheumatoid arthritis; RAG1 and RAG2, recombinase-activating genes 1 and 2; SLE, systemic lupus erythematosus.
AR (6q21.3)
Class I MHC deficiency
Same as previous entry
1-3 months Early infancy
Same as previous entry
1-3 months
AR (16p13)
Same as previous entry
1-3 months
AR (20q13.2q13.11) (ADA deficiency) AR (PNP deficiency) (14q13.1) AR (reticular dysgenesis)
Same as previous entry
1-3 months
AR (Omenn syndrome)
Same as previous entry
Manifestations
1-3 months
Onset
AR
Genetics
Class II MHC deficiency
Disorder
Table 51-7. Disorders of Lymphocyte Function—cont’d
940 Section Nine Infectious Disorders
Chapter 51 Recurrent Infection
941
Figure 51-1. Algorithm for the work-up of a patient with infections. AIDS, acquired immunodeficiency syndrome; G6PD, glucose6-phosphate dehydrogenase; GSH, reduced glutathione; IgA, IgE, IgG, and IgM, immunoglobulins A, E, G, and M; LAD, leukocyte adhesion deficiency syndrome; NBT, nitroblue tetrazolium; WBC, white blood cell. (Modified from Boxer LA: Quantitative abnormalities of granulocytes. In Beutler E, Lichtman MA, Coller BS, et al [eds]: Williams Hematology, 6th ed. New York, McGraw-Hill, 2001, p 847.)
of circulating B cells in these patients. The mutant BTK gene has been found in myeloid cells, which may account for the intermittent neutropenia associated with this condition. More than 400 different mutations in the BTK gene have been identified. Although some affected children are asymptomatic until the age of 2 years, most show symptoms in infancy between 6 and 9 months of age, when transplacentally derived maternal antibodies disappear. They develop repeated infections (recurrent otitis media, sinusitis, pneumonia, meningitis) with highly pathogenic bacteria, such as pneumococci, staphylococci, streptococci, and Haemophilus species. They handle most simple viral infections well; immunizations do not cause problems except for live polio vaccine, which has
resulted in paralysis. Exposure to other enteroviruses has led to chronic diarrhea, hepatitis, pneumonitis, and persistent meningoencephalitis. Affected patients have marked hypoplasia of lymphoid tissue (adenoids, tonsils, lymph nodes) with absence of germinal centers and rare plasma cells. The diagnosis can be suspected if serum IgG, immunoglobulin M (IgM), and IgA levels are less than 5% of age-adjusted control values in a patient with normal T cell function. On occasion, children with X-linked agammaglobulinemia present with an elevated IgA or IgG level but do not respond to immunizations with specific antibody production. Treatment includes aggressive antibiotic management of infections and replacement of
Section Nine Infectious Disorders
942
immunoglobulin, although chronic pulmonary and gastrointestinal diseases may occur (Table 51-8). COMMON VARIABLE IMMUNODEFICIENCY Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by the development of severe hypogammaglobulinemia, which results in chronic respiratory infections (sinusitis, bronchitis, pneumonia) and severe gastrointestinal disease. CVID is associated with a celiac disease–like syndrome, which occurs in up to 60% of patients. These patients experience heavy bacterial overgrowth of the small bowel, jejunal villous atrophy, and intestinal nodular lymphoid hyperplasia. The bacteria overgrowth in the gut often leads to diarrhea, steatorrhea, malabsorption, and protein-losing enteropathy. Patients can also develop noncaseating granulomas of the liver, spleen, lungs, and skin. Giardia lamblia infection is common in these patients and may play a role in the gastrointestinal problems because many such patients experience improvement with metronidazole. As in X-linked agammaglobulinemia, the most common manifestations of CVID are chronic infections of the upper and lower respiratory tracts. Hematologic abnormalities include immune-mediated thrombocytopenia, anemia, leukopenia, and systemic lupus erythematosus. There appears to be an increased susceptibility to lymphoreticular malignancies and carcinoma of the stomach in affected adults. Patients with CVID have low circulating levels of IgG, IgM, and IgA but normal to increased numbers of circulating B cells with greatly reduced numbers of plasma cells in the intestinal lamina propria. B cells fail to respond to normal maturational signals. TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY The fetus is capable of producing IgM or IgG by the 20th week of gestation when adequately stimulated; under normal conditions, however, neonatal levels of IgG are a reflection of prior maternal immunity via transplacental passage of maternal IgG. Significant
