Visual Diagnosis : A 10-year-old Boy With a Persistent Rash Since Birth Sanjeev Tuli and Sonal Tuli Pediatrics in Review 2011;32;e102 DOI: 10.1542/pir.32-11-e102
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/e102
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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visual diagnosis
A 10-year-old Boy With a Persistent Rash Since Birth Sanjeev Tuli, MD,* Sonal Tuli, MD*
Presentation
Figure 1. Erythematous macules and hyperpigmented, hyper-
keratotic plaques on the face, trunk, and extremities.
Figure 2. Scaling and peeling of the skin on the legs.
Author Disclosure Drs Tuli and Tuli have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
A 10-year-old boy presents to the clinic with a lifelong history of a rash involving the face, extremities, trunk, palms, and soles. The patient was born to healthy parents and had an unremarkable prenatal and postnatal history. At 4 hours of age, he developed blotchy red patches on his trunk. The patches waxed and waned until the age of 1 year. At age 1 year, the rash was mostly persistent and consisted of numerous erythematous patches on his trunk and extremities. Subsequently, in addition to the erythematous rash, the patient developed fixed, scaly, brown patches on the trunk and thickening, reddening patches with sharply demarcated borders on the cheeks, extensor surfaces of forearms, and knees. The palms and soles also thickened over the years. Some of the skin lesions would worsen and resolve partially over time. His condition waxed and waned without complete resolution over the years, frequently worsening during hot weather. Further history is remarkable for the following characteristics: Before 8 years of age, he could produce sweat minimally. When cut, he does not bleed or scar easily. He removes his scaly, “dirty-looking� skin from his skin folds by lubrication with ammonium lactate 12% cream (LacHydrin, Bristol-Myers Squibb, Princeton, NJ, and generic preparations) and rubbing. His skin condition has been improving steadily over the years. His vision, hearing, and development are appropriate for age. Topical antibiotic and steroid medications, emollients, and systemic antihistamine medications have been ineffective in resolving his condition. Currently, he takes no medications, has no known drug allergies, and is in good health otherwise. There is no family history of similar skin problems. Physical examination reveals normal vital signs. There are multiple irregularly shaped, well-demarcated, erythematous macules and patches and hyperpigmented, hyperkeratotic (scaly patches with increased keratin layer) plaques located on the face, trunk, and extremities (Fig. 1). There is some scaling and peeling of the skin on his legs (Fig. 2). The hair and nails appear normal. The rest of his physical examination is unremarkable.
*Associate Professor, University of Florida, Gainesville, FL.
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Complete blood count, serum electrolytes, and serum liver enzyme profile are normal. A clinical diagnosis is made.
Diagnosis: Erythrokeratodermia The boy has erythrokeratodermia variabilis based on his sharply demarcated erythematous areas that vary in size, shape, and distribution over days and thick, scaly plaques with increased keratinization.
Discussion Erythrokeratodermia variabilis is a rare dermatologic disorder characterized by hyperkeratosis with noninflammatory erythema. It is a variant of ichthyosis. Mendes da Costa coined the term in 1925 when he described the features of this disease in a mother and daughter. Erythrokeratodermia variabilis is transmitted in an autosomal dominant fashion, although sporadic and autosomal recessive cases have been reported. Males and females are affected equally. The disease usually manifests within the first year after birth and is due to abnormal keratinization. The defect has been mapped to chromosome 1p34p35.1, which contains connexin genes encoding gap junction proteins. The connexin genes are expressed preferentially in the upper, differentiated keratinocytes of human epidermis. This finding suggests that they play a crucial role during epidermal differentiation. Abnormalities in these genes can, therefore, lead to abnormal epidermal differentiation and function. Various different mutations in the connexin genes have been identified that account for the disease’s clinical heterogeneity. The prevalence of erythrokeratodermia variabilis is unknown but it is a rare disease, with approximately 200 cases published in the literature. Children present with sharply demarcated, migratory, erythematous patches on various parts of their body that appear, enlarge, or regress over time. Concurrently, or over time, persistent, well-demarcated, brown, hyperkeratotic plaques develop, which are scattered on the face, buttocks, trunk, and extremities. The erythematous patches are transient and may last only minutes to hours. In one third of cases, these red patches may be preceded or accompanied by a burning or stinging sensation. Hyperkeratosis may be generalized or localized and may have associated fine scaling or peeling. These areas appear yellowish-brown and may have a velvety surface over the distal extremities. About one half of affected children display a palmo-
plantar keratoderma (thickening and scaling of the palms and plantar surface of the feet due to increased keratinization) associated with peeling. Lesions may be precipitated by either trauma or exposure to sudden changes in temperature. The condition tends to improve in the summer and worsen in the winter months. Erythrokeratodermia variabilis displays marked intraand interfamilial variability and tends to worsen until puberty, when it may regress partially. The disorder eventually enters a stable, chronic course characterized by erythematous patches and scaly plaques over the trunk, extremities, and face. The overall health of these patients is unaffected and they have a normal lifespan. However, erythrokeratodermia variabilis can cause significant psychosocial effects from the disfigured, deformed appearance of the skin. The differential diagnosis of erythrokeratodermia variabilis includes symmetric progressive erythrokeratodermia (these plaques are large, fixed, geographic, and symmetric), plaque-type psoriasis, and other forms of ichthyosis (eg, Netherton syndrome, CHILD [congenital hemidysplasia with ichthyosiform erythroderma and limb defects] syndrome). However, this condition can be differentiated by its migratory nature of erythematous plaques and discrete erythematous and hyperkeratotic plaques. The diagnosis is essentially clinical based on the classic, sharply demarcated erythematous patches that vary in size, shape, and location as well as the scaly, thickened plaques over the trunk, extremities, and face. Histopathology is not useful for diagnosis because it is nonspecific. There is no treatment that changes the course of erythrokeratodermia variabilis. Management is geared toward decreasing the hyperkeratosis and discomfort. Hydration is the mainstay of treatment and is accomplished best by immersion in a water bath followed by application of petroleum jelly. Keratolytic agents such as propylene glycol with lactic acid, urea, and buffered lactic acid are used most commonly. Systemic retinoids (isotretinoin or acitretin) or topical retinoids such as tazarotene can result in dramatic improvement by decreasing hyperkeratosis (scales). However, they are usually reserved for severe cases because they cause relapses when discontinued. In addition, this therapy is limited by long-term toxicities. Stinging and pruritus might be ameliorated with mildly sedating antihistamines.
Patient Course Because the boy did not have significant hyperkeratosis and was asymptomatic, he and his parents were reassured Pediatrics in Review Vol.32 No.11 November 2011 e103
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about his condition and advised to treat the scaly patches on his extremities with lubrication.
Summary Erythrokeratodermia variabilis is a rare, inherited disease characterized by erythematous as well as hyperkeratotic lesions over the face, trunk, and extremities. The lesions are not life-threatening but can cause significant psychosocial issues from disfigurement of the skin. Treatment is aimed at decreasing the hyperkeratosis. Lubrication is the mainstay of therapy, but topical or systemic retinoids may be used in severe cases.
Suggested Reading 1. Richard G, Smith L, Bailey R, et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nature Genet. 1998;20:366 –369 2. Richard G, Itin P, Bale SJ, et al. Clinical heterogeneity in EKV. J Invest Dermatol. 1998;110:616 3. Hendrix JD Jr, Greer KE. Erythrokeratodermia variabilis present at birth: case report and review of the literature. Pediatr Dermatol. 1995;12:351–354 4. Van de Kerkhof PC, Steijlen PM, van Dooren-Greebe RJ, Happle R. Acitretin in the treatment of erythrokeratodermia variabilis [review]. Dermatologica. 1990;181:330 –333 5. Maekawa Y, Yasaka S. Erythrokeratodermia variabilis. J Dermatol. 1977;4:147–150
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Visual Diagnosis : A 10-year-old Boy With a Persistent Rash Since Birth Sanjeev Tuli and Sonal Tuli Pediatrics in Review 2011;32;e102 DOI: 10.1542/pir.32-11-e102
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Throat Infections Rani Gereige and Beatriz Cunill-De Sautu Pediatrics in Review 2011;32;459 DOI: 10.1542/pir.32-11-459
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/459
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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Article
ear, nose, and throat disorders
Throat Infections Rani Gereige, MD, MPH, FAAP,* Beatriz CunillDe Sautu, MD, FAAP†
Author Disclosure Drs Gereige and Cunill-De Sautu have
Objectives 1. 2. 3. 4. 5. 6.
After completing this article, readers should be able to:
Discuss the causes of pediatric throat infections. Identify the usual clinical presentation of pharyngitis in children. Describe the laboratory testing available to aid in the diagnosis of pharyngitis. Explain the treatment of bacterial throat infections. Understand the complications of pharyngeal infections. Know the differentiating features of peritonsillar and retropharyngeal abscess.
disclosed no financial relationships relevant
Introduction
to this article. This
Sore throat in children accounts for up to 7.3 million outpatient visits to the physician each year in the United States and a significant number of missed school days and parental work days. Thus, this common pediatric complaint imposes both a medical and nonmedical burden on families and society as a whole. (1) Clinicians are challenged to evaluate complaints of sore throat judiciously with careful consideration of the presenting signs and symptoms and epidemiologic factors to distinguish between patients who require further testing and antimicrobial therapy and those with benign self-limited conditions. This article reviews the common causes, clinical presentation, diagnostic evaluation, treatment, and potential complications of throat infections.
commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
Definition and Epidemiology
Abbreviations CT: EBV: GAS: HSV: RADT: US:
The medical dictionary defines pharyngitis as “inflammation of the pharynx.” Pharyngitis can be due to infectious (bacteria, viruses, and fungi) or noninfectious causes (irritants, smoking, etc.). This article will focus primarily on the infectious causes of pharyngitis. Most infectious causes of pharyngitis are transmitted by close contact via respiratory secretions, and children serve as the major reservoir of infection. Additionally, spread of illness among family members is a frequent occurrence and family illness is an important detail to elicit in the history. Viral infections are the most common cause of acute pharyngitis in infants and preschool-age children. Group A Streptococcus (GAS; Streptococcus pyogenes) is the most important bacterial cause of acute pharyngitis in older children. Streptococcal pharyngitis is rare before 2 to 3 years of age and has a peak incidence in school-age children between 5 and 11 years of age. Gonococcal pharyngitis occurs more frequently in adolescents and young adults, with 40% of reported cases occurring in females age 15 to 19 years. (2) Seasonality of pharyngitis depends on the cause, with most cases occurring during the respiratory disease season in the colder months; however, pharyngoconjunctival fever caused by adenovirus usually is seen in the summer. Pharyngitis caused by GAS is seen most frequently in winter and early spring.
computed tomographic Epstein-Barr virus group A Streptococcus herpes simplex viruses rapid antigen detection tests ultrasonography
Clinical Presentation The presentation of pharyngitis virtually always includes sore throat, fever, and pharyngeal erythema (Fig. 1, A and B). Other signs and symptoms are more variable depending on the cause. In general, sore throat in the presence of rhinitis,
*Editorial Board. Director of Medical Education, Miami Children’s Hospital, Clinical Professor of Pediatrics, Florida International University, Miami, FL. † Director, Pediatric Residency Program, Miami Children’s Hospital, Clinical Assistant Professor of Pediatrics, Florida International University, Miami, FL. Pediatrics in Review Vol.32 No.11 November 2011 459
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throat infections
Figure 1. (A) Petechiae on the palate is a clinical finding suggestive of group A Streptococcus (GAS) infection. (B) Tonsillar exudate
can be seen in both GAS and viral pharyngitis. Reprinted with permission from Zitelli BJ, Davies HW, eds. In: Atlas of Pediatric Physical Diagnosis. 5th ed. Philadelphia, PA: Mosby/Elsevier; 2007.
cough, stridor, conjunctivitis, or diarrhea is more likely to be caused by a viral infection. Conversely, the abrupt onset of fever, sore throat, headache, nausea, vomiting, abdominal pain in the absence of coryza, and cough is highly suggestive of GAS infection, the most common form of bacterial pharyngitis. GAS pharyngitis accompanied by a diffuse, erythematous rash of rough, sandpaperlike texture is called scarlet fever. This scarlatiniform rash usually blanches with pressure and concentrates along flexor creases such as the anticubital, axillary, and inguinal areas (Pastia lines). Desquamation may occur as the rash begins to fade. (3)(4)(5) Table 1 compares features of viral and GAS pharyngitis.
Differential Diagnosis Although infections are by far the most common causes of pharyngitis in children, noninfectious causes also must be considered in the differential diagnosis of a patient presenting with sore throat (Table 2). Noninfectious causes include irritants and noninfectious inflammatory conditions.
Etiology Adenovirus Adenoviruses are DNA viruses whose transmission may occur by direct contact with droplets from the respiratory tract, eye, or feces. (2)(3)(4)(5)(6)(7)(8) Adenoviruses
Comparison of Viral Pharyngitis and Group A Streptococcal Pharyngitis Table 1.
Most common age Transmission Seasonality Unique signs and symptoms
Onset Duration of symptoms
Viral
Group A Streptococcus
Infants–preschool age Inhalation or direct contact with respiratory secretions Fecal–oral (when there is enteric infection) Year-round, more common during colder months Coryza Cough Hoarseness, stridor Stomatitis Conjunctivitis Diarrhea ⴙ/ⴚ Hepatosplenomegaly ⴙ/ⴚ Nonspecific rash Gradual >4–5 d
5–11 y Inhalation or direct contact with respiratory secretions Winter–early spring Headache Nausea, vomiting Abdominal pain Palatal petechiae Scarlatiniform rash
Sudden, abrupt 3–5 d
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Table 2.
throat infections
Causes of Pharyngitis in Children
Bacterial
Viral
Noninfectious
Streptococcus, group A Streptococcus, group C, G Neisseria gonorrhoeae Mycoplasma pneumoniae Chlamydophila pneumoniae Chlamydia trachomatis Corynebacterium diphtheriae Arcanobacterium haemolyticum Francisella tularensis
Rhinovirus Coronavirus Influenza A, B Parainfluenza Respiratory syncytial virus Adenovirus Enterovirus Epstein-Barr virus Herpes simplex virus
Gastroesophageal reflux Postnasal drip Allergic rhinitis Chronic cough Foreign body Inhaled irritants, tobacco Caustic ingestions Malignancy Rheumatologic syndromes
may remain infectious for up to two weeks at room temperature; therefore, infection can occur indirectly via contact with contaminated objects or surfaces. The clinical presentation of adenoviral infection includes signs of acute upper respiratory illness such as fever, rhinorrhea, and cough; exudative pharyngitis; and conjunctivitis. Pharyngoconjunctival fever caused by adenoviruses is manifested by fever, pharyngitis, conjunctivitis, and cervical lymphadenopathy and is associated with outbreaks during the summer due to contaminated swimming waters.
Enterovirus Enteroviruses are a group of single-stranded RNA viruses whose transmission is via the fecal-oral or respiratory routes and which present most commonly in warm months. The manifestations of enteroviruses in general include fever; upper respiratory symptoms such as coryza, cough, and sore throat; gastrointestinal symptoms such as vomiting and diarrhea; and rash. Specific entities such as coxsackie virus can present with herpangina, which is characterized by pharyngeal vesicular and ulcerative lesions, or with hand–foot–mouth disease, characterized by similar vesicular lesions in the oropharynx along with a vesicular rash in the distal extremities. Tonsillar exudates are uncommon in enteroviral infection.
Herpes Simplex Virus Herpes simplex viruses (HSVs) are double-stranded DNA viruses and are transmitted via contact with infected bodily fluids or sores in the oral or genital tract. HSV-1 is more commonly transmitted via the oral route, whereas HSV-2 is acquired primarily via sexual contact. However, HSV-2 also may present as pharyngitis after oral– genital contact. Clinical manifestations of HSV may include fever, cervical lymphadenopathy, pharyngeal er-
ythema, and gingivostomatitis characterized by vesicular and ulcerative lesions involving the buccal mucosa and the lips, but sparing the posterior pharynx. Adolescents and adults with HSV may have mild pharyngitis without typical vesicular lesions.
Epstein-Barr Virus Epstein-Barr virus (EBV) is a herpesvirus whose primary infection of children usually is manifested as infectious mononucleosis. Transmission usually is from close personal contact with bodily fluids, more commonly via the oral route. EBV is an insidious infection with an incubation period of 4 to 7 weeks and clinical symptoms lasting an additional 1 to 3 weeks. The clinical presentation of infectious mononucleosis includes fever, fatigue, pharyngitis, lymphadenopathy, hepatosplenomegaly, and lymphocytosis. Additionally, a rash of variable morphology may develop, especially if antibiotic therapy, particularly with a beta-lactam antibiotic such as ampicillin, is administered in the presence of EBV infection.
Group A Streptococcus GAS is a beta-hemolytic, spherical, gram-positive bacterium transmitted via inhalation of or contact with respiratory secretions. GAS infections cause 15% to 30% of acute pharyngitis in children, peaking in those from 5 to 11 years of age. The clinical presentation of GAS pharyngitis includes sudden onset of fever, sore throat, headache, abdominal pain, nausea, and vomiting, along with the development of pharyngeal erythema with or without exudates, petechiae on the palate, and cervical lymphadenopathy. GAS infection generally is not associated with other classic upper respiratory symptoms such as rhinorrhea and cough. GAS pharyngitis with a scarlatiniform rash is caused by a strain of the bacterium that produces erythrogenic toxin. Pediatrics in Review Vol.32 No.11 November 2011 461
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Neisseria gonorrhoeae Neisseria gonorrhoeae is a gram-negative diplococcus bacteria whose transmission occurs via sexual contact. Although gonoccocal infections usually are associated with genital tract disease, the agent also may also cause pharyngitis in both males and females who engage in oral– genital sexual contact. Pharyngeal infection may be completely asymptomatic or can present with acute signs and symptoms such as fever, sore throat, pharyngeal erythema, exudate, and cervical lymphadenopathy.
Diagnosis The main objective of the primary care physician in making the diagnosis of acute pharyngitis is distinguishing which patients have a high likelihood of having GAS infection. (3)(4) Virtually all viral throat infections are benign and self-limited in immunocompetent hosts. Therefore, patients presenting with signs and symptoms consistent with viral infection do not need to undergo diagnostic testing or be treated with antibiotics. However, because there is a degree of overlap in the presentation of viral versus bacterial pharyngitis,
Figure 2. Diagnostic evaluation and management of pharyngitis.
clinical judgment alone often is not accurate in diagnosing GAS infections and often leads to overtreatment with antimicrobial therapy. Figure 2 highlights a general plan for the diagnostic evaluation and management of pharyngitis. The gold standard for diagnosing GAS pharyngitis continues to be the throat culture, which has a sensitivity of over 90%. Bacterial throat culture also may detect the presence of gonorrhoeae. Despite its high sensitivity, the quality of the throat culture specimen is dependent on collection and inoculation technique. Additionally, a positive throat culture for GAS does not distinguish between infection causing acute illness and colonization. Although throat culture is useful in the diagnosis of pharyngitis caused by GAS and gonorrhoeae, it is of no value in isolating the infectious agents associated with other diseases, such as otitis media, sinusitis, pneumonia, or meningitis. The advent of rapid antigen detection tests (RADTs), however, has given clinicians an inexpensive and rapid tool to facilitate the diagnosis of GAS pharyngitis. RADTs generally have a high specificity (95% to 99%); however, their sensitivity can range anywhere from 70% to 90%. Consequently, a positive RADT result can be considered diagnostic of GAS infection, and antimicrobial therapy may be initiated without further confirmatory testing. However, because the sensitivity of RADTs is so variable, a negative RADT result does not rule out GAS infection, and a confirmatory throat culture should be sent. As with traditional throat cultures, a positive RADT result does not distinguish between acute GAS infection and a chronic carrier state. Rapid diagnostic tests for the outpatient office setting also exist for various viral pathogens. Examples include tests for respiratory syncytial virus, influenza A and B viruses, and heterophile antibody spot tests for EBV. Of note, heterophile antibody tests have a low sensitivity in young children. Therefore, children younger than 5 years of age whose clinical presentation is suggestive of EBV infection but whose heterophile antibody test is
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negative warrant further serologic tests. Because the vast majority of viral pharyngeal infections is benign and self-limited and generally requires only supportive care, diagnostic tests to identify the viral pathogen usually are not clinically useful and will not change the patient’s management.