antibody production does not normally begin until the second or third month of life. Because maternal antibodies have a half-life of approximately 30 days, the infant may develop a variable physiologic hypogammaglobulinemia between the ages of 4 and 9 months. If profound in extent or duration, this transient hypoglobulinemia may lead to recurrent viral and pyogenic infections. Infants with such infections are capable of making specific antibodies (tetanus, diphtheria toxoids), they respond to immunizations, and they have normal numbers of circulating B and T cells. Lymph nodes are small, and germinal centers are reduced in size and number. The abnormality may be caused by decreased maturation of B cells to antibody-producing plasma cells. Most patients do not require gamma globulin therapy and achieve normal immunoglobulin levels between 12 and 36 months of age. IMMUNOGLOBULIN A DEFICIENCY IgA deficiency is the most common primary immunodeficiency. The mode of transmission appears to be variable: either autosomal recessive or autosomal dominant with variable penetrance. The defect causes an arrest in B cell maturation. Patients with IgA deficiency may be asymptomatic or may present with recurrent sinopulmonary and gastrointestinal infections. IgA deficiency is also often associated with IgG2 or IgG4 subclass deficiency, which worsens the prognosis. There is also a high incidence of autoimmune disorders and an association with CVID. Most patients with IgA deficiency do not require treatment other than antibiotic management of their infections. Blood products that include immunoglobulins are often contraindicated because patients may develop antibodies against IgA, possibly precipitating anaphylactic reactions. IMMUNOGLOBULIN G SUBCLASS DEFICIENCY Four different subclasses of IgG (IgG1 [65% of total IgG], IgG2 [25%], IgG3 [5% to 10%], and IgG4 [5%]) have been identified. Different types of antigens elicit a particular subclass of IgG
Table 51-8. Management of Infections in the Host Compromised by B and T Lymphocyte Defects Immunodeficiency Syndrome
Management
Humoral defects (predominant Intravenous immunoglobulin, 0.4 g/kg B cell deficiency) Bacterial and viral culture Incision and drainage of abscess Bactericidal antibiotics based on culture and sensitivity of microorganism Intraventricular immunoglobulin for echovirus, encephalitis, pleconaril, antiviral therapy Cellular defects (predominant Bacterial, viral, fungal, protozoal culture, T cell deficiency) microscopy, and stains Incision and drainage of abscess Biopsy, bronchoalveolar lavage if indicated Antibacterial, antiviral, antifungal, antiprotozoal therapy as appropriate for culture, sensitivity, stains, and symptoms Intravenous immunoglobulin if helper T lymphocyte–associated antibody deficiency or SCID is present
Prevention of Infection
Maintenance intravenous immunoglobulin, 0.3-0.5 g/kg q3-4wk Avoid live virus vaccines in patient and relatives Respiratory care, postural drainage, monitor for cor pulmonale Chronic antibiotic prophylaxis is controversial Prophylactic trimethoprim-sulfamethoxazole for Pneumocystis carinii No live virus vaccines or BCG Careful screening for tuberculosis Irradiated blood products decrease risk of GVH CMV-negative blood products Varicella-zoster immune globulin used for those with varicella exposure Immunologic reconstitution Bone marrow transplantation Fetal thymus transplantation for DiGeorge symptoms Polyethylene glycol ADA enzyme infusion ADA genetic reconstitution
ADA, Adenosine deaminase enzyme; BCG, bacille Calmette-Guérin; CMV, cytomegalovirus; GVH, graft-versus-host disease, which increases risk of infection; SCID, severe combined immunodeficiency.
Chapter 51 Recurrent Infection response (e.g., protein antigens tend to elicit an IgG1 response, whereas carbohydrates elicit an IgG2 response). In children younger than 2 years, it is difficult to elicit an antibody response to carbohydrate antigens (reflected by the necessity of protein conjugation for pneumococcal and Haemophilus influenzae vaccine). The spectrum of IgG subclass deficiency is variable. Some patients do well, whereas others have recurrent upper and lower respiratory infections, otitis media, sinusitis, and gastroenteritis, with both bacteria and viruses. In some children, immune function improves with age, often reaching normal levels by the age of 7 or 8 years. Total IgG level is usually normal, and only on examination of IgG subclasses can the defect be detected. Determination of antibody titers to polysaccharide antigens (Streptococcus pneumoniae, Neisseria meningitidis) aids in the assessment of immunologic function and the specific need for medical intervention. Many children with subclass deficiency do well with no treatment; others respond to prophylactic antibiotics; and still others require intravenous immune globulin replacement. IMMUNODEFICIENCY WITH INCREASED IMMUNOGLOBULIN M LEVEL Immunodeficiency with increased IgM level is a heterogeneous group of disorders characterized by normal or increased concentrations of IgM and IgD but decreased levels or absence of IgG, IgA, and IgE (see Table 51-7). The most common form of these disorders is X-linked hyper-IgM syndrome. Patients with these disorders are more susceptible to P. carinii pneumonia and to recurrent pyogenic infections. This is because of deficiency of the T cell surface molecule, CD154 (or CD40 ligand). This membrane glycoprotein is essential for T cell initiation of B cell isotype switching and CD80 and CD86 upregulation. Failure to upregulate B cell activity results in diminished B cell–derived costimulatory molecules, defective purging of autoreactive thymocytes, increased incidence of autoimmune disease, defective recognition of tumor cells, and increased incidence of cancer. An autosomal recessive form of this disorder may be caused by an intrinsic B cell defect in CD40-mediated signaling.
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congenital heart defects, and deficiency in cell-mediated immunity (see Table 51-7). The clinical anomalies are caused by the maldevelopment of structures that are derived from the first through the sixth branchial pouches during embryogenesis, resulting in variable hypoplasia of the thymus, parathyroid glands, face, ears, aortic arch, and heart. Congenital heart defects include truncus arteriosus, ventricular septal defect, interrupted aortic arch, and tetralogy of Fallot. Hypocalcemia with tetany is often the initial problem in the first and second month after birth. Facial abnormalities include microstomia, hypertelorism, and low-set ears. A majority of the cases of DiGeorge syndrome are associated with a microdeletion at chromosome 22q11.2, although a deletion at a second loci at chromosome 10p13 results in a similar clinical picture. Both chromosomal anomalies can be diagnosed with fluorescent in situ hybridization. The degree of immunodeficiency is highly variable and related to the extent of residual thymic function. Some patients have infections with opportunistic organisms (P. carinii, viruses, and fungi), whereas others exhibit normal immune function. Serum immunoglobulin levels are appropriate, but antibody response to specific antigenic challenges varies. Intradermal delayed hypersensitivity may be absent, decreased, or normal, whereas lymph node paracortical areas and thymus-dependent regions of the spleen show variable degrees of cell depletion, depending on the degree of thymic deficiency. The total lymphocyte count may vary from severely depressed to normal, but T cell levels are usually depressed. No correlation has been shown between severity of congenital defects and the severity of immunodeficiency, although immune function often improves with age. The management of DiGeorge syndrome is described in Table 51-8. WISKOTT-ALDRICH SYNDROME
T lymphocytes are the effectors for cell-mediated immunity. T lymphocytes differentiate in the thymus and serve as regulators of the humoral and the cell-mediated immune system; they modulate the activities of nonlymphocytic cells, such as monocytes. Patients with combined defects in T and B cell function have infections or other problems that are more severe than those in patients with only antibody deficiency.
Wiskott-Aldrich syndrome, an X-linked recessive disorder mapped to chromosome Xp11.22, is characterized by abnormalities in lymphocyte, platelet, and phagocyte function (see Table 51-7). The gene product encodes for a protein that controls the assembly of actin filaments and intracellular vesicle transport in lymphocytes and megakaryocytes. Wiskott-Aldrich syndrome is characterized by this triad: (1) recurrent infections involving encapsulated bacteria and opportunistic pathogens, (2) hemorrhage secondary to thrombocytopenia and platelet dysfunction, and (3) atopic dermatitis. Presenting in early infancy with pneumonia, otitis media, and meningitis, patients are susceptible to infection with encapsulated organisms. Later, they develop fungal and P. carinii infections but are also at risk for disseminated herpes simplex and cytomegalovirus infections. Patients have selective defects in multiple areas of their immune system. Initial serum IgG levels are typically normal, with elevated IgA and IgE and decreased IgM levels. Patients initially respond normally to protein antigens, such as tetanus, but serum antibody levels diminish over time. Their antibody response to polysaccharide antigens is extremely poor, and blood-group isohemagglutinins are absent. The serum half-life of immunoglobulin also appears to be decreased. There are abnormalities in cellular immunity manifested by anergy and diminished response to mitogen stimulation. They may exhibit moderately reduced numbers of CD3+, CD4+, and CD8+ T cells. Thrombocytopenia characterized by small platelets is a unique feature. Prolonged bleeding at circumcision or profuse bloody diarrhea is observed. Many children with this disorder succumb to bleeding disorders or infection; 12% die of secondary lymphomas. Bone marrow or cord blood transplantation from a human leukocyte antigen–identical sibling or a human leukocyte antigen–matched unrelated donor has corrected the immunologic and platelet abnormalities in patients with Wiskott-Aldrich syndrome.