Treatment Although throat infections caused by GAS are known to be self-limited even without treatment with antibiotics, there are secondary benefits to management with antimicrobials. (9) Antibiotic therapy decreases the duration of symptoms mildly, diminishes transmission, reduces the likelihood of suppurative complications such as retropharyngeal and peritonsillar abscesses, and prevents the development of acute rheumatic fever if treatment is given within 9 days of onset of illness. First-line therapy for GAS pharyngitis continues to be penicillin, which may be given as a single intramuscular dose of benzathine penicillin G 600,000 units if ⬍27 kg (60 lb) or 1.2 million units if ⬎27 kg (60 lb). Oral penicillin VK 250 mg twice a day if ⬍27 kg or 500 mg twice a day if ⬎27 kg (60 lb) for 10 days also is considered first-line therapy. Oral amoxicillin suspension is also commonly used as an alternative to oral penicillin because of its palatable taste and subsequent better compliance. Children with penicillin allergy can be treated with macrolides such as erythromycin, clarithomycin, and azithromycin (12 mg/kg per d for 5 d) as long as macrolide resistance has not been documented in the community. Cephalosporins and clindamycin are additional options if other first-line antibiotics are contraindicated. Clindamycin is effective also for the eradication of the carrier state in patients who continue to test positive for GAS despite treatment with penicillin. Patients with GAS pharyngitis are no longer considered contagious after 24 hours of antibiotic therapy. Viral throat infections do not require antimicrobial therapy and can be treated conservatively with supportive care. Acetaminophen or ibuprofen can be used for fever and pain management. Adequate oral hydration, frequent gargling, and over-the-counter anesthetic sprays and lozenges also may relieve the sore throat. Finally, contact sports should be avoided in patients with acute EBV infection until they are recovered and have no signs of splenomegaly.
Complications Complications of pharyngitis in children can be early, such as retropharyngeal and peritonsillar abscesses, or late, such as rheumatic fever or glomerulonephritis. Al-
throat infections
though rare, complications such as retropharyngeal and peritonsillar abscesses are serious due to their potential for respiratory compromise and diagnosis requires a high degree of suspicion from the clinician and an immediate but careful action plan. We will discuss the two more serious early complications of retropharyngeal and peritonsillar abscesses. Table 3 gives a comparative summary of the differences between retropharyngeal and peritonsillar abscesses.
Anatomic Considerations Pediatric patients are more susceptible to acute airway compromise than adults due to specific anatomic differences. (10) Children have proportionately larger heads, more lax neck muscles, relatively larger tongues, and smaller oropharynges. The subglottic area is the narrowest segment of the pediatric airway, whereas the glottis is the narrowest in adults.
Retropharyngeal Abscess The retropharyngeal space, under normal conditions, is sterile and contains loose connective tissue and lymph nodes that drain the nasopharynx, paranasal sinuses, middle ear, teeth, and adjacent bones. (10) Retropharyngeal abscesses are caused by infection of the retropharyngeal space due to lymphatic spread. Other rare causes include penetrating trauma, foreign body, or iatrogenic instrumentation. Retropharyngeal abscess is seen most commonly in young children (⬍6 y of age). The clinical presentation of retropharyngeal abscess often is nonspecific and vague. Typically, patients start with a viral upper respiratory infection for several days. Gradual onset, over days, of fever, sore throat, and poor feeding are some of the initial presenting signs and symptoms. Neck stiffness or tenderness, due to irritation of prevertebral soft tissue, might be mistaken as meningeal signs. As symptoms progress, patients begin to show signs of extrathoracic respiratory compromise, the earliest of which is tachypnea. Drooling and stridor also are seen. Hypoxia and cyanosis are late signs and indicate impending respiratory failure. On physical examination, a retropharyngeal mass may be seen in some patients as well as tender enlarged cervical lymph nodes. It is important to note that forceful introduction of tongue depressors to try to visualize the retropharyngeal mass is strongly discouraged due to the risk of abscess rupture and secondary aspiration. The diagnostic evaluation for suspected retropharyngeal abscess begins with an inspiratory lateral neck radiograph in full extension. An abnormally increased thickness of the prevertebral soft tissue (Fig. 3), in the proper Pediatrics in Review Vol.32 No.11 November 2011 463
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Table 3.
throat infections
Comparison of Retropharyngeal Abscess and Peritonsillar Abscess
Most Common Age Presentation History
Physical Examination
Etiology
Retropharyngeal Abscess
Peritonsillar Abscess
<6 y Fever (gradual onset) Symptoms of upper respiratory infection Sore throat Dysphagia Stridor Tachypnea Neck pain or stiffness Drooling Cervical lymphadenopathy Retropharyngeal mass Polymicrobial, primarily Streptococcus pyogenes Staphylococcus aureus
20–40 y Fever Sore throat Dysphagia Ipsilateral otalgia
Diagnosis
Inspiratory lateral neck radiograph Contrast-enhanced CT
Treatment
Medical (successful alone in 25% of cases) Antistaphylococcal antibiotic with or without surgical incision and drainage CT-guided needle aspiration Aspiration pneumonia due to abscess rupture Local extension
Complications
Airway obstruction Poststreptococcal glomerulonephritis Rheumatic fever
Trismus Muffled “hot potato” voice Cervical lymphadenitis Ipsilateral palatal edema Contralateral uvular deviation Aerobes Streptococcus pyogenes Staphylococcus aureus Haemophilus influenzae Neisseria species Anaerobes Fusobacterium Peptostreptococcus Prevotella Bacteroides Needle aspiration Ultrasonography (transcutaneous or intraoral) Contrast-enhanced CT or magnetic resonance imaging Aspiration or surgical incision and drainage AND Antibiotics (10–14 d)–Cover aerobes and anaerobes Aspiration pneumonia due to abscess rupture Carotid sheath rupture hemorrhage and death Poststreptococcal glomerulonephritis Rheumatic fever
CT⫽computed tomography.
clinical context, strongly suggests a retropharyngeal infection with edema. The presence on lateral neck radiograph of gas or air-fluid levels in the retropharyngeal space, as well as the presence of foreign bodies, and the loss of the normal cervical lordosis are other important and supportive clues. A contrast-enhanced computed tomography (CT) scan is needed to define the precise anatomic extension and to differentiate a true abscess from retropharyngeal cellulitis (Fig. 4). Laboratory studies are nonspecific because blood cultures are generally negative, often there is an elevated white blood cell count and the erythrocyte sedimentation rate is
elevated. If surgical drainage is performed, aerobic and anaerobic cultures of the abscess material usually yield a polymicrobial flora, including Staphylococcus aureus, various Streptococcus species, and anaerobes. The treatment of retropharyngeal abscess should start with empiric antibiotic therapy (including an antistaphylococcal antibiotic). Medical management is reportedly effective in 25% of cases (10) and requires close airway monitoring and management including otolaryngology and surgical consultation. Surgical management is reserved for cases refractory to antibiotic therapy when there is a mature abscess. Careful endotracheal intuba-
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Figure 3. Lateral neck radiograph showing abnormally increased thickness of the prevertebral soft tissue (A and B) and loss of the
normal cervical lordosis (B). (A) Department of Radiology, Miami Children’s Hospital, FL. (B) Reprinted with permission from Zitelli BJ, Davies HW, eds. In: Atlas of Pediatric Physical Diagnosis. 5th ed. Philadelphia, PA: Mosby/Elsevier; 2007.
tion followed by intraoral surgical drainage is the standard of care. CT-guided needle aspiration has been reported as an alternative that causes less trauma to surrounding tissue and carries the potential of avoiding general anesthesia. Regardless of the drainage mode, great care should be exercised to avoid aspiration of purulent material or infectious material into the airway.
Peritonsillar Abscess Peritonsillar abscess is caused by an infection in the area between the palatine tonsil and its capsule. (10)(11) It is
the most common deep infection of the head and neck in adults and occurs more commonly in 20 to 40 years olds than in children, with an equal incidence in males and females. Peritonsillar abscess is seen mostly in November to December and April to May, which correspond to peak incidence times for streptococcal pharyngitis. Chronic tonsillitis is a predisposing factor for peritonsillar abscess. The clinical manifestations of peritonsillar abscess include fever, sore throat, dysphagia, muffled or “hot potato voice,” trismus, referred ear pain, and odynophaPediatrics in Review Vol.32 No.11 November 2011 465
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Figure 4. Computed tomography scans with contrast showing retropharyngeal abscess. Department of Radiology, Miami Childrenâ&#x20AC;&#x2122;s
Hospital, FL.
gia. On physical examination, ipsilateral palatal edema is noted leading to inferior medial displacement of the infected tonsil with contralateral deviation of the uvula
(a distinguishing feature; Fig. 5). Table 4 shows the differential diagnosis of peritonsillar abscess. Peritonsillar abscess typically is caused by a combination of aerobic and anaerobic bacteria. The most common etiologic organisms include aerobic pathogens such as pyogenes, aureus, Haemophilus influenzae, and Neisseria species, as well as anaerobic pathogens such as Fusobacterium, Peptostreptococcus, Prevotella, and Bacteroides. Bacteroides and Prevotella infections associated with human disease are polymicrobial and are pleomorphic, nonspore forming, facultative anaerobic, gram-negative bacilli. They are part of the normal flora of the mouth and gastrointestinal and female genitourinary tracts. These organisms can cause chronic sinusitis, chronic otitis media, dental infection, peritonsillar
Differential Diagnosis of Peritonsillar Abscess
Table 4.
Figure 5. Clinical examination finding of peritonsillar abscess
with contralateral uvular deviation. Reprinted with permission from Zitelli BJ, Davies HW, eds. In: Atlas of Pediatric Physical Diagnosis. 5th ed. Philadelphia, PA: Mosby/Elsevier; 2007.
Peritonsillar cellulitis Tonsillar abscess Infectious mononucleosis Foreign body aspiration Neoplasms (lymphoma, leukemia)
Cervical adenitis Dental infections Salivary gland infection Mastoid infection Aneurysm of internal carotid artery
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Figure 6. Computed tomography scans with contrast showing
peritonsillar abscess. (A) Department of Radiology, Miami Childrenâ&#x20AC;&#x2122;s Hospital, FL. (B) Reprinted with permission from Zitelli BJ, Davies HW, eds. In: Atlas of Pediatric Physical Diagnosis. 5th ed. Philadelphia, PA: Mosby/Elsevier; 2007.
abscess, cervical adenitis, retropharyngeal space infection, aspiration pneumonia, lung abscess, empyema, and necrotizing pneumonia. They show no evidence of person-to-person transmission except in infections resulting from human bites. The diagnosis of peritonsillar abscess can be difficult to make based on clinical grounds alone because both peritonsillar abscess and peritonsillar cellulitis may have similar clinical presentations. A study (12) that reviewed ultrasonography, CT scan, and clinical diagnosis of peritonsillar infections revealed the sensitivity and the specificity of the clinical diagnosis by an otolaryngologist to be 78% and 50%, respectively, when compared with contrast-enhanced CT and intraoral ultra-
sonography, demonstrating that clinical impression alone is unreliable. Several diagnostic modalities can be used to confirm clinical suspicion. Needle aspiration is the gold standard for diagnosis; however, it should be performed only by a trained physician due to serious complications such as aspiration of purulent drainage, bleeding, and carotid puncture. The aspirate should be sent for both aerobic and anaerobic cultures. Blind needle aspiration should be avoided because of pain, potential serious complications, and a false-negative rate of 10% to 24%. Ultrasonography is the easiest and most useful tool for differentiating peritonsillar abscess from other conditions, for detecting the presence or absence of fluid in Pediatrics in Review Vol.32 No.11 November 2011 467
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the posterior pharynx, and for making management decisions. The study can be performed either transcutaneously or intraorally, which is best done by utilizing a high frequency endocavitary probe (usually 8 to 13 MHz in frequency) after spraying the pharynx with topical anesthetic for comfort. CT with contrast (Fig. 6) or magnetic resonance imaging may be indicated if spread beyond the peritonsillar space to deeper neck tissues is suspected. The treatment of peritonsillar abscess consists of aspiration or surgical incision and drainage and antibiotic therapy for 10 to 14 days. Most otolaryngologists consider incision and drainage to be the gold standard, although in one study, (13) no significant difference was found between needle aspiration and incision and drainage with respect to duration of symptoms or initial treatment failure. There is no evidence of benefit from tonsillectomy acutely. Tonsillectomy should be done 3 to 6 months after the occurrence of abscess in patients with recurrent tonsillitis or peritonsillar abscesses. Antibiotic therapy should be directed toward aerobes and anaerobes. Bacteroides species of the mouth and respiratory tract are susceptible to penicillin G, ampicillin, and broad-spectrum penicillins such as ticarcillin or piperacillin, as opposed to Bacteroides species of the gastrointestinal tract, which are resistant to penicillin G but sensitive to metronidazole, chloramphenicol, and sometimes clindamycin. Clindamycin is active against virtually all mouth and respiratory tract Bacteroides and Prevotella isolates and is recommended by some experts as the drug of choice for anaerobic infections of the oral cavity and lungs. Some species of Bacteroides and almost 50% of Prevotella species produce beta-lactamase. Cefuroxime, cefotaxime, and ceftriaxone are not reliably effective. It is important to highlight that no evidence has been found for the use of oral or systemic corticosteroids. Peritonsillar abscess has several potential complications, including airway obstruction, aspiration pneumonia or lung abscess in cases of rupture of abscess; death due to hemorrhage from erosion or septic necrosis of the carotid sheath; extension of infection into deeper neck tissues or posterior mediastinum; and postStreptococcus sequelae (glomerulonephritis, rheumatic fever) when the infection is caused by pyogenes. The overall risk of recurrence after first peritonsillar abscess is reportedly 10% to 15%.
References 1. Alcaide ML, Bisno AL. Pharyngitis and epiglottitis. Infect Dis Clin North Am. 2007;21:449 – 469
Summary • Based on strong research evidence, viral infections are the most common causes of acute pharyngitis in infants and preschool-age children, whereas GAS pharyngitis occurs primarily in school-age children. (2) • Based on consensus, in sexually active adolescents with pharyngitis, the clinician should think of gonorrhea as one of the potential causes and test for it in addition to GAS. (2) • Based on strong research evidence, RADTs have a high specificity, but variable sensitivity. (3)(4) Therefore, a negative RADT result does not rule out GAS infection, and a confirmatory throat culture should be sent. • Based on some research evidence, retropharyngeal abscess occurs primarily in children <6 years of age, caused mostly by pyogenes and aureus, and responds to medical management in 25% of cases. (10) • Based on strong research evidence, peritonsillar abscess is caused by polymicrobial aerobic and anaerobic pathogens. Evaluation and treatment must cover both aerobes and anaerobes. (10)(11) • Based on some research evidence, peritonsillar abscesses are treated by medical and surgical interventions together. (10)(11)
2. Jaggi P, Shulman ST. Group A Streptococcal infections. Pediatr Rev. 2006;27:99 –105
3. Ezeanolue E, Ezeanolue C, Dashefsky B, Zenel JA. Peripheral brain: rapid diagnostic tests for infectious diseases suitable for office use. Pediatr Rev. 2005;26:383–387 4. Gerber MA. Diagnosis and treatment of pharyngitis in children. Pediatr Clin N Am. 2005;52:729 –747 5. Holder NA. Gonococcal infections. Pediatr Rev. 2008;29: 228 –234 6. Junker AK. Epstein-Barr virus. Pediatr Rev. 2005;26:79 – 85 7. Langley JM. Adenoviruses. Pediatr Rev. 2005;26:244 –249 8. Pasquinelli L, Byington C. Enterovirus infections. Pediatr Rev. 2006;27:e14 – e15 9. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. Red Book. 28th ed. Pickering L, ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009 10. Rotta AT, Wiryawan B. Respiratory emergencies in children. Respir Care. 2003;48:248 –258 11. Galioto NJ. Peritonsillar abscess. Am Fam Physician. 2008;77: 199 –202 12. Scott PM, Loftus WK, Kew J, et al. Diagnosis of peritonsillar infections: a prospective study of ultrasound, computerized tomography and clinical diagnosis. J Laryngol Otol. 1999;113: 229 –232 13. Stringer SP, Shaefer SD, Close LG. A randomized controlled trial for outpatient management of peritonsillar abscess. Arch Otolaryngol Head Neck Surg. 1988;114:296 –298
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PIR Quiz Quiz also available online at: http://pedsinreview.aappubliations.org. NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim credit online. No paper answer form will be printed in the journal. 1. Among the following, the clinical finding that is MOST suggestive of Group A streptococcal infection in a 10-year-old boy with sore throat is: A. B. C. D. E.
conjunctivitis diarrhea palatal petechiae rhinorrhea tonsillar exudate
2. A 15-year-old sexually active girl presents with fever, sore throat, cough, diffuse erythematous rash that blanches with pressure, and cervical lymphadenopathy. She is MOST likely infected with: A. B. C. D. E.
adenovirus coxsackie Epstein-Barr virus Group A Streptococcus Neisseria gonorrhea
3. A 13-year-old-boy with culture-proven group A streptococcal (GAS) pharyngitis received a single intramuscular dose of 1.2 million units of benzathine penicillin 3 weeks ago. A throat culture taken yesterday was positive for GAS. Among the following, the antibiotic you are MOST likely to prescribe is: A. B. C. D. E.
amoxicillin azithromycin clindamycin erythromycin penicillin VK
4. Participation in contact sports may be contraindicated in a patient acutely infected with which of the following viruses? A. B. C. D. E.
Adenovirus type 7 Coxsackie virus Epstein-Barr virus Herpes Simplex virus type 1 Herpes Simplex virus type 2
5. Retropharyngeal abscess and peritonsillar abscess are rare but serious complications of pharyngitis in children. Which of the following is a distinguishing feature of peritonsillar abscess? A. B. C. D. E.
cervical lymphadenopathy contralateral uvular deviation drooling dysphagia positive culture for Streptococcus pyogenes
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Throat Infections Rani Gereige and Beatriz Cunill-De Sautu Pediatrics in Review 2011;32;459 DOI: 10.1542/pir.32-11-459
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This article cites 12 articles, 7 of which you can access for free at: http://pedsinreview.aappublications.org/content/32/11/459#BIB L
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Arthritis in Children and Adolescents Janice John and Latha Chandran Pediatrics in Review 2011;32;470 DOI: 10.1542/pir.32-11-470
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/470
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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Article
musculoskeletal disorders
Arthritis in Children and Adolescents Janice John, DO, MS, MPH,* Latha Chandran, MD, MPH*
Author Disclosure Drs John and Chandran have
Objectives 1. 2. 3. 4. 5.
After reading this article, readers should be able to:
Identify the common causes of arthritis in children. Develop a broad differential diagnosis for arthritis in the pediatric population. Distinguish toxic synovitis from septic arthritis. Recognize and manage a patient with septic arthritis. Discuss the diagnostic and treatment approaches to reactive arthritis, acute rheumatic fever, Lyme arthritis, toxic synovitis, and juvenile idiopathic arthritis.
disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Introduction Arthritis is simply defined as inflammation of a joint. Arthritis may affect one or more joints and often is accompanied by swelling, redness, tenderness, warmth, and pain with movement. The pathophysiology of this inflammatory process varies depending on the underlying cause of arthritis. Monoarthritis is inflammation limited to one joint. In the context of juvenile idiopathic arthritis (JIA), oligoarthritis is defined as arthritis involving fewer than five joints, whereas polyarthritis is arthritis of five or more joints. Although there is a broad differential diagnosis, a thorough history and physical examination should provide sufficient information to direct the evaluation and management of the patient with arthritis. An overview of pediatric arthritis as well as a discussion of the most common causes, evaluation, and treatment is offered in this article.
History and Physical Examination It is important to differentiate arthralgia from arthritis. Arthralgia is the presence of joint pain without objective signs of inflammation (warmth, erythema, tenderness, and swelling) on physical examination. Several rheumatologic diseases, such as systemic lupus erythematosus, may present with arthralgia early in the course; it is also important to consider viral as well as other causes of arthralgia. Children who have arthritis may present with pain, limited range of motion, limp, and refusal to use or move the affected joint. Presence of fever, rash, and other constitutional symptoms may suggest an infectious or autoimmune cause. It is important to discern whether the arthritis is migratory and to ascertain the specific joints and number of joints Abbreviations affected. A complete history, including the history of present illness, recent illness, or injury, associated symptoms, prior ANA: antinuclear antibody similar episodes, and prior signs and symptoms, must be ARF: acute rheumatic fever elicited. In addition, immunization status and family history CRP: C-reactive protein of autoimmune disorders must be obtained. ESR: erythrocyte sedimentation rate Because the causes of arthritis are varied, patients may FDA: Food and Drug Administration present with a multitude of other organ system findings GAS: group A Streptococcus suggestive of the underlying cause. Therefore, a comprehenHLA: human leukocyte antigen sive physical examination is necessary. A toxic or ill appearIg: immune globulin ance may suggest a serious disorder such as pyogenic arthriJIA: juvenile idiopathic arthritis tis. Signs of concurrent upper respiratory infection such as MRI: magnetic resonance imaging rhinorrhea or pharyngitis may be present in patients who NSAIDs: nonsteroidal anti-inflammatory drugs have toxic synovitis. In sexually active patients, reactive arRF: rheumatoid factor thritis and gonococcal arthritis may occur; hence, a thorough SCFE: slipped capital femoral epiphysis genital and pelvic examination is necessary to evaluate for *Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY. 470 Pediatrics in Review Vol.32 No.11 November 2011
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Common Conditions Causing Arthritis and Associated Additional Physical Findings
Table 1.