DIGEORGE SYNDROME
ATAXIA-TELANGIECTASIA
DiGeorge syndrome is characterized by a constellation of clinical features that include dysmorphic facies, hypoparathyroidism,
Ataxia-telangiectasia is an autosomal recessive disorder characterized by neurologic dysfunction, endocrine abnormalities, oculocutaneous
X-LINKED LYMPHOPROLIFERATIVE DISEASE (DUNCAN SYNDROME) X-linked lymphoproliferative disease is a rare genetic disorder characterized by immunodysregulation in response to Epstein-Barr virus (EBV). The usual manifestation is a fulminant, often fatal infection with EBV. Survivors of primary EBV infection often develop acquired hypogammaglobulinemia, B cell lymphoma, aplastic anemia, vasculitis, and lymphomatoid granulomatosis. The gene responsible for X-linked lymphoproliferative disease has been localized to chromosome Xq25. It encodes for a ligand-receptor pair on B and T cell that results in their coregulation. Mutations are thought to result in the uncontrolled proliferation of B cells after EBV infection.
COMBINED DISORDERS OF T AND B CELLS
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Section Nine Infectious Disorders
telangiectasia, immunodeficiency, and a high rate of malignancy (see Table 51-7). The defective gene, located on chromosome 11q22.3, encodes for a phosphatidylinositol 3-kinase involved in intracellular signal transduction and DNA repair. Cerebellar ataxia is usually the first presenting sign, occurring when the child begins to walk. The patient’s neurologic status often worsens, and choreoathetosis, involuntary myoclonic jerks, and oculomotor abnormalities develop. Telangiectasias first appear in the bulbar conjunctivae between 2 and 5 years of age and later spread to areas of trauma. Endocrine abnormalities, such as insulin-resistant diabetes mellitus, and hypogonadism are common. There is a 15% risk of malignancy; non-Hodgkin lymphoma is the most common. Patients with ataxia-telangiectasia are extremely sensitive to ionizing radiation, as a result of alteration in DNA repair. This accounts for the high incidence of chromosomal translocations involving chromosomes 7 and 14 at the site of T cell receptor genes and immunoglobulin heavy-chain genes. The degree of immunodeficiency is quite variable; both B cell and T cell abnormalities occur. The most common B cell abnormalities include IgA deficiency (75% of patients), IgE deficiency (85%), and monomeric IgM (80%). IgG subclass deficiency occurs in about 50%; IgG2 and IgG4 deficiencies are the most common. T cells show abnormal, delayed-type hypersensitivity reaction, proliferative response to mitogens, and allograft rejection. The thymus is abnormally small, and although circulating T lymphocyte numbers appear to be normal, peripheral lymphoid tissue reveals depletion in resident T cells. Patients with ataxia-telangiectasia have sinopulmonary infections. Administration of blood products that include immunoglobulins can lead to anaphylactic reactions because IgA-deficient patients often produce autoantibodies to IgA. CARTILAGE-HAIR HYPOPLASIA (SHORT-LIMBED DWARFISM) Cartilage-hair hypoplasia is an autosomal recessive disease characterized by metaphyseal dysostosis; sparse, thin hair; and variable immunodeficiency (see Table 51-7). Lymphocyte numbers may be normal or dramatically depressed. Proliferative responses to mitogens are generally depressed; immune function may deteriorate with time. The immunodeficiency can range from mild to severe; in most affected patients, it is relatively mild, and patients benefit most from replacement immunoglobulin. Patients may have moderate to severe neutropenia, making them susceptible to both viral and bacterial infections.
SEVERE COMBINED IMMUNODEFICIENCY SYNDROMES Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by profound abnormalities in B cell and T cell function. In the first few months after birth, patients present with recurrent pneumonia, failure to thrive, and chronic diarrhea. They often have candidiasis of the mouth, esophagus, face, and diaper area, in addition to other infections (bacterial, viral, fungal, protozoal). Adenovirus and cytomegalovirus frequently progress into chronic pneumonitis; disseminated, life-threatening varicella and measles infections occur; and live-virus vaccines can result in a fatal infection such as disseminated mycobacterial infection with bacille Calmette-Guérin. Severe graft-versus-host disease frequently develops after blood transfusions that contain live donor lymphocytes. Most patients exhibit severe deficits in immunoglobulin synthesis that range from agammaglobulinemia to isolated subclass deficiencies; responses to specific antigens are usually impaired. B cells may be absent or increased, but T cell abnormalities are always present. T cell numbers are generally fewer than 10% of normal in
more than 80% of patients. Patients are anergic, and T cells show decreased proliferative responses to mitogens, decreased cytotoxicity, and decreased immunoregulatory activity. Residual host natural killer cell activity may account for graft failure in patients with SCID who are treated with haploidentical bone marrow transplantation. X-LINKED RECESSIVE SEVERE COMBINED IMMUNODEFICIENCY X-linked recessive SCID is the most common form of SCID (approximately 46% of the cases) and is characterized by T cell and natural killer cell depletion in the presence of normal numbers of B cells (see Table 51-7). The abnormal gene has been mapped to the Xq13 region encoding for the γ chain that is common to five interleukin molecules (interleukins-2, -4, -7, -9, and -15). The interleukin-2 receptor is necessary for thymic maturation of T cells; its deficiency explains T cell depletion. T cell depletion in conjunction with diminished levels of several cytokine receptors arising from a single mutated gene further explains how T cells, B cells, and natural killer cells can all be affected. Female carriers can be identified because lymphocytes and natural killer cells exhibit nonrandom inactivation of the X chromosome. The management of X-linked recessive SCID is noted in Table 51-8. Isolated deficiencies in the α subunits of the interleukin-2 and interleukin-7 (5p13) receptor that clinically manifest with SCID have also been identified. DEFICIENCY OF JANUS-ASSOCIATED KINASE-3 Janus-associated kinase 3 (Jak 3) is the only signaling molecule known to associate with the γ chain of interleukin receptors (see Table 51-7). This disorder resembles X-linked recessive SCID with regard to susceptibility to infections and transfusion-related graftversus-host disease. Affected patients also have low levels of T cells and natural killer cells but elevated levels of B cells. Natural killer cell numbers remain low even after successful bone marrow transplantation. DEFICIENCY OF CD45 CD45 is a transmembrane tyrosine phosphatase, found exclusively on hematopoietic cells, which regulates src tyrosine kinases (required for signal transduction of T and B cell receptors). Deficiency of CD45 manifests clinically as SCID with low numbers of T cells but normal B cells (see Table 51-7). Although serum immunoglobulin levels may be normal initially, they decrease with time, and there is a diminished response to specific antigen challenge. CD8 LYMPHOPENIA ζ-Associated protein 70 (ZAP-70) is a tyrosine kinase that plays an essential role in the positive and negative selection of maturing T cells (see Table 51-7). The gene encoding ZAP-70 is located at chromosome 2q12; its deficiency results in CD8 lymphopenia. The severity of the immunodeficiency is variable; however, affected patients generally have normal or elevated CD4+ T cells and essentially no CD8+ T cells. OMENN SYNDROME This form of SCID is characterized by the absence of functional T cells and B cells (see Table 51-7). The circulating lymphocytes are predominantly natural killer cells. Mutation in recombinase-activating gene 1 or 2 (RAG1 and RAG2) leads to impaired rearrangement of B cell receptor and T cell receptor genes. Affected patients develop a generalized erythroderma and desquamation, diarrhea, hepatosplenomegaly, hypereosinophilia, and hyper-IgE. Omenn syndrome is fatal unless corrected by bone marrow transplantation.