Underlying condition
Physical examination findings associated with the arthritis
Disseminated gonorrhea
Fever, new heart murmur (in endocarditis), tenosynovitis, urethral discharge, cervicitis, genital lesions, oral or other lesions, meningismus, impaired mental status, and a maculopapular, pustular, necrotic, vesicular rash Fever, uveitis, pericardial rub, lung fields dull to percussion, decreased pulmonary aeration, hepatomegaly, splenomegaly, salmon patch (evanescent, maculopapular, linear rash prominent when febrile) Fever, Bell palsy, other cranial nerve palsies, mild meningismus Fever, conjunctivitis, uveitis, episcleritis, keratitis, corneal ulcerations, axial spine tenderness, enthesitis (especially of the plantar aponeurosis and Achilles tendon), dactylitis, urethritis, cervicitis, salpingitis, vulvovaginitis, small shallow penile ulcers (balanitis circinata), pustules that coalesce into psoriatic-like plaques (keratoderma blennorrhagica) Fever, ill appearance, pericardial rub, new heart murmur, erythema marginatum, subcutaneous nodules (wrist, elbow, knees), choreiform movements Ill appearance, fever, refusal to bear weight, pseudoparalysis Fever, pallor, pericardial rub, lung fields dull to percussion, decreased aeration, ulcerations, malar rash, discoid rash, other rashes, psychosis Low grade fever, rhinorrhea, pharyngitis
Juvenile idiopathic arthritis Late Lyme disease Reactive arthritis
Rheumatic fever Septic arthritis Systemic lupus erythematosus Toxic synovitis
urethritis or cervicitis. The presence of a rash or a typical lesion may be suggestive of a specific disorder. Table 1 lists several disease processes that present with arthritis and their additional physical findings that may be helpful in narrowing the broad differential diagnoses. On physical examination, the joints must be evaluated for crepitus, warmth, tenderness, swelling, joint effusion, erythema, contractures, or decreased range of motion. The patient’s preferred position at rest must be observed. The joints should be tested for passive and active range of motion. Examination of the contralateral joints is important for comparison purposes. The patient’s gait should be observed carefully.
Differential Diagnosis of Arthritis/Limping Commonly encountered causes of arthritis in children include septic arthritis, reactive arthritis, acute rheumatic fever (ARF), Lyme arthritis, toxic synovitis, and JIA. Arthritis may occur in patients afflicted with inflammatory bowel disease, systemic lupus erythematosus, Henoch-Scho¨nlein purpura, Kawasaki disease, sarcoidosis, and other autoimmune and connective tissue disorders. Patients who have arthritis affecting the lower extremities often present with a limp. In a limping child, orthopedic processes such as trauma, slipped capital femoral epiphysis (SCFE), Legg-Calve´-Perthes disease, enthesitis (inflammation of the enthesis, the point at which ligaments, tendons, and fascia attach to bone), and overuse injuries such as Osgood-Schlatter disease must be
considered. Leukemia, lymphoma, bone and other soft tissue masses, neuroblastoma, hemarthrosis and sickle cell crisis may present with limping as well. Other infectious causes such as osteomyelitis or a psoas muscle abscess also must be considered in a febrile limping child. Because the differential diagnosis for arthritis is extensive, this article will focus on a few common conditions that affect children and adolescents.
Septic Arthritis Septic arthritis, also known as pyogenic arthritis, occurs when there is bacterial invasion of the synovium and joint space followed by an inflammatory process. In the pediatric population, the incidence of septic arthritis peaks between 2 and 3 years of age and has a male predominance (2:1). Except in the neonatal population, Staphylococcus aureus is the most common pathogen implicated in pediatric septic arthritis. The most common pathogens that cause septic arthritis in neonates are group B Streptococcus, Staphyloccus aureus, and gram-negative bacilli. Other common pathogens causing pyogenic arthritis in childhood include Streptococcus pyogenes and S pneumoniae. Kingella kingae is isolated in young children who have a recent history of upper respiratory infection. Because of widespread immunization in the United States, Haemophilus influenzae is no longer a frequent pathogen causing septic arthritis. However, the incidence of community acquired methicillin-resistant Staphylococcus aureus in cases of musculoskeletal infecPediatrics in Review Vol.32 No.11 November 2011 471
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Pathogens and Antimicrobials in Septic Arthritis Based on Age Group/Risk Factors Table 2.
Population/Pattern
Organism(s)
Empiric Treatment
Neonate
Group B Streptococcus, Staphylococcus aureus (MSSA, MRSA), Escherichia coli, and other enteric gramnegative organisms
If premature or exposed to broad spectrum antibiotics, intravenous alimentation, intravascular catheter Children younger than 5 y
Candida albicans
Nafcillin or oxacillin OR Vancomycin or clindamycin PLUS Cefotaxime or gentamicin Amphotericin B ⴞ Fluconazole
S. aureus (MSSA, MRSA), Kingella kingae, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenza type b (rare if immunized)
Children older than 5 y
S. aureus and S. pyogenes
History of intravenous drug use
Pseudomonas aeruginosa
Preceding upper respiratory infection Sickle cell anemia History of sexual activity Contact with livestock Ingestion of unpasteurized dairy products or travel to endemic area
Candida spp. Haemophilus influenzae type b (rare if immunized), Kingella kingae Salmonella spp. Neisseria gonorrhoeae Brucella spp.
Nafcillin or oxacillin OR Vancomycin or clindamycin if MRSA suspected PLUS third-generation cephalosporin Nafcillin or oxacillin OR Vancomycin or clindamycin if MRSA suspected Antipseudomonal cephalosporin ⴞ aminoglycoside Amphotericin B ⴞ fluconazole Nafcillin or oxacillin PLUS third generation cephalosporin Cefotaxime or ceftriaxone Ceftriaxone Doxycycline or TMP-SMZ PLUS gentamicin PLUS Rifampin
Antibiotic choices, dosing, and duration of therapy should be confirmed because each clinical situation is unique and practice standards may change with time. MRSA⫽methicillin-resistant Staphylococcus aureus; MSSA⫽methicillin-sensitive Staphylococcus aureus; TMP-SMZ⫽trimethoprim-sulfamethoxazole.
tion, including septic arthritis, has been increasing. Other pathogens to consider when more than one joint is involved include Neisseria gonorrhoeae, N meningitidis, and Salmonella species. Table 2 details some common causes of pyogenic arthritis in specific populations and presents treatment options. Because the synovial membrane is vascular in nature, hematogenous seeding of bacteria is the most common mechanism of infection in septic arthritis. Alternatively, septic arthritis may result from the spread of an adjacent osteomyelitis or other infection. The hip and shoulder are particularly vulnerable to contiguous spread. Besides hematogenous and contiguous spread, it is important to consider trauma, instrumentation, and intra-articular injections as potential precursors to arthritis. Patients present often with localized symptoms such
as pain, swelling, limp, and refusal to ambulate or to move the affected area (pseudoparalysis). Generalized symptoms such as fever, malaise, fussiness, and decreased appetite are other common manifestations of septic arthritis. The joints of the lower extremities (hips, knees, and ankles) are affected in the vast majority of cases, with the knee being the most commonly affected joint. (1)(2) The patient often is febrile with signs of inflammation and limited range of motion of the affected joint. Patients position the affected limb to optimize intracapsular volume and minimize pain. Therefore, it is important to note the patient’s position at rest. Individuals who have septic arthritis of the knee tend to keep the affected knee moderately flexed. Those with septic arthritis of the hip keep the hips flexed, externally rotated, and abducted. (2)
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Characteristics of Pyogenic Arthritis, Toxic Synovitis, and Lyme Arthritis Table 3.
Feature
Pyogenic Arthritis
Toxic Synovitis
Lyme Arthritis
Clinical General Appearance Fever Limp Range of Motion
Generally ill appearing Usually present Yes, if affecting lower extremity Markedly decreased
Generally well appearing Low-grade or absent Often Slightly decreased, limited by pain
Generally well appearing Low-grade or absent Possible Decreased, depending on extent of effusion
Laboratory Serum WBC count ESR
Elevated with left shift Elevated (usually >40 mm/h)
Usually normal Normal to mildly elevated (<40 mm/h) Less than 1 mg/dL
Usually normal Elevated
Yellow, white, gray >50,000
Yellow 5,000–15,000
Positive 50%–80% of the time
Negative
Xanthochromic, white ⬃25,000 (wide range reported) Negative
Early soft tissue swelling, subchondral bony changes (2–4 wk later), obliteration or lateral displacement of the gluteal fat planes and capsular swelling Joint effusion always present
Usually normal
Usually normal, soft tissue swelling
Joint effusion may be present but small Normal or thickening of the articular surface
Joint effusion often present Often normal, limited data
CRP
Greater than 1 mg/dL (modest to significant increase)
Synovial Fluid Results Color WBC (WBC/mm3) Culture Imaging Plain radiograph
Ultrasonography MRI
Abnormalities of soft tissue, bone, and cartilage damage. Low signal on T1 weighted and a high signal on T2 weighted
Greater than 1 mg/dL (modest increase)
CRP⫽C-reactive protein; ESR⫽erythrocyte sedimentation rate; MRI⫽magnetic resonance imaging; WBC⫽white blood cell.
Laboratory Testing Arthrocentesis is mandatory for any patient in whom septic arthritis is considered strongly. Arthrocentesis can serve both diagnostic and therapeutic purposes. Laboratory tests most useful in diagnosing pyogenic arthritis are culture, Gram stain, and white blood cell counts of the synovial fluid (Table 3). Synovial fluid cultures are positive in 70% to 80% of cases; (3) however, a negative culture does not exclude the diagnosis of pyogenic arthritis. A complete blood count may indicate leukocytosis with a left shift. A blood culture may be positive in approximately one third of septic arthritis cases. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration also are supportive of this diagnosis. If N. gonorrhoeae is suspected in sexually active patients, pelvic, urethral, throat, skin, and rectal cultures should be obtained.
Imaging Plain radiographs in patients who have septic arthritis may reveal widened joint spaces or bulging of the soft tissues. Soft tissue swelling may be identified in radiographs as early as 48 hours into the infection. Plain radiographs also may reveal subchondral bony changes after 2 weeks of onset of the illness. (4) It is important to bear in mind that a normal plain radiograph does not rule out a pyogenic joint. Ultrasonography is a fast and noninvasive test that is useful in identifying and quantifying the joint effusion, as well as aiding in needle aspiration of the joint. In contrast to plain radiographs, magnetic resonance imaging (MRI) with gadolinium contrast is more sensitive for early detection of a septic joint. Because MRI gives reliable soft tissue and bone contrast, this modality is effective in identifying cartilaginous involvement. MRI may reveal abnormalities in surroundPediatrics in Review Vol.32 No.11 November 2011 473
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ing soft tissue and bone and delineate the extent of cartilaginous damage. A low signal on T1 weighted studies and a high signal on T2 weighted studies are indicative of active inflammatory or infectious processes. (4) Making the diagnosis of septic arthritis requires a high degree of suspicion while evaluating the constellation of symptoms, physical findings, and laboratory and imaging results.
Septic Arthritis in Neonates and Infants Clinically, septic arthritis is more challenging to diagnose in neonates, infants, and young children. Because neonates and infants have less mature inflammatory and immune responses, they may present with only vague symptoms. There may be no obvious joint involvement or fever. Pseudoparalysis is observed often. The hip is the most common joint affected in the neonatal population. (2) Infants have a higher rate of coexisting osteomyelitis and septic arthritis because the spread of infection from the metaphysis to the joint space is enhanced by the unique transphyseal vasculature in this age group. (4) Unique risk factors predisposing patients in this age group to the development of septic arthritis include a history of urinary infection, prematurity, and umbilical catheterization. (4) Young infants may not show an elevation in inflammatory markers such as white blood cells, ESR, and CRP. Due to the decreased overall muscle tone in neonates, widening of the hip space may lead to upward displacement or lateral subluxation of the femoral head being evident on plain radiograph. (4)
However, it is important that parenteral antibiotic therapy be administered at least for the first week. A downward trend in ESR and CRP concentrations is reassuring evidence of the effectiveness of ongoing therapy in reducing inflammation. When patients are not improving clinically, additional or alternate antibiotic regimens should be considered. Especially in community acquired methicillin-resistant Staphylococcus aureus infection, input from infectious disease specialists must be obtained to tailor therapy specifically to the results of local antibiotic susceptibility testing. Ultimately, the management of a pediatric patient who has septic arthritis is accomplished best by using a multidisciplinary approach with input from the orthopedic surgeon and the infectious disease specialist.
Complications and Pitfalls Pyogenic arthritis affecting the hip is particularly challenging to diagnose because frequently there is no apparent joint swelling. However, it is critical to make a timely diagnosis of septic arthritis, especially of the hip, because pressure on the precarious vascular supply to the femoral head makes it susceptible to long-term sequelae such as avascular necrosis, limb length disparities, pseudarthrosis (false joint), joint dislocations, and other bony or joint deformities. (4) Risk factors for long-term complications include age younger than 6 months, concomitant osteomyelitis, involvement of high risk joints such as the hip or shoulder, and delay in appropriate initial management (decompression and initiation of antibiotics) by 4 days or longer. (1)
Treatment Ideally, empiric antimicrobial therapy should be initiated promptly after joint aspiration is completed and cultures are obtained. However, antibiotic therapy should not be delayed while waiting for arthrocentesis. Immediate aspiration of the synovial fluid is essential to decompress the intracapsular space, remove infected fluid, and provide specimens for Gram stain, cell count, and culture. Although some patients respond well to needle aspiration and antibiotics, specific joints such as the hips and shoulder require open drainage. Many cases necessitate repeat needle aspiration, arthroscopic drainage, or even arthrotomy. Age, risk factors, and Gram stain (when positive) should direct initial antibiotic choice. Ultimately, positive synovial fluid or other culture and sensitivity results (as from blood, cerebrospinal fluid, cervix, and urethra) should dictate antibiotic selection. Antibiotics generally are administered for 2 to 6 weeks, depending on the organism and clinical resolution of signs and symptoms.
Reactive Arthritis Reactive arthritis is a type of arthritis associated with an infection at a distant site, distinct from that of the affected joints. Reactive arthritis is more common in the adult population than in children. However, it is an important entity to consider, particularly in adolescence. There is a 3:1 male predominance. Male patients and those who are human leukocyte antigen-B27 (HLA-B27) positive tend to have more severe disease. The pathogenesis of reactive arthritis is understood poorly. Although commonly associated with sexually transmitted pathogens such as Chlamydia trachomatis and N gonorrhoeae, reactive arthritis can be associated with other genitourinary, gastrointestinal, and upper respiratory pathogens. The most common pathogen associated with reactive arthritis in the United States is Chlamydia trachomatis. Gastrointestinal infections caused by Shigella species, Salmonella species, Yersinia species, or Campylobacter species potentially can lead to
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Treatment Approach to Common Causes of Pediatric Arthritis Table 4.
Disease Process
General Treatment Approach
Septic arthritis
● ● ●
Reactive arthritis
● ●
●
Rheumatic fever
● ● ● ●
Lyme arthritis
● ● ●
Toxic synovitis
● ●
Juvenile idiopathic arthritis
● ● ● ●
Arthrocentesis/drainage Obtain cultures Immediate administration of antibiotics Supportive care: NSAIDs, cold packs, rest Antibiotics and treatment of sexual partners when indicated Chronic reactive arthritis: possible DMARDS Penicillin Anti-inflammatory drugs Cardiac medications if indicated Medications to control chorea if needed Rest Antibiotic prophylaxis First line: doxycycline or amoxicillin Second line: ceftriaxone Supportive care: rest, NSAIDs NSAIDs Local and systemic steroids (selective cases) DMARDs Biologics
DMARD⫽disease-modifying antirheumatic drug; NSAID⫽nonsteroidal anti-inflamatory drug.
reactive arthritis. Among respiratory pathogens, S pyogenes has been known to cause reactive arthritis. N meningitidis can be associated with reactive arthritis as well. Clinically, patients who have reactive arthritis present with monoarthritis or oligoarthritis, frequently accompanied by other musculoskeletal inflammatory changes, as well as ophthalmologic, dermatologic, and genitourinary changes. One well-known presentation of reactive arthritis (previously known as Reiter syndrome) is the triad of arthritis, urethritis, and bilateral mucopurulent conjunctivitis. Other manifestations include pain, enthesitis, dactylitis, urinary symptoms, urethral discharge, cervicitis, uveitis, photophobia, and skin findings. In the presence of HLA-B27, reactive arthritis typically presents with calcaneal and plantar pain and
arthritis
tenderness. Systemic symptoms that can accompany reactive arthritis include arthralgia, fever, weight loss, and malaise. Reactive arthritis is asymmetric and often involves large joints such as the knee, hip, ankle, and sacroiliac joint. The joints of the lower extremity are implicated more often than those of the upper extremities. Symptoms start from a few days to 6 weeks after infection. According to one study, reactive arthritis should be diagnosed clinically based on two major criteria: 1) the presence of mono or oligoarthritis of the lower extremities, and 2) exclusion of other causes of arthritis, such as septic arthritis, Lyme arthritis, ARF, and trauma. (5) If both criteria have been met in a patient who has a history of preceding Chlamydia infection, the diagnosis of reactive arthritis is highly probable (up to 90%). If both criteria have been met, and the patient has a positive stool culture, the diagnosis of reactive arthritis is highly probable also (up to 70%). (5) Because reactive arthritis can be triggered by a multitude of pathogens, there is no single gold standard diagnostic test. However, this diagnosis is supported by an elevated ESR and CRP concentration or positive urine, cervical, or urethral culture for C. trachomatis. Synovial fluid tests can be helpful in excluding other disease processes. HLA-B27 positivity is supportive of the diagnosis of reactive arthritis in a patient who has a consistent history and physical findings. Antinuclear antibody (ANA) and rheumatoid factor (RF) should be considered in a patient who has a history or physical finding consistent with an autoimmune process. Imaging studies often are normal, but should be obtained particularly if other disorders such as pyogenic arthritis or osteomyelitis are considered. Treatment is primarily supportive and involves giving nonsteroidal anti- inflammatory drugs (NSAIDs), local cold treatment, and avoidance of overuse of the affected joints. A positive genitourinary culture requires treatment of the patient and sexual partners with appropriate antibiotics. The beneficial effects of treatment of gastrointestinal infections accompanying reactive arthritis are unclear. Certain musculoskeletal manifestations can be treated with local corticosteroid injections. Symptoms of reactive arthritis may last weeks to months. If the arthritis fails to resolve in 6 months, it is categorized as chronic reactive arthritis. This outcome occurs in approximately 4% to 19% of patients for whom a rheumatology referral is warranted. In this subset, diseases modifying antirheumatic drugs may be used to manage the patient’s symptoms. (5) Pediatrics in Review Vol.32 No.11 November 2011 475
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Acute Rheumatic Fever ARF is an inflammatory process involving many organ systems precipitated by preceding group A Streptococcus (GAS) pharyngitis. In the United States, the incidence of ARF has declined in the past several decades; however, focal outbreaks occur periodically. ARF is diagnosed clinically using the well-established Jones criteria. The major Jones criteria are polyarthritis, carditis, subcutaneous nodules, chorea, and erythema marginatum. Erythema marginatum is a rash that involves the extremities and trunk in a serpiginous fashion with central clearing and salmon-colored margins. The minor criteria are fever, arthralgia, prolonged P-R interval on electrocardiogram, and elevated acute phase reactants. Confirmation of an antecedent GAS infection plus two major criteria or one major and two minor criteria must be fulfilled to make the diagnosis of ARF. Prior GAS infection can be confirmed by positive throat culture, positive rapid streptococcal antigen test, and elevated titers of anti- streptolysin O or other streptococcal antibodies. The arthritis of ARF is a nondeforming migratory polyarthritis usually involving large joints such as the knees, wrists, elbows, or ankles. Most experts recommend a single dose of intramuscular benzathine penicillin G or 10 days of oral penicillin to eliminate any remaining GAS infection regardless of throat culture results. The other mainstays of treatment are anti-inflammatory drugs, restriction of activity, and antibiotic prophylaxis. Antibiotic prophylaxis is critical in the prevention of future streptococcal infections, which potentially may worsen the cardiac disease. The arthritis in ARF tends to be exquisitely responsive to aspirin. In patients afflicted with carditis, cardiology consultation is helpful in determining the role of diuretics (in those who have secondary heart failure) and for the follow-up of potential longterm cardiac sequelae.