Chapter 51 Recurrent Infection RETICULAR DYSGENESIS Reticular dysgenesis is the most severe form of SCID. It is characterized by agammaglobulinemia, lymphopenia, and neutropenia; erythroid and platelet precursor numbers are normal. Affected patients die shortly after birth of overwhelming infection unless they are treated successfully with bone marrow transplantation (see Table 51-8). DEFICIENCY OF MAJOR HISTOCOMPATIBILITY COMPLEX MOLECULES (BARE LYMPHOCYTE SYNDROME) The expression of cell surface major histocompatibility complex (MHC) molecules is important for cell-cell recognition; the failure to express these molecules is associated with SCID. Deficiencies have been described in the expression of both class I and class II MHC molecules (see Table 51-7). Deficiency in class II MHC molecules is more common, accounting for 5% of cases of SCID. It is also more severe because class II molecules are required for the positive selection of T helper cells in the thymus, for T cell recognition of antigen-presenting cells, and for T helper cell interactions with B cells. Deficiency in class I MHC molecules results in decreased numbers of CD8+ T cells but normal numbers of CD4+ T cells, whereas deficiency in class II MHC molecules results in low numbers of CD8+ T cells and normal or elevated numbers of CD8+ T cells. The defect is not in the class II MHC gene itself but in genes regulating the transcription of class II MHC genes. A similar defect exists for class I MHC gene expression. Patients with these forms of SCID have altered T helper/suppressor interaction, as well as altered antigen presentation. ADENOSINE DEAMINASE DEFICIENCY Adenosine deaminase deficiency, an autosomal recessive trait, results in an inability to catalyze the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. The gene is located on chromosome 20q13.2-q13.11, and its deficiency results in the accumulation of deoxyadenosine, which is phosphorylated to deoxy–adenosine triphosphate (deoxy-ATP) (see Table 51-7). Deoxy-ATP is toxic to lymphocytes, leading to their demise and to subsequent SCID. Patients with this enzyme deficiency have different degrees of agammaglobulinemia and lymphopenia. In addition, they often have associated chondroosseous dysplasia with multiple skeletal abnormalities. Treatment is described in Table 51-8. PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY Purine nucleoside phosphorylase (PNP) is the enzyme (chromosome 14q11) that follows adenosine deaminase in the purine salvage pathway and catalyzes the conversion of inosine and guanosine to hypoxanthine and guanine, respectively (see Table 51-7). PNP deficiency leads to the intracellular buildup of deoxy-guanosine triphosphate (deoxy-GTP). Like deoxy-ATP, deoxy-GTP is toxic to T cells, resulting in T cell lymphopenia, whereas the number of B cells remains normal. Serum immunoglobulin and isohemagglutinin levels are normal. Specific antibody production is impaired because T helper function is abnormal. In patients with SCID, a low serum uric acid level is suggestive of PNP deficiency.
COMPLEMENT SYSTEM DEFICIENCIES The complement system has an integral role in the regulation of the immune system and its response to infectious agents. As the complement cascade is activated and progresses, all areas of the immune system are affected: C4a and C2a regulate vascular permeability, C3b and C3bi regulate phagocytosis, C5a mediates the release of
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cytokines from monocytes and is chemotactic for neutrophils, and C9 complex formation mediates cell lysis. Activation of the classic pathway begins with fixation of C1, by way of Clq to the crystallized fragment receptor of an antigen-antibody complex. A conformational shift results in the activation of C1s, which activates C4 and then C2. The C142 complex acts as a C3 convertase, which activates C3 from C3b, whereas in the alternative pathway, BbC3b activates C3. C3bi, an important opsonin, is formed by cleavage of C3b by C3b inactivator. C3b formation results in the sequential activation of C5 through C9. C9 activation results in the formation of the membrane attack complex, consisting of 12 to 18 C9 molecules that form a transmembrane channel, resulting in cell lysis. Teichoic acid from bacterial cell wall, endotoxic lipopolysaccharides, and aggregates of immunoglobulin, especially IgA, are potent activators of the alternative pathway. Although protein deficiencies or abnormalities have been identified for all 11 components in the classical complement pathway, the severity and the type of infection varies because of the considerable overlap between the two pathways (Table 51-9). In addition, C1 inhibitor deficiency is an autosomal dominant disorder that results in dysregulation of the classic complement pathway. Activation of the classic pathway results in angioneurotic edema secondary to the uncontrolled formation of C4a and C2a, two vasoactive proteins. After minor trauma, affected patients develop swelling and edema without urticaria, pain, or erythema. The swelling usually lasts 24 to 48 hours before subsiding spontaneously. Angioedema involving the larynx or upper airways can be lifethreatening, and involvement of the bowel leads to abdominal pain, vomiting, and diarrhea. Affected children often do not come to medical attention until after puberty; androgens such as danazol or stanozolol are effective at preventing attacks. SECONDARY COMPLEMENT DEFICIENCIES IgG binds to C1q, protecting it from rapid catabolism; therefore, children with hypogammaglobulinemia develop partial C1q deficiency. Patients with chronic membranoproliferative glomerulonephritis and partial lipodystrophy may develop nephritic factor, an antibody that protects the C3bBb complex from inactivation, resulting in the consumption of C3 and a relative C3-deficient state. These patients are at risk for developing pyogenic infections, including meningitis, if their serum C3 levels fall below 10% of normal levels. Patients with acute postinfectious glomerulonephritis and systemic lupus erythematosus may develop an antibody similar to nephritic factor, which protects the C3 convertase of the classic pathway. Most newborns are relatively deficient in all components of the classic pathway, as well as in factor B and properdin in the alternative pathway; their ability to generate serum-derived chemotactic factors and opsonization is markedly diminished. Complement activity is even lower in premature infants. Malnutrition and anorexia nervosa may lead to decreased levels of all components of complement, whereas cirrhosis of the liver is associated with decreased synthesis of C3. Immune complex disease (systemic lupus erythematosus, postinfectious nephritis) can result in increased complement consumption and relative deficiency. Increased complement consumption has also been demonstrated in lepromatous leprosy, bacterial endocarditis, malaria, dengue fever, acute hepatitis B, and infectious mononucleosis. Burn injuries can induce massive activation of complement, which accounts at least partially for the increased risk of infection in burned patients. In patients with erythropoietic protoporphyria or porphyria cutanea tarda, hypocomplementemia develops because certain wavelengths of light activate complement, which results in abnormal consumption. DIAGNOSIS AND MANAGEMENT The most useful screening test is the total hemolytic complement activity (CH50). The CH50 measures the ability of all 11 components
Section Nine Infectious Disorders
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Table 51-9. Genetic Deficiencies of Complement Components Associated Clinical Findings Component
Genetics
Associated Diseases
C1q C1s C1r C1 inhibitor C4 C2
Autosomal recessive Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive
C3
Autosomal recessive
SLE, MPGN, vasculitis SLE SLE, CGN, vasculitis Hereditary angioedema, SLE SLE, HSP, Sjögren syndrome SLE, HSP, ITP, CGN, dermatomyositis, vasculitis, MPGN SLE, MPGN, vasculitis
C5
Autosomal recessive
SLE
C6
Autosomal recessive
C7
Autosomal recessive
C8
Autosomal recessive
SLE, MPGN, Sjögren syndrome, Raynaud phenomenon SLE, scleroderma, ankylosing spondylitis, rheumatoid arthritis, Raynaud phenomenon SLE
C9
Autosomal recessive
Factor D
X-linked/autosomal recessive Autosomal recessive Autosomal recessive X-linked Autosomal recessive
Factor I Factor H Properdin Factor B
Hemolytic-uremic syndrome
Recurrent Infections
Septicemia, meningitis, pyoderma, dermatitis Recurrent pneumonia, meningitis Recurrent pneumonia, meningitis Recurrent pneumonia, meningitis Recurrent septicemia, especially pneumococcal; meningitis; pneumonia Severe pyogenic infection caused by meningococci and pneumococci Disseminated gonococcal and meningococcal disease, pyoderma, meningitis Disseminated gonococcal and meningococcal disease Disseminated gonococcal and meningococcal disease Disseminated gonococcal and meningococcal disease Meningococcal meningitis, extragenital gonococcal infections Recurrent sinusitis, bronchitis, DGI Pyogenic infections, septicemia Pyogenic infections, septicemia Septicemia Meningococcal meningitis
CGN, chronic glomerulonephritis; DGI, disseminated gonococcal infection; HSP, Henoch-Schönlein purpura; ITP, idiopathic thrombocytopenia purpura; MPGN, membranoproliferative glomerulonephritis; SLE, systemic lupus erythematosus.