Lyme Arthritis Lyme arthritis is the most common late manifestation of Lyme disease, a tick-borne disease caused by Borrelia burgdorferi. Although early Lyme disease tends to occur more in the late spring or early summer, late disease has no true seasonality. The Borrelia organisms residing within the digestive tract of the Ixodes ticks migrate to the salivary glands after the tick bites and attaches to the victimâ&#x20AC;&#x2122;s skin. Approximately 48 hours post bite, the organisms are transmitted to the bloodstream of the victim. Seeding the synovium hematogenously, the Borrelia induces mononuclear cell infiltration and stimulates complement, cytokines, neutrophils, and immune complexes to accumulate within the joint space, leading to
inflammation and pain. In contrast to septic arthritis, B burgdorferi does not produce proteases that are responsible for rapid joint destruction. (6) A history of a rash consistent with erythema migrans is supportive but not required for the diagnosis of Lyme arthritis. In about 30% of patients given a diagnosis of Lyme disease, this rash is not identified. (3) Patients may experience migratory arthralgias, myalgias, or fatigue early in the course. Occasionally, patients who have Lyme arthritis have fever or other systemic symptoms. Lyme arthritis usually presents as an asymmetric mono or oligoarticular arthritis. Typically, a single knee joint is affected. However, other joints, such as the shoulder, ankle, elbow, temporomandibular joint, and wrist, are affected commonly. Unlike a patient who has pyogenic arthritis in which pain is severe and constant, the pain of Lyme arthritis waxes and wanes and is of lesser severity. In fact, this joint involvement tends to resemble the symptoms experienced by children who have oligoarticular juvenile arthritis and was misdiagnosed historically as JIA before the epidemiologic and basic science research that elucidated the etiology of Lyme disease. Physical examination reveals a mild to moderately inflamed joint with an effusion. Range of motion is not decreased significantly. Lyme arthritis occasionally is confused with trauma because it may present with remarkable joint effusion and no fever. Confirmation of B burgdorferi infection requires a two-step process. The first step involves a sensitive enzyme immunoassay for serum antibodies. The second step is a confirmatory result on a Western immunoblot for specific bands of antibodies in the immune globulin G (IgG) or IgM classes, depending on the stage of the disease. Synovial fluid testing may reveal a white blood cell count around 21,000 to 24,000 cells/ microliter (6) (can vary significantly), with a neutrophil predominance. ESR rates usually are about 20 to 30 mm/hour. Soft tissue changes and joint effusions are noted on imaging studies. However, imaging generally is not helpful. If treated adequately, early Lyme disease does not progress to arthritis or other manifestations of late disease. Once arthritis develops, generally 28 days of appropriate oral antibiotic therapy is required. Treatment options include doxycycline (for children older than 8 y) 4 mg/kg per day divided in two doses (maximum 100 mg/dose) or amoxicillin 50 mg/kg per day divided in three doses (maximum 500 mg/dose). Cefuroxime 30 mg/kg per day divided in two doses (maximum 500 mg/dose) is the second line treatment. The vast majority of patients respond to a single course of oral
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antibiotics. If the patient experiences minimal improvement of symptoms, a second course of oral antibiotics is recommended. In those who exhibit minimal or no response despite an additional 4 weeks of oral antibiotics, parenteral antibiotic therapy for 1 month (usually employing ceftriaxone) is warranted. (6) Adjunctive use of NSAID therapy can be helpful in controlling symptoms of some patients who have Lyme arthritis. If Lyme arthritis is accompanied by neurologic symptoms, disease should be treated as per the management of the neurologic disease. Although the prognosis for those who have Lyme arthritis is good, a small subset of patients has symptoms lasting months to years after given a diagnosis of Lyme disease. Immunogenetic factors have been implicated in the variation of the clinical course of Lyme disease.
Other Infectious Etiologies Nonbacterial pathogens implicated in arthritis include viruses and fungi. Viral pathogens commonly implicated include rubella, parvovirus B19, arboviruses, and hepatitis B. Other viral pathogens less commonly associated with arthritis are coxsackie, Epstein-Barr, herpes simplex, varicella-zoster, and mumps virus. Mycobacterium species, Candida species, and other fungi are rare but are potential pathogens that may cause arthritis in children and should be considered, particularly if any risk factors exist.
Toxic Synovitis and Hip Pain Toxic synovitis, also called acute transient synovitis, is a relatively common cause of sudden onset of hip pain and limping and is frequently considered in the differential diagnosis of septic arthritis of the hip. Hip pain can be due to a variety of disease processes depending on the age and sex. SCFE, Legg-Calve´-Perthes disease, and osteoidosteoma all can result in significant hip pain. In SCFE, disruption of the proximal femoral growth plate results in varying degrees of displacement of the femoral head. This entity typically presents in the obese peri-pubertal patient, with boys being affected almost twice as often as girls. Legg-Calve´-Perthes disease is an osteonecrosis of the capital femoral epiphysis. This disorder occurs in younger children but with an impressive male predominance (4:1 male-to-female ratio). Often affecting the upper femur, osteoid osteoma may present with hip pain. The pain associated with this benign tumor is localized to the lesion, is worse at night, and often improves with oral salicylates. Osteoid osteoma affects individuals of all ages but occurs most frequently in the second and third decades after birth.
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Toxic synovitis is a relatively benign entity that is characterized by inflammation of the synovium, most frequently of the hip joint. Often there is a joint effusion as well. Toxic synovitis commonly affects children 3 to 10 years of age. The male-to-female ratio is about 2:1. The exact pathophysiology of this process is uncertain. However, most children who have toxic synovitis have had a prodrome of upper respiratory or gastrointestinal symptoms or have a concurrent infectious process. This process often presents as an acute onset of hip, thigh, or knee pain or limp. Patients often are not ill appearing and are afebrile, although low-grade fevers may be present. The patient may be uncooperative because of pain when eliciting range of motion of the knee or hip, making the range of motion appear more limited than it actually is. Often there is decreased internal rotation and adduction of the affected hip. Distinguishing transient synovitis from septic arthritis is critical because clinical presentations may overlap. Often patients who have toxic synovitis are not as irritable or ill appearing, may have bouts of improved pain (in contrast to the constant pain of septic arthritis), and although they may limp, often can bear weight. In one pediatric study, four independent multivariate predictors were found to be useful in distinguishing septic arthritis from toxic synovitis. (7) These variables are a history of fever, inability to bear weight, ESR over 40 mm/hour, and white blood cell count higher than 12,000/mm3. Presence of all four variables had a 99.6% predictive probability of septic arthritis. In toxic synovitis, the white count often is normal, with normal to mildly elevated ESR and CRP. Another study revealed a CRP concentration ⬍1.0 mg/dL as an excellent negative predictor for septic arthritis. (8) If clinical presentation and blood tests are reassuring (afebrile, full range of motion in the joint, and low risk ESR, CRP, and white blood cell count), the patient may be watched without further testing. If the clinical picture is not reassuring, a synovial fluid aspirate is required to rule out septic arthritis. The synovial fluid in toxic synovitis often is yellow and clear or slightly turbid, has a normal to slightly elevated white blood cell count, and usually is small in volume in contrast to septic arthritis. Table 3 compares the clinical features and diagnostic test results of septic arthritis, toxic synovitis, and Lyme arthritis. Synovial fluid testing is by far the most reliable way to distinguish toxic synovitis from septic arthritis, and one should never be reluctant to proceed with hip aspiration if there is any question as to the presence of a septic process. Radiographs may reveal capsular distension, widening of the joint space, and distortion of soft tissue planes. Ultrasonography Pediatrics in Review Vol.32 No.11 November 2011 477
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and plain radiography may not help differentiate toxic synovitis from septic arthritis because children who have toxic synovitis often have joint effusions. However, MRI may be helpful. MRI usually is normal or may show thickening of the articular surface or joint effusion in toxic synovitis. The usual treatment for toxic synovitis is antiinflammatory medication and limitation of activity. Most commonly, symptoms resolve within days; occasionally, it may take up to 2 weeks from the onset of symptoms for the patient to return to baseline. Overall, this condition is self-limited; however, a small percentage experience recurrences. The risk of future development of Legg-Calve´-Perthes disease in those who have a history of toxic synovitis may be slightly higher than in the general population.
Juvenile Idiopathic Arthritis Previously known as juvenile rheumatoid arthritis, JIA is a term used to label a wide spectrum of arthritides that occur before the age of 16 years, last longer than 6 weeks, and do not fulfill the diagnostic criteria of other known entities. JIA is the most common pediatric rheumatic disease; however, it is a diagnosis of exclusion. Although the pathophysiology is not fully elucidated, evidence suggests an autoimmune process. Both genetic and environmental components have been implicated. For many years, T lymphocytes have been thought to be central to the pathogenesis of JIA. New research reveals that innate immunity, specifically neutrophils, may play additional important roles in this disease process. The International League of Associations for Rheumatology has classified this heterogeneous group of arthritides into seven subgroups. These groups are oligoarthritis (⬃40% of cases), RF positive polyarthritis (⬃5%), RF negative polyarthritis (⬃20%), systemic arthritis (⬃10% of cases), enthesitis related arthritis (⬃5%), psoriatic arthritis (⬃5%), and undifferentiated arthritis (⬃15%). Children afflicted with oligoarthritis have arthritis limited to four or fewer joints within the first 6 months of onset of the disease. Iridocyclitis, inflammation of the iris and ciliary body, occurs in about one third of patients who have oligoarthritis and potentially can lead to loss of vision. Typically, patients have asymptomatic iridocyclitis; therefore, regular screening for this condition should be part of their routine care. There is a strong female predominance in those who have oligoarthritis who present at less than 6 years old (early onset). Individuals who have oligoarthritis have a positive ANA about 70% of the time, normal complete blood count
results, and normal to mildly elevated acute phase reactants. RF positive and negative polyarthritis involve a minimum of five joints being affected during the first 6 months after onset. RF positive polyarthritis requires two positive IgM RFs documented at least 3 months apart. Typically, these patients have an insidious onset of inflammation in the small joints of the hands and feet. Both RF positive and negative polyarthritis have a female predominance. A slight elevation in ESR is likely for both groups. Systemic arthritis is the most serious of the JIA subtypes. This variation classically presents with fever, rash, and arthritis. Frequently evaluated for infectious diseases, these children typically have quotidian spiking high fevers (ⱖ39°C) that defervesce quickly. A salmoncolored migratory rash, typically accentuated by showering, often accompanies this fever. Fever must persist for at least 2 weeks to meet the diagnostic criteria. Fever and rash can precede arthritis by several weeks, making the diagnosis difficult. Contrary to a septic child, children who have systemic arthritis usually are well appearing between their febrile episodes. Although initially the arthritis involves only a few joints, chronic polyarthritis eventually ensues in most cases. Lymphadenopathy, hepatosplenomegaly, and serositis also are potential manifestations of systemic onset JIA. Boys and girls are affected equally. Leukocytosis, anemia, thrombocytosis, and elevated ESR and CRP are supportive laboratory findings. However, these test results, along with the nonspecific initial presentation, may make it challenging to differentiate early systemic arthritis from infectious and malignant causes. Patients who have systemic arthritis are at risk for developing macrophage activation syndrome, which presents with an acute onset of persistent fever, hepatosplenomegaly, neurologic changes, hematologic symptoms, and pancytopenia. This fatal complication requires early diagnosis and aggressive immediate treatment. Enthesitis-related and psoriatic arthritis have more elaborate criteria than what is mentioned here. However, simply stated, enthesitis-related arthritis is a form of JIA in which patients present with both arthritis and enthesitis; this subtype is most common in boys older than 6 years. Psoriatic arthritis is characterized by the presence of arthritis with psoriasis. Those affected by this subtype of JIA may have chronic and erosive disease, making early aggressive therapy necessary. Patients who have psoriatic arthritis often are ANA positive. Finally, undifferentiated JIA captures those patients who do not meet the criteria of the other subtypes.
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An interdisciplinary approach addressing physical and occupational therapy, psychosocial support, and pharmacologic treatments must be utilized for optimum management of JIA. (9) NSAIDs serve as the initial treatment for patients who have JIA. Triamcinolone hexacetonide intra-articular injections may be used in addition to or instead of NSAIDs in patients who have a limited number of affected joints. Rheumatologists may use systemic corticosteroids in specific situations (eg, acute flares); however, corticosteroids are not considered the treatment of choice for long-term management. Methotrexate is used as a second-line agent to treat persistent and active arthritis. Etanercept and adalimumab are the only anti-tumor necrosis factor agents approved by the Food and Drug
Summary • Arthritis can be a manifestation of multiple disease processes. Therefore, the clinician must consider a broad differential diagnosis, keeping a high degree of suspicion for diseases that may have serious consequences. Although this article reviews more common disease processes that present with arthritis, it is imperative to think outside of the scope of infectious and musculoskeletal entities and consider autoimmune, oncologic, and other processes as well. • The diagnostician should use a complete history and physical examination to determine further evaluation. In most cases, the diagnosis can be confirmed by the constellation of supporting historic features, examination findings, and laboratory or imaging results. • Appropriate diagnosis and management of pediatric arthritis can facilitate prompt recovery and prevent debilitating consequences. Table 4 offers a brief summary for treatment management. • Strong research evidence suggests that delay in decompression of infected joints, especially the hips and shoulders, and delayed initiation of antibiotics are poor prognostic factors. • Moderate research evidence indicates that the presence of fever, inability to bear weight, ESR >40 mm/hour, and a white blood cell count >12ⴛ106 is highly suggestive of pyogenic arthritis. • Some evidence exists regarding safety and efficacy of the use of biologic agents in treating children who have JIA. • Based on expert opinion, an interdisciplinary approach to the treatment of JIA results in improved quality of life.
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Administration (FDA) for use in children over 4 years of age with JIA. (10) Abatacept, an interleukin 6 blocker, is the first of a new class of biologic agents approved for severe polyarticular JIA in children older than 6 years of age. (10) Recent clinical trials suggest other biologics may be effective as well and are used currently by rheumatologists in the treatment of JIA. Other drugs may be beneficial, depending on the JIA subtype and individual patient. Long-term prognosis has been affected favorably by the advances in pharmacologic therapy and better utilization of multidisciplinary teams.
Suggested Reading Gutierrez K. Bone and joint infections in children. Pediatr Clin North Am. 2005;52:779 –794, vi Kim PS, Klausmeier TL, Orr DP. Reactive arthritis: a review. J Adolesc Health. 2009;44:309 –315 Marques AR. Lyme disease: a review. Curr Allergy Asthma Rep. 2010;10:13–20 McCarthy JJ, Noonan KJ. Toxic synovitis. Skeletal Radiol. 2008; 37:963–965
References 1. Gutierrez KM. Infectious and inflammatory arthritis. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases, 3rd ed. Philadelphia: Churchill Livingstone/Elsevier; 2009:484 – 492 2. Frank G, Mahoney HM, Eppes SC. Musculoskeletal infections in children. Pediatr Clin North Am. 2005;52:1083–1106, ix 3. Frank G, Eppes SC. Bone, joint, and soft tissue infections. In: Zaoutis LB, Chiang WV, eds. Comprehensive Pediatric Hospital Medicine. Philadelphia: Mosby; 2007 4. Offiah AC. Acute osteomyelitis, septic arthritis and discitis: differences between neonates and older children. Eur J Radiol. 2006;60:221–232 5. Sieper J, Rudwaleit M, Braun J, van der Heijde D. Diagnosing reactive arthritis: role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum. 2002;46:319 –327 6. Puius YA, Kalish RA. Lyme arthritis: pathogenesis, clinical presentation, and management. Infect Dis Clin North Am. 2008;22: 289 –300, vi–vii 7. 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 8. Levine MJ, McGuire KJ, McGowan KL, Flynn JM. Assessment of the test characteristics of C-reactive protein for septic arthritis in children. J Pediatr Orthop. 2003;23:373–377 9. Ravelli A, Martini A. Juvenile idiopathic arthritis. The Lancet. 2007;369:767–778 10. Breda L, Del Torto M, De Sanctis S, Chiarelli F. Biologics in children’s autoimmune disorders: efficacy and safety. Eur J Pediatr. 2011;170:157
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PIR Quiz Quiz also available online at: http://pedsinreview.aappublications.org. NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim credit online. No paper answer form will be printed in the journal. 6. Among the following, the clinical characteristic that arthritis and arthralgia have in common is A. B. C. D. E.
erythema pain swelling tenderness warmth
7. The most common mechanism of infection in septic arthritis is A. B. C. D. E.
contiguous spread hematogenous seeding instrumentation intra-articular injections trauma
8. A 16-year-old-boy has had signs of arthritis in his left ankle for almost 2 weeks. He denies any trauma to the joint. His antistreptolysin O and Lyme titers are negative. Aspiration of the joint reveals clear fluid. He also complains of crusting of his eyelids in the morning. Among the following, the additional test you are most likely to order is a A. B. C. D. E.
blood culture sputum culture stool for ova and parasites urethral culture urinalysis
9. Among the following, the preferred treatment of arthritis associated with acute rheumatic fever is A. B. C. D. E.
acetaminophen ibuprofen naproxen salicylate steroid
10. Which of the following findings commonly occurs in both septic arthritis and toxic synovitis A. B. C. D. E.
effusion of a hip joint marked elevation of erythrocyte sedimentation rate high fever inability to bear weight white blood cell count higher than 12,000/mm3
Parent Resources From the AAP at HealthyChildren.org The reader is likely to find material to share with parents that is relevant to this article by visiting this link: http://www.healthychildren.org/English/health-issues/conditions/ orthopedic/pages/Arthritis.aspx.
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Arthritis in Children and Adolescents Janice John and Latha Chandran Pediatrics in Review 2011;32;470 DOI: 10.1542/pir.32-11-470
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including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/32/11/470
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Consultation with the Specialist : Asperger Syndrome Louis Pellegrino and Gregory S. Liptak Pediatrics in Review 2011;32;481 DOI: 10.1542/pir.32-11-481
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/481
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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Asperger Syndrome Louis Pellegrino, MD,* Gregory S. Liptak, MD†
Objectives
After completing this article, readers should be able to:
1. Define Asperger syndrome and review the history and prevalence of the condition. 2. Describe the clinical characteristics of Asperger syndrome and comorbid conditions. 3. Review the major elements in the management of Asperger syndrome. 4. Describe the role of the primary care physician or practitioner (PCP) and medical home in the lives of children who have Asperger syndrome. 5. Describe current controversies relevant to the diagnosis and treatment of Asperger syndrome.
What is Asperger Syndrome? Author Disclosure Drs Pellegrino and Liptak have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/device.