of the classic pathway to lyse antibody-coated red blood cells. This assay does not identify abnormalities in the alternative pathway, but with factor H and I deficiency, increased consumption of C3 is identified by a decrease in CH50. The alternative pathway can be screened by use of a hemolytic assay in which rabbit erythrocytes serve as both the activating surface and the target. Measurements of C3 and C4 can help distinguish complement deficiencies. Although deficiency in several of the complement components results in an increased susceptibility to meningococcal disease, the routine screening of infected patients has a low yield. However, the incidence of complement deficiency in individuals with meningococcal disease caused by uncommon serogroups is significantly higher, warranting an evaluation of the complement cascade (terminal complement and properdin deficiency being most common). In hereditary angioneurotic edema, C4 levels are generally low, but C3 levels are normal. Low C3 and C4 levels are seen when the classic pathway is activated, whereas activation of the alternative pathway characteristically results in low C3 levels and normal C4 levels. No specific therapy exists for any of the genetic disorders of complement. Replacement factors are not available. Some patients with angioedema respond to androgen therapy, especially in short-term use. For patients at increased risk for infection as a result of other deficiencies in the complement system, appropriate immunizations and aggressive management of infections are the bulwark of therapy.
PHAGOCYTE DISORDERS Neutrophils are important in protecting the skin, mucous membrane, and the lining of the respiratory and gastrointestinal tracts. They
form the first line of defense against microbial invasion. During the critical first 2 to 4 hours after tissue invasion by pathogenic organisms, the arrival of phagocytic cells at the site of infection is crucial for the containment of the infection, limiting the size of the local lesion, and preventing dissemination. To arrive at the site of inflammation and be effective, phagocytic cells must attach (adhere) to the vascular endothelium near the site of invasion or inflammation. Once attached to the endothelium, they pass through the vessel wall (diapedesis), move in a unidirectional manner toward the site of inflammation (chemotaxis), adhere to and ingest the offending organisms (phagocytosis), and activate biochemical pathways important in intracellular microbial killing (degranulation and oxidative metabolism). Microbial killing is accomplished by two mechanisms: (1) respiratory burst and (2) degranulation. The respiratory burst consists of the de novo synthesis of highly toxic and often unstable derivatives of molecular oxygen (respiratory burst oxidase). Degranulation is the process by which lysosomal granules, containing preformed polypeptide antibiotics and proteases, fuse with the phagocytic vacuoles containing the ingested microbes. Patients whose neutrophils have defects in adhesion or cell motility generally have cutaneous abscesses with common pathogens such as Staphylococcus aureus or have mucous membrane lesions caused by agents such as Candida albicans or oral anaerobic bacterial flora. Individuals with defects in the interferon γ–interleukin-12 axis are more susceptible to infections with atypical mycobacteria. If the defect in adhesion and chemotaxis is profound, lesions may contain few, if any, neutrophils. Disorders of phagocyte microbicidal activity (chronic granulomatous disease) are associated with cutaneous abscesses, lymphadenitis, pulmonary infections, and gastrointestinal problems, such as antral obstruction. Affected patients tend to have more deep-seated and chronic infections involving the liver and lung (Table 51-10).
Chapter 51 Recurrent Infection
DISORDERS OF MACROPHAGE FUNCTION DEFECTS IN THE INTERFERON γ – INTERLEUKIN-12 AXIS The interferon γ–interleukin-12 axis is crucial to host defense against intracellular pathogens, including Mycobacteria, Listeria, and Salmonella organisms. Dendritic cells and macrophages produce interleukin-12 in response to bacterial pathogens (see Table 51-10). Various defects with this axis have been described with both autosomal dominant and recessive inheritance patterns. Interleukin-12, in turn, stimulates the secretion of interferon γ by T cells and natural killer cells. Interferon α release binds to macrophage stimulating the production of tumor necrosis factor α and augmenting the respiratory burst that promotes bacterial killing. The classic members of this group of disorders involve mutations in the interferon γ receptor, the signaling chain of the interferon γ receptor, the interleukin-12 receptor, or interleukin-12 itself. The interferon-γ receptor contains two chains (ligand-binding and signaling). Complete absence of either chain causes the most severe disease, manifesting early in infancy, often with disseminated atypical mycobacterial infection, recurrent Salmonella infection, or fatal infection after bacille Calmette-Guérin vaccination. Partial receptor chain loss causes milder disease, often in early childhood, but nonetheless with increased susceptibility to nontuberculous mycobacterial disease. Deficiencies in the production of interferon γ have been described, as have defects in interleukin-12 production and in the interleukin-12 receptor expression. Many affected patients have increased susceptibility to nontuberculous mycobacteria but show some response to treatment with interferon γ.
DISORDERS OF NEUTROPHIL NUMBERS CYCLIC NEUTROPENIA Cyclic neutropenia is an autosomal dominant disorder characterized by periodic episodes of profound neutropenia (absolute neutrophil counts