Abbreviations autistic disorder attention deficit hyperactivity disorder AS: Asperger syndrome ASD: autism spectrum disorder EI: early intervention HFA: high-functioning autism NVLD: nonverbal learning disability OCD: obsessive-compulsive disorder PCP: primary care physician or practitioner PDD-NOS: pervasive developmental disorder—not otherwise specified AD: ADHD:
Asperger syndrome (AS) is one of a group of conditions referred to as autism spectrum disorders (ASDs). Children on the autism spectrum demonstrate impairments in socialization and communication (especially social and nonverbal aspects of communication) and have atypical and repetitive behaviors and interests. However, individuals on the spectrum vary widely in the manifestations of these impairments. Kanner first described “early infantile autism” in 1943. He described a group of children who had a profound disturbance in social responsiveness and pronounced language deficits associated with evidence of intellectual disability. A year later, Hans Asperger, an Austrian pediatrician, described four children who had intact intellectual ability but nonetheless showed marked impairments in socialization, notable difficulties with nonverbal and social communication (despite intact general language ability), and unusual, all-consuming interests. Some of *Assistant Professor of Pediatrics, Upstate Medical University, Syracuse, NY. † Professor of Pediatrics., Upstate Medical University, Syracuse, NY.
these children showed a tendency to engage in long-winded recitations of their favorite subjects, leading Asperger to describe them as “little professors.” Unaware of Kanner’s previous work, Asperger referred to this condition as “autistic psychopathy” and conceptualized the condition as a personality disorder with a strong genetic basis. In 1981, Lorna Wing published a case series and coined the term “Asperger’s syndrome” to characterize the features that Asperger had described. The diagnosis was officially recognized (as Asperger disorder) for the first time in the International Classification of Diseases, 10th Edition, and subsequently in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; see Table 1). The DSM-IV currently recognizes five “pervasive developmental disorders,” including autistic disorder (AD), AS, pervasive developmental disorder—not otherwise specified (PDD-NOS), Rett syndrome, and childhood disintegrative disorder. ASD, as currently conceived, is thought to include AD, AS, and PDD-NOS. Rett syndrome and childhood disintegrative disorder are specific, rare conditions that include Pediatrics in Review Vol.32 No.11 November 2011 481
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autistic traits but do not typically enter into discussions of the “autism spectrum.” Although AS is currently recognized as a distinct ASD, a proposal under consideration for the fifth edition of the DSM suggests including AS along with the other distinct forms of ASD under the broader ASD heading (see discussion below). The most recent study by the Centers for Disease Control and Prevention (CDC) estimates the prevalence of all ASDs to be 1 in 110. A few studies have determined the specific prevalence of ASD subtypes; however, comparisons among these studies are difficult because of differences in definitions and ascertainment. As a general statement, individuals who have AD represent about one third to one half of those on the autism spectrum, whereas individuals who have AS, high-functioning autism (HFA; referring to individuals having less severe social and cognitive deficits who still meet criteria for autism), and PDD-NOS represent about one half to two thirds of those on the spectrum. In one Swedish study, the prevalence of AS was 1/250 (1); prevalence estimates have varied greatly among studies, but generally have increased over the past two decades. Although the specific causes of ASD and AS are not well defined, a strong genetic component to these disorders is apparent. Children who have AS frequently have a family history of relatives who have AS or “AS traits,” such as social awkwardness or obsessive compulsive tendencies. Children who have AS have a higher than expected frequency of parents and grandparents in engineering or the natural sciences. The male to female ratio among individuals who have ASD, including AS, is 4:1; several authors suggest that ASD and AS in particular may represent an ex-
Comparison of Autistic Disorder and Asperger Disorder Using DSM-IV Criteria
Table 1.
Social interaction Impaired nonverbal behavior (eg, eye contact); lack of appropriate peer relationships; lack of spontaneous sharing of experience; lack of social/emotional reciprocity Restrictive/repetitive behaviors and interests Restricted/obsessive play interests; rigid adherence to nonfunctional routines; repetitive/stereotyped movements (eg, hand flapping); preoccupation with parts of objects Communication Delayed speech without compensatory nonverbal communication; inability to initiate or sustain conversation; idiosyncratic language (eg, echolalia); lack of imaginary/imitative play Onset Delays or abnormal functioning before 3 y with social, communication, or play
Autistic Disorder
Asperger Disorder
ⴙ
ⴙ
ⴙ
ⴙ
ⴙ
ⴚ
ⴙ
ⴚ
DSM-IV⫽Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
treme form of “maleness,” noting the predisposition of males to deal with the world as a problem or puzzle to be solved, rather than a place populated by people who have relationships that can be understood through social connection and intuition. The long-term prognosis for individuals who have ASD correlates with cognitive ability; so those who have AS and HFA theoretically should have better outcomes than those who have AD, and generally they do. The effect of the social disability associated with AS may be underestimated, however. For example, although individuals who have AS are more likely to complete college than others who have highfunctioning or milder forms of ASD, they are not necessarily more likely to hold a job as a consequence of having a college degree. Likewise, individuals who have AS may have significant challenges with establishing and maintaining long-term, intimate relationships such as marriage.
Recognizing the Characteristics of Asperger Syndrome Jeremy is a 10-year-old boy who is doing well academically in fifth grade but struggling socially. He complains often that no one wants to be his friend but has very little idea of how to approach other children. At recess, he interrupts games and tries to impose his own wishes and rules; he is bewildered when his classmates react negatively. Sometimes he is not even aware of their negative reactions. At the lunch table, he often makes inappropriate comments, insults others without realizing it, or dominates the conversation by lecturing about his favorite topic, professional wrestling, regaling anyone who is within earshot on the subject in encyclopedic detail. In the classroom, his teacher has to remind him to use his “indoor voice” because he speaks loudly at all times; he tends to speak in a mechanical or robotic fashion that other students mock. He has poor eye contact and often has to be re-
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minded to look at others when speaking. Until second grade Jeremy’s classmates seemed to enjoy his interests and precocious verbal expositions, but more recently have found reasons to avoid him. He has become the target of teasing and bullying, is increasingly disenchanted with school, and comes home sullen and irritable. His parents are at a loss as to how to help him. This example illustrates several characteristics typical of children who have AS. Although many children who have AS are gifted academically and intellectually, they struggle with social skills. In contrast to children afflicted with AD, who often are socially aloof and uninterested in social contact, most children who have AS are interested in having friends and being accepted but are severely limited in their ability to form and maintain relationships. These children demonstrate impairments both in their social perceptions and responses. Many are lacking in what is referred to in autism research as “theory of mind.” This concept refers to a lack of understanding that others have ideas and perceptions that differ from one’s own, resulting in an inability to see things from another person’s point of view. Children who have AS are particularly known for their lack of social empathy; they may be able to recognize the more obvious aspects of emotional response (if someone is yelling or crying), but completely miss the more nuanced manifestations of emotion. Research suggests that individuals who have AS have a specific impairment in the ability to read facial expressions and must rely on other cues to sort out the meaning of a specific social situation. This inability to read and interpret the rapid flux of social interaction leads to mishandling of social reactions and responses. Children who have AS act as though their view of the world is shared by everyone.
Typically they say what they think and do what they want without referencing the responses of those around them. Lacking the ability to “read” the social environment, they tend to rely heavily on knowing and applying rules, and often are heavyhanded in their application of these rules to others. Although they are aware of explicit rules, such as “no talking in class,” they often are unaware of unwritten rules, such as “students do not tell on their classmates.” Poor eye contact and other deficits in nonverbal communication further complicate their ability to engage in reciprocal social responses. Although many children who have AS have well-developed and even precocious general language skills, their ability to interact in conversation is severely limited. This impairment in the social aspect of language use is referred to as pragmatic language dysfunction. They have difficulty with greeting and requesting skills. They have difficulty taking turns and are particularly known for engaging in pedantic diatribes on preferred topics. They are poor at recognizing the rules and nuances of conversation, and have trouble going beyond the literal meaning of sentences; they struggle with humor, sarcasm, and irony. They may have difficulty regulating the volume and inflection of speech, resulting in voice quality that is described often as robotic or “sing-song,” and which comes across to the listener as artificial and incongruent with what is being said (impaired speech prosody). Children who have AS especially are known for their all-encompassing, obsessive interests. These interests often involve a scientific or historical topic but can relate to anything that lends itself to in-depth, systematic analysis of details, such as baseball statistics. Children who have ASD as a group are known to have a pro-
nounced need for predictability and sameness. For children who have severe autism, this often manifests as a need for ritualistic behavior focusing on primitive forms of repetition (such as turning things on and off, or opening and closing things repetitively). For children who have AS, this need for predictability and sameness manifests in a more sophisticated effort to classify and systematize the world. Because the world of social interactions eludes simple classification and systemization, children who have AS gravitate towards subjects that are more amendable to this stylized treatment, and, to the chagrin of their parents, siblings, and peers, it is one of their greatest joys to share the fruits of their efforts with anyone who will listen. This facility for organizing and understanding the world in terms of detail often extends into other aspects of interaction and cognition. Children who have AS tend to interpret things very literally, seeing everything as “black or white.” They are concrete thinkers, and often misunderstand expressions, idioms, and jokes. This tendency may extend into academics: the early elementary grades often go very well, but as the curriculum shifts from basic academics and rote learning to more abstract materials, many children who have AS begin to show signs of difficulty (especially beginning in third or fourth grade). Although sensory processing dysfunction is not a specific criterion for the diagnosis of AS, many children who have AS have pronounced differences in how they perceive and react to sensory stimuli. Oversensitivity to loud noises, ambient light, tactile sensations, smells, and tastes are described commonly. At the same time, some children exhibit undersensitivity to pain, whereas others exhibit “sensory seeking bePediatrics in Review Vol.32 No.11 November 2011 483
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havior” (a desire for movement, contact, pressure, or repetitive action). Although the sensory processing differences can be associated with many different developmental disorders, they may be particularly pronounced in children who have AS.
Conditions Associated With Asperger Syndrome and High-Functioning Autism AS is associated with an increased prevalence of a number of developmental, behavioral, and emotional disorders (Table 2). Developmental issues encountered include difficulties with motor control, attention, and impulse control; specific learning problems are common. Although most children who have AS begin walking at about the expected time (around 1 y of age), many are described as being awkward or “clumsy.” These coordination difficulties are associated with a mild degree of muscular hypotonia, but focal neurologic abnormalities rarely are found; special neurologic testing usually is not indicated. Difficulties with motor planning and sequencing of motor actions associated with judging body position in space are the hallmarks of developmental coordination disorder, a diagnosis frequently applied to children who have AS. A significant number of children who have AS experience disordered sleep, including difficulty falling asleep as well as maintaining sleep. This problem typically is managed by insuring sleep hygiene and treating anxiety if it is present. Rarely, a formal sleep study is indicated. Occasionally medications such as melatonin or clonidine may be helpful. Many children who have AS also show evidence of attention deficit hyperactivity disorder (ADHD). Problems with attention and poor impulse
control affect classroom functioning and academic progress and often complicate social interactions in children who already are severely challenged in their efforts to relate to peers. Standard treatments for ADHD are appropriate to consider, including the use of stimulant medications, but pharmacologic inter-
ventions are less effective, and children who have AS are more prone to adverse effects, such as increased irritability or anxiety. Nonverbal learning disability (NVLD) has been associated with AS. Children who have NVLD typically have strong verbal cognitive abilities but show pronounced weak-
Characteristics of Asperger Syndrome and Interventions Often Utilized Table 2.
Findings Primary Characteristics Impaired communication Impaired social interactions Restricted interests Secondary Conditions Anxiety/OCD
ADHD Auditory processing disorder Depression Developmental coordination disorder Disruptive/Explosive behavior Learning disabilities Oppositional defiant disorder Sensory differences Sleep disorders
Interventions Speech and language therapy* Social competence groups† Social competence groups† Individual behavioral counseling† Social competence groups§ Individual behavioral counseling§ Family communication§ Physical activity* Relaxation/Meditation/Massage† Cognitive behavioral therapy* SSRIs† Environmental modifications§ Medications, including stimulants* Speech and language therapy* Headset with FM radio amplification system for classroom† Individual counseling† SSRIs† Physical activity§ Physical therapy* Occupational therapy† Omega-3 oils* Individual behavioral counseling† Family counseling† Medications, including alpha-2 agonists, antipsychotics, and mood stabilizers† Specialized educational interventions* Individual behavioral counseling† Family counseling† Medications, including alpha-2 agonists† Sensory (integration) therapy§ Sleep hygiene† Treatment for anxiety, if present§ Medications, including melatonin§ or clonidine†
ADHD⫽attention deficit hyperactivity disorder; OCD⫽obsessive SSRI⫽selective serotonin reuptake inhibitor. *Based on strong evidence of efficacy; approved use. † Based on moderate evidence of efficacy; approved and off-label uses. § Based on weak or anecdotal evidence; off-label use.
compulsive
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ness with visual spatial tasks and certain nonverbal problem-solving skills. This characteristic is reflected in a marked discrepancy between verbal intelligence quotient scores, which are average or above, and nonverbal or performance intelligence quotient scores, which are below average. Basic reading skills are well developed, but math may be difficult. Children who have NVLD (with or without AS) often exhibit “cognitive rigidity.” They tend to excel at rotelearning tasks and memorization but are challenged by abstract thinking that requires cognitive flexibility. Other learning and information processing problems have been described in association with AS. Central auditory processing dysfunction in particular is invoked frequently for children who have difficulties listening and processing auditory information, especially in a challenging acoustic environment, such as a noisy classroom. It may be difficult to separate attentional weaknesses, learning disability, and specific auditory processing deficits in a child who has AS. Behavioral and emotional difficulties commonly occur in association with AS. Anxiety disorders, including obsessive-compulsive disorder (OCD) and depression, are more common in children who have AS. Problems with impulse control, behavioral rigidity, and anxiety lead to problems with explosive outbursts, disruptive behavior, and defiance; oppositional defiant disorder may be diagnosed in these children. Behavioral and social difficulties conspire to increase the likelihood that children who have AS will become the targets of bullying, although some children who have AS, in their desire to control the behavior of others, may become bullies themselves.
Overall Care of Children Who Have Asperger Syndrome Helping children who have AS to develop to their fullest potential involves a collaborative effort of many individuals, systems, and agencies. Chief among these are educational and related services. Early intervention (EI) can be a critically important starting point for these interventions. However, many children are not given a diagnosis of AS until after they start school. Some children who have AS may not be eligible for EI services because they may not be sufficiently delayed. Similar difficulties may be encountered in getting the school system to provide extra services, especially if a particular child who has AS excels academically. Early recognition of the diagnosis of AS or high-functioning autism can be critical to ensure that these children receive the educational support, classroom accommodations, and related services necessary for them to succeed. A major emphasis for the special education team will be on helping the child who has AS learn to cope with the complexities of school life, which will necessarily include support for the development of adaptive and social skills. School-based counseling, speech-language therapy to support the development of social communication skills, and participation in social-skills groups are important facets of such a program. Many children who have AS benefit from activities, programs, and interventions outside the educational domain. For children who have specific difficulties related to emotional regulation, anxiety, or behavior, access to mental health services and counseling often is critically important. In many communities, social skills (competence) groups have been developed to provide targeted interventions for school-age children
to learn and practice social skills in a controlled and safe environment. (2) Psychopharmacologic interventions may be indicated in some instances. These therapies typically will target specific difficulties such as attention and impulse control problems, anxiety with or without obsessive-compulsive traits, or emotional lability and explosive outbursts. Commonly used agents include stimulant medications for attention and impulse control difficulties, selective serotonin reuptake inhibitors for anxiety, OCD, and depression, alpha-2 agonists (clonidine and guanfacine) for impulsivity and explosive outbursts, and, in some instances, antipsychotic drugs and anticonvulsant mood stabilizers for severe emotional lability, outbursts, and aggression. These medications, which often are used “offlabel,” should be used cautiously and conservatively, under the direction of a trained professional, and in the context of ongoing counseling, both with the child and the family.
The Medical Home The PCP engages in an integrated process to promote early identification of children who have AS and to expedite referral to community services. The first step is to establish a diagnosis of AS, which rarely can be made before entry into kindergarten, and may not be made until the child is in middle school. The second step is to evaluate the child and family to determine the interventions that are most likely to optimize the health and well being of both child and family. AS may be suspected by the child’s family, teacher, PCP, or another provider (eg, occupational therapist). The PCP obtains a history, reviews any documents (eg, school records, formal testing), observes the child, and performs a physical examination. Pediatrics in Review Vol.32 No.11 November 2011 485
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Screening Instruments Used to Help Identify Children Who Have Asperger Syndrome
Table 3.
Screening Instrument Asperger Syndrome Diagnostic Scale Australian Scale for Asperger Syndrome Autism Spectrum Screening Questionnaire Childhood Asperger Syndrome Test Gilliam Asperger Disorder Scale Krug Asperger Disorder Index Social Communication Questionnaire
Once AS is suspected, a screening test may be administered either by the PCP or by a consultant. Table 3 lists some screening tests that have been studied. Each of these screening tests has its strengths and weaknesses but a positive screening test, clinical history, and observations may be sufficient to make a diagnosis of AS. If uncertainty exists, the child may be referred to diagnostic and assessment services, for example, a developmental pediatrician. Etiologic testing, focusing on genetic tests such as a karyotype, DNA testing for fragile-X syndrome, and chromosome microarray often are considered for children who have
Ages (y)
Completed by
Number of items
Free online
5–18 6–12
Clinician Clinician
50 24
No Yes
6–17
Parent
27
No
4–11 3–22 6–22 4–22
Parent Clinician Clinician Parent
38 32 32 40
Yes No No No
AD; they may be considered also for children who have AS, although the yield of positive findings for individuals who have AS is low. In addition to determining the diagnosis, the PCP should assess the child for intervention planning. This evaluation includes characterizing the severity of the AS and determining the occurrence of associated conditions, such as anxiety or ADHD (see Table 2), which helps to identify the needs of the child and family. Similarly, the strengths of the child and family should be ascertained. The child may need to be referred for specialized medical care, behavioral programs and therapies, educational
and related services, and social competence groups; the family may benefit from family training or support services. The child may benefit from formal evaluations (Table 4) to identify his or her strengths and needs. These services may be obtained through EI programs, school districts, or private practitioners. Family goals, structure, and resources should be considered when developing treatment plans that may include clinical consultations, communitybased programs, and educational services. Although EI is known to improve adjustment and there is evidence of the effectiveness of psychoeducation and cognitive behavioral therapy in managing AS, there is limited research on some of the other medical, behavioral, educational, and family interventions listed in Table 2. After diagnosis and assessment for intervention planning are complete, the PCP starts ongoing care and monitoring of the child. This responsibility includes ongoing review with the family of the child’s current test results and progress, input from the family regarding therapeutic decisions, care coordination, and advocacy, especially with education (or EI) services. This task requires the PCP to be knowledgeable about available community resources as
Formal Assessments That May Be Part of the Evaluation of a Child Who Has Asperger Syndrome and Examples of Instruments That Can Be Used
Table 4.
Component
Instrument
Cognitive functioning Academic abilities Adaptive behavior Communication—speech and language Fine motor skills Gross motor skills Social, emotional, and behavioral functioning Sensory differences Family functioning
Wechsler Intelligence Scale for Children–Fourth Edition Wechsler Individual Achievement Test–Second Edition Vineland-II Adaptive Behavior Scales Clinical Evaluation of Language Fundamentals–Fourth Edition Bruininks–Oseretsky Test of Motor Proficiency Peabody Developmental Motor Scales–Second Edition Behavioral Assessment System for Children–Second Edition Sensory Profile Parenting Stress Index
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well as the child’s current care. The PCP can help explain the rights of the family with regard to educational services, including obtaining a functional behavior analysis and behavior support plan from the school district. High-quality care for the child who has AS depends on collaborations among parents, health-care providers, and community agencies (eg, educational services, recreation programs, and parent groups), with ongoing monitoring of the child’s health and function. The person primarily responsible for treating specific conditions will depend on the expertise of the individuals as well as the resources available in the community. For example, a child’s anxiety and depression may be managed by a psychologist or psychiatrist, whereas the PCP manages the child’s sleep disorder and monitors the educational interventions. Whatever specific aspects of care the PCP manages, the child’s physical fitness, nutrition, health maintenance, and overall well being should be addressed by the PCP. Because many children who have AS have difficulty with team sports because of the complexity of social interactions and rules, alternate ways to maintain fitness, such as bicycling, skate boarding, swimming, and sports such as tennis or badminton, should be identified. Medications such as stimulants used for ADHD may decrease appetite (and interfere with sleep), whereas those used for behavior problems, such as the atypical antipsychotics may increase appetite, thus heightening the need for monitoring nutrition and growth. Children who have AS and their families also may benefit from referrals to parent support and advocacy groups, respite programs, and community programs of recreational sports. Because teasing and bullying at school are common with children
who have AS, the PCP should determine the extent of this problem, find out the policies in force in the child’s school, provide insights to the family on this issue, and advocate for the child within the school system if necessary. Issues related to the transition from adolescence to adulthood are similar to those for other teens who have a chronic condition. The teen who has AS may be sexually naive and require specific and repeated instructions and guidance to avoid becoming victimized or performing inappropriate activities in public. Isolation accompanied by sadness and depression needs to be identified and addressed.
social awareness and empathy interferes with their ability to socialize and to participate in commonly performed activities. As noted above, children who have AS are more likely to have associated conditions such as anxiety with OCD, depression, ADHD, and problems with sleep. All of these factors suggest that AS is a disability. To some extent, the difference between disability and difference is academic; however, many have argued that AS should continue to be viewed as a disability to enable children to continue getting the special services that they need.
Controversies
A new version of the DSM is being planned. One change that has been discussed is the elimination of the diagnosis of AS, including it under the “Autism Spectrum Disorder” heading. The diagnosis of AS is clinical and is not based on biologic markers or changes in cranial imaging. Differentiation from HFA often is difficult. For example, in one study 57% of children given a diagnosis of AS also qualified for a diagnosis of AD (3); some experts use the terms AS and HFA synonymously. Genetically related individuals can show different manifestations of autism spectrum, with one person having AS and the other AD. In addition, some preschool-age children who are given a diagnosis of AD meet criteria for AS by the time they are in elementary school. Thus far, no biologic or genetic markers have been found that differentiate between AS and HFA. These findings suggest that AS and HFA are not separate entities. Others have argued that children who have AS are different from those having HFA. They have a different quality of social impairment, tending to be active and odd rather than passive and aloof. Their special interests
Disability or Difference? When Tony Atwood, an international expert on AS, gives a diagnosis to a child who has the condition, he tells them, “Congratulations, you have Asperger’s syndrome!” He then explains that this means that the child is “not mad, bad, or defective, but has a different way of thinking.” Children who have AS clearly do have differences: they are more interested in objects and concepts (like math) than they are in people; they pay attention to detail and can remember rote information very well; they follow their own interests rather than being distracted by the interests of others; they systematize, ie, they are interested in categories of objects or information; and they have a strong desire to be in control. These characteristics can be adaptive, as in certain work situations such as computer programming. In addition, no specific defect in body structure has been identified, just differences, for instance, in connectivity and cell number in certain parts of the brain. In this regard, AS would be a difference and not a disability. On the other hand their lack of
Should Asperger Syndrome Remain a Separate Condition?
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often are sophisticated and intellectual rather than simple. They communicate in a pedantic, verbose, tangential style (like little professors) rather than in stilted phrases and typically had developed spontaneous phrases before age 3 years. Many have a later age of onset of symptoms (7 to 8 y) than those who have HFA. These specialists have argued that the diagnosis of AS should remain, but be modified to reflect these differences. AS is not just a medical diagnosis but a social phenomenon. Some individuals given a diagnosis of AS call themselves “Aspies” and have formed groups, embracing their differences. AS has become a household word; it is a fairly neutral term and suggests high intelligence, unlike HFA, which is more stigmatizing. Use of the category has increased general understanding of the concept of autism and has been helpful for teachers and others to gain insight into the behavior of many children. Some individuals worry that if the AS category is eliminated, adolescents and adults who have symptoms will not be assessed for autism. It is not clear what would happen to individuals already given a diagnosis of AS; the change likely would cause them some distress. Others have argued the category should remain because we have not had enough time to determine whether a biologic or genetic difference really exists between AS and classic autism.
mentary and alternative therapies for children who have autism have been published. (4) However, most of these studies included children who had AD and not AS; thus, generalizing the findings to AS may not be warranted. The safety and cost of any intervention should be balanced against its efficacy. Thus, although omega-3 oils have not specifically been studied in children who have AS, generally they are safe and inexpensive. On the other hand, intravenous chelation has been linked with several deaths and should never be recommended. In some instances, such as the use of oxytocin to promote socialization, neither efficacy nor safety has been established. Sensory integration therapy to help children who have AS deal with sensory differences remains controversial because studies to evaluate this intervention are limited by small sample sizes and lack of standardized interventions and outcomes. Novel treatments also are available for secondary conditions such as ADHD and anxiety. However, most of these have not been well studied either. In summary, very few novel treatments have been studied specifically in children who have AS. The PCP needs to stay up to date with scientific publications and to help families who are interested in these treatments by providing them with information on evidence-based methods and current knowledge about those specific interventions.
Controversial Therapies Because children who have AS have multiple symptoms for which no curative treatment exists, their families seek therapies from many sources. Many treatments touted as being helpful for children who have AS are not based on scientific evidence. Several excellent reviews of comple-
Suggested Reading Attwood T. The Complete Guide to Asperger’s Syndrome. London: Jessica Kingsley Publishers; 2007 Baron-Cohen S. What’s so special about Asperger Syndrome. Brain Behav. 2006; 61:1– 4 Johnson CP, Myers SM. Identification and evaluation of children with autism spec-
Summary • Based on strong research evidence, children who have AS have a high occurrence of ADHD, learning problems, clumsiness, emotional and behavior disorders, sensory differences, and disordered sleep. • Based on strong research evidence, children who have AS are teased and bullied more often than other children • Based on some research evidence as well as consensus, counseling, group interventions, environmental modifications, and medications can improve emotional and behavioral disorders. • Based primarily on consensus due to lack of relevant clinical studies, the medical home can increase the rate of early diagnosis and coordinate comprehensive management of children who have AS.
trum disorders. Pediatrics. 2007;120: 1183–1215 Leekam S, Libby S, Wing L, Gould J, Gillberg C. Comparison of ICD-10 and Gillberg’s criteria for Asperger syndrome. Autism. 2000;11–28
References 1. Kadesjo B, Gillberg C, Hagberg B. Brief report: Autism and Asperger syndrome in seven-year-old children: a total population study. J Autism Dev Disord. 1999;29: 327–331 2. Stichter JP, Herzog MJ, Visovsky K, et al. Social competence intervention for youth with Asperger Syndrome and highfunctioning autism: an initial investigation. J Autism Dev Disord. 2010;40:1067–1079 3. Mahoney WJ, Szatmari P, MacLean JE, et al. Reliability and accuracy of differentiating pervasive developmental disorder subtypes. J Am Acad Child Adolesc Psychiatry. 1998;37:278 –285 4. Levy SE, Hyman SL. Complementary and alternative medicine treatments for children with autism spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2008;17: 803– 820
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PIR Quiz Quiz also available online at http://pedsinreview.aappublications.org. NOTE: Beginning in January 2012, learners will only be able to take Pediatrics in Review quizzes and claim credit online. No paper answer form will be printed in the journal. 11. Children on the autism spectrum demonstrate, with variation, impairments in: A. B. C. D. E.
Anxiety, communication impairment, and aggressive behaviors Sensory integration disorder, communication impairment, and obsessive compulsive behaviors Sensory integration disorder, learning disability, and atypical and repetitive behaviors and interests Social impairment, learning disability, and obsessive compulsive behaviors Socialization and communication impairments, atypical and repetitive behaviors and interests
12. A 10-year-old boy who has Asperger syndrome has had prominent difficulties with distractibility, off-task behavior, and impulsiveness at school that are affecting his school work and peer interactions. He has had similar difficulties throughout his academic career and has similar problems at home. Which of the following statements regarding diagnosis and treatment is correct: A. A diagnosis of Asperger syndrome excludes a diagnosis of ADHD by definition. B. Treatment of distractibility and impulsivity with psychostimulant medications is contraindicated in children with Asperger syndrome and other autism spectrum disorders. C. Nonstimulant ADHD medications are the first choice for children with Asperger syndrome. D. A trial period of a psychostimulant medication is warranted, but the response to the medication is less predictable than for a child with ADHD alone. E. Children with Asperger syndrome who present with ADHD usually have bipolar disorder and should be treated as such. 13. The earliest age at which most children with Asperger syndrome are identified as meeting criteria for the condition is: A. B. C. D. E.
early grade school kindergarten middle school preschool toddlerhood
14. A 10-year-old boy has been identified as having Asperger syndrome. He is academically gifted, but over the past year, he has become more resistant to completing his math homework. He is a good reader and excels at memorizing historical facts. He is delayed in math. His teacher notes that he more frequently displays outbursts in the classroom, but he has no significant behavior concerns at recess. His teacher maintains a structured classroom, and the boy is allowed to leave the classroom for breaks as needed. You are most likely to recommend evaluation of: A. B. C. D. E.
attention, impulsivity, and anxiety auditory processing skills cognitive abilities sensory integration concerns social skills
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Consultation with the Specialist : Asperger Syndrome Louis Pellegrino and Gregory S. Liptak Pediatrics in Review 2011;32;481 DOI: 10.1542/pir.32-11-481
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References
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Ethics for the Pediatrician : Genetic Testing and Newborn Screening Janis L. Gonzales Pediatrics in Review 2011;32;490 DOI: 10.1542/pir.32-11-490
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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ethics for the pediatrician
Genetic Testing and Newborn Screening Janis L. Gonzales, MD, MPH, FAAP*
Introduction
Author Disclosure Dr Gonzales has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Recent technological advances have made genetic testing possible for an unprecedented number of disorders. However, this technology brings with it complicated ethical questions in which individual and societal rights frequently are in conflict. The practitioner caring for children cannot help but be affected by these issues because more than 98% of the 4.3 million babies born in the United States every year participate in newborn screening (NBS). Of these, approximately 5,000 infants annually are found to have one of the heritable conditions identified by the screening process. (1) Primary care clinicians are called on to counsel the families of these infants and to assist them through the process of diagnosis and treatment. NBS is a public health success story that began with testing for phenylketonuria in the 1960s. Recently, testing has expanded due to the availability of multiplex and DNA technologies. In 2005, the American Academy of Pediatrics (AAP) and the Secretary of Health and Human Servicesâ&#x20AC;&#x2122; Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children (SACHDNC) endorsed a report from the American College of Medical Genetics recommending that all states screen newborns for 29 core conditions (with an additional 25 conditions as second-tier recommendations). The purpose of NBS is to identify,
*Medical Director, Childrenâ&#x20AC;&#x2122;s Medical Services, New Mexico Department of Health, Santa Fe, NM.
as early as possible, those babies who are at a higher-than-normal risk for a condition to promote health and prevent disease and disability. For newborns who have potentially fatal conditions and are asymptomatic at birth, such early identification can be lifesaving. Ideally, an NBS program involves much more than just the screening itself; an integrated program should include testing, shortand long-term follow-up, diagnosis, consultation, quality assurance, and evaluation, all coordinated with appropriate specialists and the infantâ&#x20AC;&#x2122;s medical home.
Ethical Issues The application of ethical principles does not always give definitive answers to difficult medical questions, but these principles may be helpful in providing guidelines for making decisions. Although many ethical principles could be applied to genetic testing, the most commonly cited are autonomy/individual rights, beneficence and nonmaleficence (to do good and avoid harm), privacy, and justice. NBS programs are run by state public health departments that focus on the health of a population as a whole. Public health ethics often come into conflict with autonomy and respect for individual rights, as when public health acts to minimize disease in a population, even if this action disadvantages some individual members of the population. The concept of autonomy includes the freedom to choose for oneself as well as issues of informed consent. With NBS, the parents are granted the authority to make the choice for their child, either by con-
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senting directly to the screening or by exercising the option of waiving a mandatory screening test. Although an AAP policy statement on genetic testing in pediatrics (issued in 2001 and reaffirmed in 2009) (2) recommended that parental informed consent be standard procedure for NBS, most states continue to have mandatory screening based on passive consent: parents can opt out of testing (usually by signing a waiver) but are not required to give written consent before testing.
The Newborn Screening Panel Wilson and Jungner, in a 1968 report for the World Health Organization, defined 10 criteria for determining whether certain medical screening tests should be implemented. (3) Among these guidelines are: 1) the condition should be an important public health problem, 2) there should be an effective treatment for patients in whom the disease is diagnosed, and 3) an effective screening test should exist that is “acceptable to the population.” The SACHDNC has developed its own guidelines for evaluating disorders nominated for inclusion in the screening panel. The Committee considers factors such as the clinical utility (benefit and harm) associated with screening, diagnosis, and treatment; the cost effectiveness of screening, diagnosis, and treatment; and the clinical validity of the screening test. There is good reason to be cautious about adding new conditions to the NBS panel. Identifying a baby as having a “disease” when none exists may lead to unnecessary parental anxiety and labeling of the child. For example, several programs in the 1970s began screening for histidinemia but soon realized that this was a normal variant that did not require treatment. Since the current panel was rec-
ommended in 2005, new disorders have continued to be proposed by various researchers and parent advocacy groups. Severe combined immunodeficiency was recommended by the Advisory Committee in May 2010 for inclusion on screening panels, and several other conditions are being evaluated for screening or are being piloted by a few states, including lysosomal storage disorders (eg, Krabbe or Pompe disease), fragile X syndrome, and Duchenne muscular dystrophy. In September 2010, the SACHDNC voted to recommend adding critical congenital cyanotic heart disease to the panel; in September 2011, Secretary Sebelius agreed, bringing the total number of disorders recommended for screening to 31. It is still unclear how states will implement the recommendations. Screening is now being proposed for disorders in which treatment is still experimental or may not exist, such as lysosomal storage disorders and fragile X syndrome, as well as for conditions that have later onset (outside of the newborn period), such as Duchenne muscular dystrophy. In addition to not meeting the Wilson and Jungner criteria, such expansion of NBS raises questions about the benefit versus harm of providing a diagnosis if no good treatment is available, whether it is ethical to test babies for a condition that most likely will not develop or show symptoms for many years, and whether individuals should be allowed to make the testing decision for themselves when they are older.
Genetic Discrimination and Carrier Testing Identification of carrier status can be justified when such status affects health or helps inform reproductive choices. Carriers for sickle cell trait (SCT), those who have one sickle
hemoglobin gene and one normal hemoglobin gene, are routinely identified today on NBS. Ever since a 1970 New England Journal of Medicine article described four military recruits born with SCT who died during basic training, (4) there has been debate over whether the carrier status is benign or associated with potentially life-threatening medical problems. Recent case reports of football players who had SCT and suffered exercise-related deaths led the National Collegiate Athletic Association to require that collegiate athletes be tested to confirm their SCT status if it was not already known. Although the intent of this testing is good, privacy concerns and possible discrimination based on carrier status have yet to be addressed. Discrimination based on genetic difference is not new, but in the past it was largely limited to conditions that were phenotypically evident, such as Down syndrome. Since the Human Genome Project was completed, it is now possible to test for minute genetic differences that may never have any significant effect on a person’s health but that, if made public, could lead to discrimination in insurance applications, employment, and other opportunities. These genetic differences, if tested for prenatally, have the potential to be used for what some have termed “eugenics.” The average lifespan for people born with Down syndrome has increased from 25 years in 1983 to nearly 60 years today, (5) and children who have Down syndrome are achieving more than previously believed possible in inclusive classrooms. However, studies show that 92% of women who receive a prenatal diagnosis of Down syndrome choose to terminate their pregnancies. (6) Ethics demands that genetic testPediatrics in Review Vol.32 No.11 November 2011 491
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ing be accompanied by complete, unbiased information to allow thoughtful decisions. However, mothers of children who have Down syndrome report frequently that they felt pressured to make decisions quickly in response to the test results and that they were given incorrect information regarding their child’s potential and, most importantly, the joy the child could bring into their lives. (7) Pediatricians can assist expectant parents greatly by ensuring that the information they receive is complete and accurate.
Retention and Storage of Blood Spots Retention and use of residual blood spots is another controversial topic that the SACHDNC examined recently in a briefing paper. (8) Because NBS programs are run by the states, retention and storage practices vary widely. However, in general, these policies tend to fall into one of two groups: short-term storage (⬍3 y) for screening and quality control only, and long-term storage (18 to 21 y or more), which allows for the possibility of using the stored cards for research purposes. NBS cards have been called the “ultimate biobank” and are looked on by many as a valuable resource for studying genetic factors in populations. On the other hand, states that destroy the cards relatively quickly report having concerns about the cost of storage, the space required for storage, legal questions around ownership of the cards, and the possible effect on NBS rates if parents suspect that research could be performed on their baby’s blood in the future without their consent. In both Minnesota and Texas, parents have sued the state health departments over use of stored blood samples for research, and a new Oklahoma law, passed in September 2010, prohibits storage
of infant DNA without parental consent.
Health Disparities and Treatment of Ethnic Minorities The principle of justice requires that people receive fair and equal treatment. With regard to genetic testing, that principle means, at a minimum, equal access to genetic testing and counseling services. A 2006 study of predictive genetic testing showed that differential access to testing and counseling services “has led to growing health care disparities in clinical cancer genetics.” (9) Equality of access is complicated by the lack of universal medical coverage in the United States and by the fact that the prevalence of certain genetic mutations varies by ethnicity. Minorities tend to be more concerned about privacy of genetic information, which can lead to resistance to genetic testing among certain populations. African Americans have been shown to be less likely to believe that their privacy is well protected and to have less confidence in the ability of doctors and institutions to keep their information private. (10) The Havasupai tribe recently won a legal battle with Arizona State University over DNA samples first given to researchers in 1990. (11) The blood samples were taken originally to study diabetes, but tribe members say they discovered later that the samples had been used for other purposes without their consent.
Future Issues in Genetic Testing and Screening There is no doubt that the NBS panel will be expanded in the future as new technologies are developed, but it is not yet clear how new disorders will be selected and how the critical follow-up, education, and counsel-
ing will be provided and financed. Public health programs, legislators, and researchers need to work together to ensure that as screening expands, funding is adequate to ensure appropriate short- and longterm follow-up. Direct-to-consumer marketing of genetic testing has begun already and is certain to grow in the future. However, there is great potential for harm from an individual obtaining testing without the knowledge of a physician, especially when the validity and interpretation of the results are questionable. The United States Food and Drug Administration issued letters to 20 companies in 2010, temporarily stopping them from marketing their kits at drug stores without its approval. According to a July 2010 report, the Government Accountability Office is concerned about deceptive marketing practices and lack of standardization of results for over-thecounter genetic tests. (12)
Role of the Primary Care Clinician It is important for primary care clinicians to be aware of which conditions are screened for on an individual state’s panel and to remember that NBS is not diagnostic by itself. To minimize missed cases, false-positive results occur necessarily. On the other hand, the diagnosis for a child who has symptoms of a metabolic or genetic disorder may be delayed when physicians feel reassured by a negative screening test result. With each new condition added to the screening panel, the likelihood increases that an individual physician will be called with a positive result. The pediatrician should continue to be a primary source of education for parents and a valuable guide for them as they move through the NBS system. Likely there will not be enough genetic counselors to meet demand,
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Summary • Technology has allowed mapping of the human genome and screening for multiple genetic conditions with small drops of blood. Genetic tests are being marketed directly to consumers, bypassing the traditional role of the physician in determining which tests are appropriate for an individual patient. • As genetic testing becomes even more widely available and NBS continues to expand, ethical issues must continue to be discussed and debated, including risks of discrimination and stigmatization, respect for autonomy of individuals, privacy rights, and anxiety associated with testing. • The increase in direct-to-consumer marketing of genetic tests and the huge amount of genetic knowledge currently available make genetic counseling a vital resource that will become increasingly in demand. Primary care physicians will be called to coordinate care of patients who have genetic conditions as well as to counsel families and assist them in the decisionmaking process. • Counseling should be nondirective, open-minded, and respectful of the individual’s autonomy and cultural values.
and knowledgeable, empathic communication from the pediatrician will be crucial. As with any genetic testing, the patients’ or parents’ values (including cultural values) need to be considered to assist families in making decisions.
References 1. The President’s Council on Bioethics. The Changing Moral Focus of Newborn Screening: An Ethical Analysis by the Presi-
dent’s Council on Bioethics. December 2008. Accessed May 2011 at: http://bio ethics.georgetown.edu/pcbe/reports/new born_screening 2. AAP Committee on Bioethics. Ethical issues in genetic testing in pediatrics. Pediatrics. 2001;107:1451–1455 3. Wilson JMG, Jungner G. Principles and practice of screening for disease. WHO Chronicle. 1968;22:473 4. Jones SR, Binder RA, Donowho EM. Sudden death and sickle cell trait. N Engl J Med. 1970;282:323–325 5. Hearing Before the Down Syndrome
Congressional Caucus. 111th Cong, 1st Sess (2009) (testimony of Brian G. Skotko, MD) 6. Skotko BG. With new prenatal testing, will babies with Down syndrome slowly disappear? Arch Dis Child. 2009;94: 823– 826 7. Skotko BG. Prenatally diagnosed Down syndrome: mothers who continued their pregnancies evaluate their health care providers. Am J Obstet Gynecol. 2005;192: 670 – 677 8. Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children. Considerations and Recommendations for National Guidance Regarding the Retention and Use of Residual Dried Blood Spot Specimens After Newborn Screening: Briefing Paper. September 2010. Accessed May 2011 at: http:// www.hrsa.gov/heritabledisorderscommittee/ reports/RBSBriefingPaper0923.pdf 9. Hall MJ, Olopade OI. Disparities in genetic testing: thinking outside the BRCA box. J Clin Oncol. 2006;24:2197–2203 10. Robert Wood Johnson Foundation. Public Opinion Survey Finds Racial and Ethnic Differences Regarding Genetic Testing. October 2005. Accessed May 2011 at: http:// www.rwjf.org/reports/grr/035311.htm 11. Harmon A. Indian tribe wins fight to limit research of its DNA. New York Times. April 22, 2010:A1 12. Udesky L. The ethics of direct-toconsumer genetic testing. Lancet. 2010; 376:1377–1378
Parent Resources From the AAP at HealthyChildren.org The reader is likely to find material to share with parents that is relevant to this article by visiting this link: http://www.healthychildren.org/English/ages-stages/baby/pages/ newborn-screening-tests.aspx.
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Ethics for the Pediatrician : Genetic Testing and Newborn Screening Janis L. Gonzales Pediatrics in Review 2011;32;490 DOI: 10.1542/pir.32-11-490
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References
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Index of Suspicion Dorothy J. Ganick, Tara Federly, Muhammad Adeel Rishi, Karl J. Henrikson, Donny Suh, Jennifer Cook, Duangchai Narawong and Rashid Nadeem Pediatrics in Review 2011;32;495 DOI: 10.1542/pir.32-11-495
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Data Supplement (unedited) at: http://pedsinreview.aappublications.org/content/suppl/2011/10/12/32.11.495.DC1.html
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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The reader is encouraged to write possible diagnoses for each case before turning to the discussion.
The editors and staff of Pediatrics in Review find themselves in the fortunate position of having too many submissions for the Index of Suspicion column. Our publication slots for Index of Suspicion are filled through 2013. Because we do not think it is fair to delay publication longer than that, we have decided not to accept new cases for the present. We will make an announcement in Pediatrics in Review when we resume accepting
Case 1: Abdominal Trauma, Pain, and Tenderness Associated With Anemia and Hematuria in a 14-year-old Boy Case 2: Ptosis, Diplopia, Tremors, and Mild Exophthalmos in a 9-year-old Girl Case 3: Persistent Cough, Shortness of Breath, and Localized Decreased Aeration in an 18-year-old Girl Case 1 Presentation A 14-year-old boy is transferred from a local hospital. He was playing football and was struck in the abdomen by the head of another player who was wearing a helmet. He then fell on his abdomen. He immediately complained of left upper quadrant pain, and nausea. He was taken to a local ED and hospitalized. On admission, he was alert and oriented but experienced episodic hypotension. On examination, he looked pale and was found to have significant left upper quadrant abdominal tenderness. His initial Hct was 37%. Abdominal CT showed a 12⍝10⍝11 cm lobular enhancing mass over the left kidney,
new cases. We apologize for having to take this step, but we wish to be fair to all authors. We are grateful for your interest in the journal.
Author Disclosure Drs Ganick, Henrikson, Federly, Suh, Cook, Narawong, Rishi, and Nadeem have disclosed no financial relationships relevant to these cases. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
Frequently Used Abbreviations ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR: GI: GU: Hct: Hgb: MRI: WBC:
alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal fluid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate gastrointestinal genitourinary hematocrit hemoglobin magnetic resonance imaging white blood cell
Figure 1. A CT scan of the abdomen shows a lobular enhancing mass over the left kidney.
with questionable involvement of the colon and perinephric hematoma (Fig. 1). There was no free air. He was transfused with 1 unit of packed red blood cells and received 1 L of normal saline. His pain was controlled with morphine and he was transported to this institution. On arrival, he appears to be well developed and is in no acute distress, having a heart rate of 86 beats/min, respiratory rate of 20 breaths/min, blood pressure of 120/84 mm Hg, and oxygen saturation of 100% in room air. His abdomen is nondistended and has normal bowel sounds. However, he has left upper quadrant and left flank tenderness. Laboratory evaluations show Hct of 31.6%, normal coagulation studies and liver enzymes, lactose dehydrogenase concentration of 258 U/L Pediatrics in Review Vol.32 No.11 November 2011 495
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(normal, 150 to 300 U/L), and urinalysis positive for blood and protein. Chest radiograph shows normal heart and lung fields. Additional investigation leads to the diagnosis.
Case 2 Presentation A 9-year-old girl presents with a 4-week history of a drooping right eyelid and occasional double vision. She does not complain of easy fatigability, and she is able to ride her bike long distances without difficulty. She denies recent weight loss, heat intolerance, changes in her skin, and a racing heart. Her mother has rheumatoid arthritis. Physical examination reveals a healthy-appearing, thin girl. Her temperature is 36°C, heart rate is 108 beats/min, blood pressure is 112/66 mm Hg, and respiratory rate is 20 breaths/min. Her weight is 35.7 kg (70%) and height is 144.5 cm (85%). Her right eye has mild ptosis but the pupils are equal and extraocular movements are intact. There is no evidence of goiter. She does have a slight resting tremor of both hands. The remaining physical findings are normal. Initial laboratory evaluation, including CBC, serum electrolytes, and renal and liver function tests are normal. Due to the tremor and eye findings, thyroid tests are performed. Tri-iodothyronine is 266 ng/dL (normal, 60 to 181 ng/dL), free thyroxine is 3.2 ng/dL (normal, 0.0.8 to 1.8 ng/dL), thyroid stimulating hormone (TSH) is 0.009 mcIU/mL (normal, 0.35 to 5.5 mcIU/mL), anti-thyroglobulin antibodies are ⬍20 IU/L (normal, ⬍40 IU/L), anti-thyroperoxidase antibodies are ⬍10 U/mL (normal, ⬍35 U/mL) and thyroid stimulating immunoglobulin is 2.7 (normal, ⬍1.3). Thyroid ultrasonography shows small right thyroid nodules. Head CT is
reported as normal. Additional evaluation reveals the diagnosis.
Case 3 Presentation A previously healthy 18-year-old girl presents with a one-week history of persistent cough and shortness of breath on exertion. The cough is nonproductive, awakens her from sleep, and is associated with chest tightness and intermittent wheezing. There is no history of fever, chest pain, nausea, or vomiting. Although she has a history of environmental allergies, there is no history of previous lung infections or asthma. She is not taking any medications and is a nonsmoker. Family history is negative for pulmonary disease. Birth and developmental histories are normal. On presentation, vital signs, including the respiratory rate, are within normal limits. Physical examination reveals decreased air movement of the right upper chest and intermittent bilateral wheezing, without retractions or nasal flaring. Chest radiograph (Fig. 2) reveals prominence of the right hilum and hyperlucency of the right upper lobe area
without a midline shift. The differential diagnosis includes congenital lobar emphysema, bronchial obstruction with benign or malignant tumors, lobar sequestration, bronchogenic cyst, bronchial atresia, and pulmonary arterial aplasia or hypoplasia. Further evaluation leads to the diagnosis.
Case 1
Discussion
A biopsy of the mass in the kidney performed by an interventional radiologist showed renal cell carcinoma (RCC), clear cell type, well differentiated with characteristic cytogenetics involving the X chromosome, the Xp 11.2 translocation.
Differential Diagnosis The differential diagnosis for a renal mass in children characteristically is age-specific. In the neonate, multicystic dysplastic kidney, a congenital renal malformation, and congenital mesoblastic nephroma are the most common causes. The latter is a benign (very rarely malignant) tumor confined to the kidney. The most common kidney malignancy in children is Wilms tumor, which occurs most frequently in the 2- to 5-yearold child. Less common malignant tumors of the kidney include rhabdoid tumor and angiomyolipoma, which is associated with tuberous sclerosis. In the older child and adolescent, RCC is found at an equal frequency with Wilms tumor as a cause of kidney mass. Other causes of malignant renal tumors include rhabdomyosarcoma, malignant fibrous histiocytoma, teratoma, and liposarcoma.
The Condition Figure 2. Chest radiograph shows prominence of the right hilum (red arrow) and hyperlucency of the right upper lobe area (blue arrows).
RCC is uncommon in children, representing only 2% to 7% of malignant renal tumors. It presents in children between 8 and 11.5 years of age,
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probably occurring at equal frequency with Wilms tumor. In 19% of adults, the RCC presents with the triad of flank pain, hematuria, and abdominal mass. At least one or two elements of the triad may be seen in children. In one small series of RCC in children, abdominal trauma just before the diagnosis was not infrequent. As in this patient, the vascular and friable tumor located in the kidney may rupture after trauma, despite its retroperitoneal location. This phenomenon has been described in patients with Wilms tumor also. In contrast to Wilms tumor, congenital kidney anomalies are not associated with RCC. In adults, the tumor has an increased frequency in patients who have Von HippelLindau disease, whereas in children, RCC has been associated with tuberous sclerosis, Saethre-Chotzen syndrome, and chronic renal failure. Interestingly, in the pediatric cases of RCC, characteristic chromosomal translocations, including those of chromosomes X and 6, have been described in primary tumors as well as in second malignancies after therapy for another cancer. A particular histologic type of renal cell tumor, oncocytoid, has been seen after neuroblastoma therapy. The pathology of RCC is characterized as clear cell, papillary, or spindle cell. Clear cell is the most common form in adults. The papillary type is more frequent in children, as compared with adults. The most frequent site for distant metastatic disease is the lungs, and less frequently bone, distant lymph nodes, liver, and adrenal gland.
unresectable RCC has not improved survival. In adults, trials of targeted therapy with vascular endothelial growth factor inhibitors, interleukin, and interferon have shown modest success in treating metastatic RCC. Also, immunotherapy with a tumor vaccine is in early clinical trials. In this patient, after extensive multidisciplinary consultation involving surgery, urology, and radiation oncology, an enbloc left nephrectomy, partial pancreatectomy, splenectomy, and resection of the left diaphragm were performed. Sampling of lymph nodes and a left retroperitoneal fibrous hematoma was performed also. The histopathology studies did not show tumor outside of the kidney and the tumor was classified as T3a, NO (meaning the tumor was found in the renal sinus but lymph nodes were negative for metastatic disease). Additional therapy was not recommended. He was followed every 3 months with radiologic studies and has had no evidence of recurrence at 3 years since his diagnosis.
Prognosis The prognosis for RCC in children is better than in adults. Even in cases of lymphatic spread or operative spillage, children have a better prognosis than adults. The most important prognostic feature predicting diseasefree survival for RCC is stage at diagnosis. Children have shown earlier tumor recurrence 2 to 3 years past diagnosis as compared with adults; in Wilms tumor, late recurrences are more common. Overall survival rate for children has been reported to be 60% to 65% for resectable tumors and 10% to 20% for unresectable tumors.
Lessons for the Clinician
Management Surgical resection is the mainstay of therapy for RCC. Chemotherapy or radiation therapy for metastatic or
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The majority of cases of blunt abdominal trauma may result in contusion, hemorrhage, or laceration
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of the liver and spleen. The kidney usually is spared because of the retroperitoneal location. However, in children who have a malignant or vascular kidney tumor, the organ may rupture due to the trauma and cause hemorrhage. Complete surgical resection can result in cure of RCC. The tumor is not responsive to chemotherapy and radiation but may show some response to immunologic/ biologic therapy. Children with RCC do better than adults.
(Dorothy J. Ganick, MD, Lynnfield Pediatrics, Lynnfield, MA; Karl J. Henrikson, MD, University of Massachusetts Medical School, Worcester, MA.)
Case 2
Discussion
A pediatric ophthalmologist performed exophthalmometry, which did not show significant exophthalmos. The visual acuity and visual fields were normal. The patient did have lid fatigability and ice pack testing revealed full recovery of her ptosis. Acetylcholine receptor (AChR) antibodies were positive. On examination by a pediatric neurologist, her initial right eye opening was 1 cm, which decreased to 8 mm after sustained upward gaze. Due to her suggestive history, physical findings, and positive AChR antibodies, an edrophonium test and electrophysiologic studies were not performed. A CT scan of the chest was negative for thymoma. The final diagnoses were ocular myasthenia gravis (MG) and Graves disease (GD). Other diagnoses considered as causes of acquired ptosis included oculomotor nerve (cranial nerve III) palsy, Horner syndrome, brain stem glioma, ophthalmoplegic migraine, Bell palsy, orbital masses Pediatrics in Review Vol.32 No.11 November 2011 497
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(rhabdomyosarcoma), orbital trauma, Lyme disease, multiple sclerosis, and botulism. The girl was started on pyridostigmine and continued to have rightsided ptosis. Initially she did not have significant signs of hyperthyroidism. However, a few months later she began having problems focusing at school and struggled with emotional lability and hyperactive behavior. She was started on methimazole and within one month had considerable improvement in her behavior and near resolution of her right-sided ptosis. Due to the possibility of other autoimmune disorders, antinuclear antibody, ESR, serum glucose concentration, serum electrolytes, liver function panel, and hemoglobin concentration were monitored, and results remained normal.
The Condition MG is rare in children but is the most common primary disorder of neuromuscular transmission. MG is an autoimmune disease in which antibodies bind to AChR in the neuromuscular junction causing increased degradation of these receptors, thus functionally blocking acetylcholine from binding to the receptor. MG affects girls more often than boys and usually occurs after 10 years of age. The disease often involves ocular muscles initially, causing ptosis and diplopia. This form is referred to as ocular MG. However, two thirds of patients may gradually progress to generalized MG, with other muscle group involvement and possible respiratory compromise. Muscle weakness is exacerbated by repetitive muscle use, and symptoms generally worsen late in the day due to muscle fatigue. During examination, ptosis can be increased by sustained upward gaze for 30 to 90 seconds. MG can be confirmed by giving anticholinesterase medications such
as edrophonium, which will cause transient improvement in the involved muscle groups. Electrophysiologic studies with repetitive nerve stimulation, showing decremental response until the muscle becomes refractory to further stimulation, also may be diagnostic. In addition, AChR antibodies are present in 50% to 90% of patients. Thymoma is seen in fewer than 5%, and up to 10% of patients with MG have other autoimmune disorders, with thyroid disease being the most common. GD is the most common cause of thyrotoxicosis in children and adolescents and can be found in association with MG. It is an autoimmune disorder in which antibodies bind to TSH receptors and result in excess synthesis and secretion of thyroid hormone. GD affects girls more often than boys, and the peak incidence is between 10 and 15 years of age. Clinical manifestations of GD include tachycardia, weight loss, increased appetite, heat intolerance, tremor, exophthalmos, eyelid lag, moist skin, fine hair, restlessness, emotional lability, short attention span, declining school performance, and fatigue. The diagnostic studies for GD include elevated concentrations of serum tri-iodothyronine and free thyroxine with suppressed TSH. Serum thyroid antibodies, specifically thyroid stimulating immunoglobulin, also may be present. The association of MG and GD was first described in 1908. It is unclear how the two diseases are related, but it is hypothesized that there is an immunologic crossreactivity between thyroid and neuromuscular junction components. MG associated with GD has a milder clinical expression, with a preference for ocular involvement. GD in patients with MG has a higher prevalence of euthyroid ophthalmopathy, with or without clinical hyperthy-
roidism. In differentiating the ocular signs of these two disorders it is important to understand that diplopia may occur in both, but ptosis and fatigability are not seen in thyroid ophthalmopathy and exophthalmos is not seen in ocular MG.
Management There are multiple treatment options for managing MG effectively. Anticholinesterase medications, such as pyridostigmine, may provide improvement in some patients but is less likely to be helpful in cases of pure ocular MG. Due to the autoimmune nature of MG, most patients require immunotherapeutic agents, such as prednisone, cyclosporine, or azathioprine. Myasthenic crisis or acute worsening of MG symptoms may be treated with plasmapheresis or intravenous immune globulin. In patients who have MG and GD, resolution of ocular symptoms may occur only when a euthyroid state is restored. Therefore, it is important to treat GD when it occurs in association with ocular MG. GD is treated with antithyroid medications, such as methimazole. Surgical treatment of MG involves thymectomy for patients who have a thymoma. This procedure may induce remission in the majority of patients with MG but is not recommended in patients with MG occurring with GD due to potential worsening. Autoimmune polyglandular syndromes always should be considered in a patient with MG and GD. These patients should be monitored for other autoimmune disorders including type I diabetes mellitus, Addison disease, pernicious anemia, autoimmune hepatitis, celiac disease, hypoparathyroidism, and rheumatoid arthritis. With current therapies, MG can be managed effectively, and mortality has decreased to less than 5%.
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Figure 3. CT scan of the chest shows bronchocele (blue arrows), occlusion of the bronchus (red arrow) central to the bronchocele, and emphysematous changes in the right upper lung.
Fortunately, if ocular MG has not progressed to generalized MG in the first 2 years, it will stabilize with treatment and often is self-limited with resolution of symptoms.
Lessons for the Clinician ●
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●
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Case 3
Discussion
CT scan (Fig. 3) of the chest showed a bronchocele, occlusion of the bronchus central to the bronchocele, and emphysematous change in the right upper lung. Pulmonary function testing demonstrated mild air-
way obstruction that normalized with bronchodilators, a pattern consistent with asthma. A ventilation scan (Fig. 4) demonstrated delayed filling of the right upper lobe as well as delayed clearance. The perfusion component of the study revealed compromised filling of the right upper lobe (Fig. 5). An MRI (Fig. 6) of the lungs showed high signal intensity on T1 and T2 weighed images at the site of the bronchocele consistent with mucus. Bronchoscopic evaluation did not demonstrate the origin of the anterior segment of the right upper lobe. These findings were indicative of congenital bronchial atresia, which was considered an incidental finding in a patient having her first episode of asthma. Her symptoms resolved with treatment with short-acting bronchodilators and inhaled corticosteroids.
The Sign Lobar or segmental hyperinflation seen on a chest radiograph may be caused by a variety of conditions. Some of these disorders are found incidentally, seldom progress, and need little if any treatment, whereas others may be
Ptosis is a common initial presentation of MG. GD should be suspected in patients with ocular MG even if symptoms of hyperthyroidism are not evident. Treatment of ocular MG may need to include both pyridostigmine and immunomodulators as well as treatment of hyperthyroidism to achieve resolution of ocular symptoms. Patients given a diagnosis of MG and GD should be monitored for other autoimmune disorders.
(Tara Federly, MD, Donny Suh, MD, Jennifer Cook, MD, Duangchai Narawong, MD, Blank Children’s Hospital, Des Moines, IA.)
Figure 4. A ventilation scan shows delayed filling of the right upper lobe as well as delayed clearance. Pediatrics in Review Vol.32 No.11 November 2011 499
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on occasion, the hyperinflation may appear segmental.
The Condition
Figure 5. The perfusion component of the study reveals compromised filling of the
right upper lobe.
progressive and need surgical intervention. The causes include: â&#x2014;?
Pathologic lesions or processes involving the bronchial tree, which compromise emptying of the lung. Bronchial atresia and extrinsic compression of bronchi caused by conditions such as congenital heart disease or anomalies of the great vessels can interfere with drainage of alveoli. Bronchogenic cysts, lymphadenopa-
â&#x2014;?
thy, and tumors, as well as kyphoscoliosis, can compromise airway integrity and cause obstruction as well. Any lesion or process leading to loss of lung volume on the contralateral side. These conditions include absent lung and lobar or lung collapse due to bronchial obstruction. Although this situation usually causes hyperinflation of the whole lung on the other side,
Figure 6. MRI of the lungs showing high signal intensity on T1 and T2 weighed images at the site of the bronchocele (red arrow), indicating the presence of mucus.
Bronchial atresia consists of atresia or stenosis of a lobar, segmental, or subsegmental bronchus near its point of origin. Since its initial recognition in 1953 by Ramsay and Byron, (2) approximately 100 cases have been described. Because many patients are asymptomatic, the actual incidence is unknown. The average age at diagnosis is 22 years, although bronchial atresia has been described in both newborns and in a patient in her 60s. A male predominance of the disorder is noted. Although most individuals remain asymptomatic, others require evaluation for recurrent infections, unexplained dyspnea, or as with this patient, abnormal radiograph findings. Both sides can be involved. For unclear reasons, there is a predisposition towards upper lobar involvement. The pathogenesis of anomalous bronchial development remains unknown. Given recent insights into the molecular underpinnings of branching morphogenesis of the lung, there may be further understanding of the transcription factors that account for bronchial branching. At present, however, there are two fundamental, albeit relatively crude, explanations for the anomalies. First, an island of multiplying cells at the tip of a bronchial bud loses its connection with the bud itself but continues to branch independently, resulting in a normal distal bronchial branch pattern without a connection between distal and central airways. The second hypothesis involves a localized intrauterine interruption of the bronchial artery blood supply, resulting in bronchial atresia. The lung parenchyma that loses its blood supply usually is emphysematous. The air that is noted in the affected
500 Pediatrics in Review Vol.32 No.11 November 2011
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index of suspicion
parenchyma is the result of the collateral ventilation through the pores of Kohn, the bronchoalveolar channels of Lambert, or interbronchiolar channels. Given that collateral circulation may not be developed until the second 6 months after birth, hyperinflation may not be apparent in the perinatal period. Alternatively, hyperinflation may occur shortly after birth with the start of respiration, because the proposed pathways for collateral ventilation favor the movement of air into the obstructed segment by a check-valve type mechanism. At the root of the involved tissue, a mucus-filled cystic structure (the mucocele) with finger-like projections represents the atretic bronchus, which is isolated from the proximal bronchial tree and is dilated by the accumulated mucus. The bronchial pattern distal to the mucocele usually is normal. The only physical finding may be decreased breath sounds over the affected area. When a major bronchus is atretic, the affected distal lobe may
be significantly hyperinflated, causing compression of surrounding healthy lung and shift of the mediastinum to the opposite side. In such patients, symptoms of reduced exercise tolerance and possibly wheezing and shortness of breath may be prominent. CT or, less commonly, MRI is used to confirm the diagnosis. Bronchoscopy may be used to rule out other causes.
Management In many cases, bronchial atresia warrants no intervention. Surgical excision is indicated when overdistention of the affected lung segment or lobe leads to compromise of surrounding normal lung (as in congenital lobar emphysema) and the patient has significant complications, such as recurrent infections.
Lessons for the Clinician ●
●
When a teenager presents with lobar or segmental hyperinflation of the lung, bronchial atresia should be considered in the differential diagnosis. Congenital bronchial atresia is a rare
●
and benign entity that might occasionally resemble serious underlying diseases on radiographic examination. There are occasions when infection might result and antibiotic treatment might be necessary. CT scan of the chest is the procedure of choice for the diagnosis, but in doubtful cases, bronchoscopy may be useful to exclude other conditions and infection.
(Muhammad Adeel Rishi, MD, Rashid Nadeem, MD, Rosalind Franklin University of Science and Medicine, Chicago Medical School, Chicago, IL.)
References 1. Rennie G. Exophthalmic goiter combined with myasthenia gravis. Rev Neurol Psychiatry. 1908;6:229 –233 2. Ramsay BH, Byron FX. Mucocele, congenital bronchiectasis, and bronchiogenic cyst. J Thorac Surg. 1953;26:21–30
To view Suggested Reading lists for the cases, visit pedsinreview. aappublications.org and click on Index of Suspicion.
Clarification The article entitled “Acid-Base Disorders” in the June issue (Pediatr Rev. 2011;32:240 – 251) contains this statement: “Lowering the arterial pH below 7.35 is termed acidosis, and an increase of the arterial pH above 7.45 constitutes alkalosis.” This terminology is indeed used in common clinical parlance with which readers are familiar. Technically, acidosis and alkalosis refer to the physiologic processes that affect the pH of the blood, with the terms acidemia and alkalemia designating abnormalities of the blood pH specifically.
Correction In the In Brief article entitled “Growth” in the September issue (Pediatr Rev. 2011;32: 404 – 406), the formula for estimating height based on parental measurements for girls should read as follows: For girls: [father’s height (cm) ⫺ 13 ⫹ mother’s height (cm)]/2 or [father’s height (in) ⫺ 5 ⫹ mother’s height (in)]/2. The journal regrets the error.
Pediatrics in Review Vol.32 No.11 November 2011 501
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Index of Suspicion Dorothy J. Ganick, Tara Federly, Muhammad Adeel Rishi, Karl J. Henrikson, Donny Suh, Jennifer Cook, Duangchai Narawong and Rashid Nadeem Pediatrics in Review 2011;32;495 DOI: 10.1542/pir.32-11-495
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/32/11/495
References
This article cites 2 articles, 0 of which you can access for free at: http://pedsinreview.aappublications.org/content/32/11/495#BIB L
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The following Suggested Reading lists are included online only for the “Index of Suspicion.”
Suggested Reading for Case 1 Argani P, Lae M, Ballard ET, et al. Translocation carcinoma of kidney after chemotherapy in childhood. J Clin Oncol. 2006;24:1509 –1524 Aronson DC, Medary I, Finlay JL, Herr HW, Exelby PR, LaQuaglia MP. Renal cell carcinoma in childhood and adolescence: a retrospective survey for prognostic factors in 22 cases. J Pediatr Surg. 1996;23:772–780 Carcao MD, Talor GP, Greenberg ML, et al. Renal cell carcinoma in children: a different disorder from its adult counterpart? Med Pediatr Oncol. 1998;31: 153–158 Futrell JW, Filston HC, Reid JD. Rupture of renal cell carcinoma in a child: fiveyear tumor-free survival and literature review. Cancer. 1978;41:1565–1570 Ganick DJ. Other renal tumors of child-
hood. In: Pochedly C, ed. Neoplastic Diseases of Childhood. Newark, NJ: Harwood Academic Publishers; 1996: 715–724 Geller JI, Dome JS. Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer. 2004;101:575–583 Lack EE, Cassady JR, Sallan SE. Renal cell carcinoma in childhood and adolescence: a clinical and pathological study of 17 cases. J Urol. 1985;133:822– 828 Selle B, Furtawongler R, Graf N, Kaatsch P, Bruder E, Leuschner I. Populationbased study of renal cell carcinoma in children in Germany, 1980 –2005. Cancer. 2006;107:2900 –2914
Suggested Reading for Case 2 Koves I, Cameron F, Kornberg A. Ocular myasthenia gravis and Graves disease in a 10-year-old child. J Child Neurol. 2009; 24:615– 617 Marino M, Riccardi R, Pinchera A, et al. Mild clinical expression of myasthenia gravis associated with autoimmune thy-
roid diseases. J Clin Endocrinol Metab. 1997;82:438 – 443
Suggested Reading for Case 3 Laberge J-M, Puligandla P, Flageole H. Asymptomatic congenital lung malformations. Semin Pediatr Surg. 2005;14: 16 –33 Matsushima H, Takayanagi N, Satoh M, et al. Congenital bronchial atresia: radiologic findings in nine patients. J Comput Assist Tomogr. 2002;26:860 – 864 Metzger RJ, Klein OD, Martin GR, Krasnow MA. The branching program of mouse lung development. Nature. 2008;453:745–750 Psathakis K, Lachanis S, Kotoulas C, et al. The prevalence of congenital bronchial atresia in males: presentation of seven cases, diagnostic approach and review of the literature. Monaldi Arch Chest Dis. 2004;61:28 –34 Zylak CJ, Eyler WR, Spizarny DL, Stone CH. Developmental lung anomalies in the adult: radiologic–pathologic correlation. RadioGraphics. 2002;22:25– 43
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Clarification Pediatrics in Review 2011;32;501 DOI: 10.1542/pir.32-11-501
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/501.1
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Downloaded from http://pedsinreview.aappublications.org/ by Enrique Mendoza-Lopez on November 3, 2011
index of suspicion
parenchyma is the result of the collateral ventilation through the pores of Kohn, the bronchoalveolar channels of Lambert, or interbronchiolar channels. Given that collateral circulation may not be developed until the second 6 months after birth, hyperinflation may not be apparent in the perinatal period. Alternatively, hyperinflation may occur shortly after birth with the start of respiration, because the proposed pathways for collateral ventilation favor the movement of air into the obstructed segment by a check-valve type mechanism. At the root of the involved tissue, a mucus-filled cystic structure (the mucocele) with finger-like projections represents the atretic bronchus, which is isolated from the proximal bronchial tree and is dilated by the accumulated mucus. The bronchial pattern distal to the mucocele usually is normal. The only physical finding may be decreased breath sounds over the affected area. When a major bronchus is atretic, the affected distal lobe may
be significantly hyperinflated, causing compression of surrounding healthy lung and shift of the mediastinum to the opposite side. In such patients, symptoms of reduced exercise tolerance and possibly wheezing and shortness of breath may be prominent. CT or, less commonly, MRI is used to confirm the diagnosis. Bronchoscopy may be used to rule out other causes.
Management In many cases, bronchial atresia warrants no intervention. Surgical excision is indicated when overdistention of the affected lung segment or lobe leads to compromise of surrounding normal lung (as in congenital lobar emphysema) and the patient has significant complications, such as recurrent infections.
Lessons for the Clinician ●
●
When a teenager presents with lobar or segmental hyperinflation of the lung, bronchial atresia should be considered in the differential diagnosis. Congenital bronchial atresia is a rare
●
and benign entity that might occasionally resemble serious underlying diseases on radiographic examination. There are occasions when infection might result and antibiotic treatment might be necessary. CT scan of the chest is the procedure of choice for the diagnosis, but in doubtful cases, bronchoscopy may be useful to exclude other conditions and infection.
(Muhammad Adeel Rishi, MD, Rashid Nadeem, MD, Rosalind Franklin University of Science and Medicine, Chicago Medical School, Chicago, IL.)
References 1. Rennie G. Exophthalmic goiter combined with myasthenia gravis. Rev Neurol Psychiatry. 1908;6:229 –233 2. Ramsay BH, Byron FX. Mucocele, congenital bronchiectasis, and bronchiogenic cyst. J Thorac Surg. 1953;26:21–30
To view Suggested Reading lists for the cases, visit pedsinreview. aappublications.org and click on Index of Suspicion.
Clarification The article entitled “Acid-Base Disorders” in the June issue (Pediatr Rev. 2011;32:240 – 251) contains this statement: “Lowering the arterial pH below 7.35 is termed acidosis, and an increase of the arterial pH above 7.45 constitutes alkalosis.” This terminology is indeed used in common clinical parlance with which readers are familiar. Technically, acidosis and alkalosis refer to the physiologic processes that affect the pH of the blood, with the terms acidemia and alkalemia designating abnormalities of the blood pH specifically.
Correction In the In Brief article entitled “Growth” in the September issue (Pediatr Rev. 2011;32: 404 – 406), the formula for estimating height based on parental measurements for girls should read as follows: For girls: [father’s height (cm) ⫺ 13 ⫹ mother’s height (cm)]/2 or [father’s height (in) ⫺ 5 ⫹ mother’s height (in)]/2. The journal regrets the error.
Pediatrics in Review Vol.32 No.11 November 2011 501
Downloaded from http://pedsinreview.aappublications.org/ by Enrique Mendoza-Lopez on November 3, 2011
Clarification Pediatrics in Review 2011;32;501 DOI: 10.1542/pir.32-11-501
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/32/11/501.1
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online: /site/misc/reprints.xhtml
Downloaded from http://pedsinreview.aappublications.org/ by Enrique Mendoza-Lopez on November 3, 2011
Correction Pediatrics in Review 2011;32;501 DOI: 10.1542/pir.32-11-501-a
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/501.2
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
Downloaded from http://pedsinreview.aappublications.org/ by Enrique Mendoza-Lopez on November 3, 2011
index of suspicion
parenchyma is the result of the collateral ventilation through the pores of Kohn, the bronchoalveolar channels of Lambert, or interbronchiolar channels. Given that collateral circulation may not be developed until the second 6 months after birth, hyperinflation may not be apparent in the perinatal period. Alternatively, hyperinflation may occur shortly after birth with the start of respiration, because the proposed pathways for collateral ventilation favor the movement of air into the obstructed segment by a check-valve type mechanism. At the root of the involved tissue, a mucus-filled cystic structure (the mucocele) with finger-like projections represents the atretic bronchus, which is isolated from the proximal bronchial tree and is dilated by the accumulated mucus. The bronchial pattern distal to the mucocele usually is normal. The only physical finding may be decreased breath sounds over the affected area. When a major bronchus is atretic, the affected distal lobe may
be significantly hyperinflated, causing compression of surrounding healthy lung and shift of the mediastinum to the opposite side. In such patients, symptoms of reduced exercise tolerance and possibly wheezing and shortness of breath may be prominent. CT or, less commonly, MRI is used to confirm the diagnosis. Bronchoscopy may be used to rule out other causes.
Management In many cases, bronchial atresia warrants no intervention. Surgical excision is indicated when overdistention of the affected lung segment or lobe leads to compromise of surrounding normal lung (as in congenital lobar emphysema) and the patient has significant complications, such as recurrent infections.
Lessons for the Clinician ●
●
When a teenager presents with lobar or segmental hyperinflation of the lung, bronchial atresia should be considered in the differential diagnosis. Congenital bronchial atresia is a rare
●
and benign entity that might occasionally resemble serious underlying diseases on radiographic examination. There are occasions when infection might result and antibiotic treatment might be necessary. CT scan of the chest is the procedure of choice for the diagnosis, but in doubtful cases, bronchoscopy may be useful to exclude other conditions and infection.
(Muhammad Adeel Rishi, MD, Rashid Nadeem, MD, Rosalind Franklin University of Science and Medicine, Chicago Medical School, Chicago, IL.)
References 1. Rennie G. Exophthalmic goiter combined with myasthenia gravis. Rev Neurol Psychiatry. 1908;6:229 –233 2. Ramsay BH, Byron FX. Mucocele, congenital bronchiectasis, and bronchiogenic cyst. J Thorac Surg. 1953;26:21–30
To view Suggested Reading lists for the cases, visit pedsinreview. aappublications.org and click on Index of Suspicion.
Clarification The article entitled “Acid-Base Disorders” in the June issue (Pediatr Rev. 2011;32:240 – 251) contains this statement: “Lowering the arterial pH below 7.35 is termed acidosis, and an increase of the arterial pH above 7.45 constitutes alkalosis.” This terminology is indeed used in common clinical parlance with which readers are familiar. Technically, acidosis and alkalosis refer to the physiologic processes that affect the pH of the blood, with the terms acidemia and alkalemia designating abnormalities of the blood pH specifically.
Correction In the In Brief article entitled “Growth” in the September issue (Pediatr Rev. 2011;32: 404 – 406), the formula for estimating height based on parental measurements for girls should read as follows: For girls: [father’s height (cm) ⫺ 13 ⫹ mother’s height (cm)]/2 or [father’s height (in) ⫺ 5 ⫹ mother’s height (in)]/2. The journal regrets the error.
Pediatrics in Review Vol.32 No.11 November 2011 501
Downloaded from http://pedsinreview.aappublications.org/ by Enrique Mendoza-Lopez on November 3, 2011
Correction Pediatrics in Review 2011;32;501 DOI: 10.1542/pir.32-11-501-a
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/32/11/501.2
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online: /site/misc/reprints.xhtml
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Bipolar Disorders Maria T. Nanagas Pediatrics in Review 2011;32;502 DOI: 10.1542/pir.32-11-502
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/32/11/502
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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in brief
In Brief Bipolar Disorders Maria T. Nanagas, MD Children’s Medical Center and Wright State University Boonshoft School of Medicine Dayton, OH
Author Disclosure Dr Nanagas has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Pediatric Bipolar Disorder: A Review of the Past 10 Years. Pavuluri M, Boris B, Naylor M, J Am Acad Child Adolesc Psychiatry. 2005;44:846 – 871 Pediatric Bipolar Disorder: Evidence for Prodromal State and Early Markers. Luby J, Navsaria N. J Child Psychol Psychiatry. 2010;51:459 – 471 The Early Course of Bipolar Disorder in Youth at Familial Risk. Duffy A. J Can Acad Child Adolesc Psychiatry. 2009;18:200 –205 Beyond Genetics. Etain B, Henry C, Belliver F, Matthew F, Leboyer M. Bipolar Disorder. 2008;10:867– 876 Diagnosing Bipolar Disorder in Children and Adolescents. Chang K. J Clin Psychiatry. 2009;70:e41
Pediatric bipolar disorder (PBD) is a recurring complex psychopathological mood disorder causing significant impairment in children. PBD spectrum includes bipolar I (full manic episode), bipolar II (depression with hypomania) and bipolar not otherwise specified (NOS) (“others” in mid-spectrum who may be exhibiting prodromal PBD states but do not fit criteria clearly).
The clinical presentation of PBD often does not meet the Diagnostic and Statistical Manual of Mental Disorders criteria for bipolar disorder (BD), which was developed in adults and not adapted for children. The diagnosis becomes difficult because symptom presentation is variable and largely dependent on developmental age. Although discrete episodes of mania and depression that define BD in adults may match the presentation of some patients who have BD in adolescence, patients who have BD of childhood and prepubertal onset may or may not manifest these clear-cut episodes. The duration of episodes in children may be as short as 1 to 2 days. Mood symptoms can be chronic, can present as predominantly mixed episodes, or can continuously cycle rapidly, with severe irritability or aggression as the usual presenting symptoms. Disruptive behavior, hyperarousal, racing thoughts, elation, and grandiosity also may characterize the moods. A major depressive presentation is associated with a significant risk for developing subsequent BD. Poor psychosocial skills as well as cognitive and attention deficits may manifest along with mood and behavior changes. The chronic relapsing mode of PBD may extend into early adulthood. Longitudinal studies abound on PBD; yet, there is no firm agreement on exactly what constitutes the diagnosis of PBD. Complicating the diagnosis of PBD is the high rate of comorbidity with attention deficit hyperactivity disorder (ADHD) and psychiatric disorders such as anxiety, conduct, substance abuse, and oppositional defiant disorders. Children who have both PBD and ADHD tend to manifest a more severe course of illness, presenting with psychosis
and comorbid depression often requiring hospitalization. Although both PBD and ADHD include symptoms of distractibility and hyperactivity, the distinguishing symptoms of mania, flight of ideas, decreased need for sleep, and exhibition of sexual tendencies are present in PBD but usually not in ADHD. PBD is thought to result from an interaction among genetic and environmental risk factors in which family environment is important. The genetic endowment of parents might contribute to the family dysfunction, predisposing already genetically affected offspring to evolution of the disorder. PBD is a highly heritable disorder having a documented genetic determinant, although its basis is not yet fully elucidated. Family history is the most significant risk factor for developing the illness. Studies show an increased risk of psychopathology in the offspring of parents who have BD. Early depression, anxieties, and dysregulated behavior may be useful markers for later development of BD in high-risk children. Those symptoms may be episodic. Some researchers suggest that PBD markers may be detectable almost a decade before the onset of the clinical disorder. Ongoing research is searching to identify PBD prodromes and early risk markers for the later developments of PBD. Clinical staging is proposed in identifying the PBD evolution among at-risk children. Early symptoms in the evolution include abnormalities in temperament, anxiety, sleep disruption, minor mood disturbance, difficulties with emotion regulation, and adjustment problems, progressing into mixed mood episodes, followed by frank bipolarity later in adolescence and adulthood. Heritable biomarkers in the areas of
502 Pediatrics in Review Vol.32 No.11 November 2011
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in brief
attention, executive function, and affect processing are subjects of ongoing research. There may be structural, functional, and biochemical alterations in the brain predisposing the child to mood instability. Research has suggested that physical, sexual, and emotional childhood traumas that occur at a time of sensitivity of the maturing central nervous system may predispose to and modulate the clinical expression and course of the PBD. Traumas cause organic changes in the brain that lead to mood dysregulation. These changes may result in a rapid cycling course, psychotic features, suicidal behavior, and an earlier age of onset, all of which induce a more severe clinical PBD profile. Traumas can result from any stressful event. Examples include behavioral, educational, family related, or substance abuse induced episodes; negative life events, such as low socioeconomic status, ongoing family conflicts, or low quality of
life; or any disappointing life events such as school failure or termination of relationships. As many as two thirds of adults given a diagnosis of BP had symptoms beginning in childhood. This finding underscores the importance of risk and prodrome recognition, along with early and accurate diagnosis that allows intervention before full development of the highly impairing disorder. Expert agreements on what constitute key features and valid biomarkers for PBD diagnosis are needed. Comments: When reviewing community-based studies, the diagnosis of PBD has increased dramatically over the past decade. In retrospective studies in adults, 10% to 20% revealed the onset of symptoms when they were younger than 10 years of age, and 60% when younger than 20 years, with most self-reporting a delay of 10 years in making the diagnosis. Although unfor-
tunate, this finding may not be surprising, because there are less clear diagnostic criteria for children and because pediatricians have not been trained to consider this diagnosis. Early diagnosis is important in order to initiate appropriate treatment and minimize morbidity and mortality, such as through suicide. As pediatricians, we need to consider the diagnosis in children who exhibit irritability and aggression, and a family history of bipolar disease is important to determine. Future research is needed to better examine treatment options in children and whether earlier treatment will result in better outcomes. The challenge of managing PBD is yet another example of the importance of mental health training for pediatricians and for collaboration with mental health providers to provide the best possible care to our patients. Janet Serwint, MD Consulting Editor, In Brief
Pediatrics in Review Vol.32 No.11 November 2011 503
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Bipolar Disorders Maria T. Nanagas Pediatrics in Review 2011;32;502 DOI: 10.1542/pir.32-11-502
Updated Information & Services
including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/32/11/502
References
This article cites 5 articles, 0 of which you can access for free at: http://pedsinreview.aappublications.org/content/32/11/502#BIB L
Permissions & Licensing
Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml
Reprints
Information about ordering reprints can be found online: /site/misc/reprints.xhtml
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