PIR February2014

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visual diagnosis
12-Year-Old Girl With Constipation And Rectal Bleeding

Arvind Srinath, MD,* Danielle Wendel, MD, Geoffrey Bond, MD, Mark Lowe, MDx
Presentation
A 12-year-old girl with a history of well-controlled constipation presents to the emergency department after having an uncomfortable, large, nonbloody bowel movement at home followed by sacral numbness and bright red blood seeping out of her rectum. Her review of systems is remarkable for 1 to 2 soft bowel movements per day with occasional cramping, painful defecation (dyschezia), and sensation of incomplete evacuation (tenesmus). She is premenarchal and denies any history of easy bleeding or bruising or trauma. She additionally denies constitutional symptoms, oral ulcers, heartburn, or a history of anemia. Her family history is remarkable for food allergies and developing glioblastoma multiforme on both sides of the family. There is no family history of inammatory bowel disease, polyps, coagulopathy, or rheumatologic conditions. Vital signs are as follows: heart rate, 124 beats per minute; respiratory rate, 20 breaths per minute; blood pressure, 117/72 mm Hg; temperature, 98.8F (37.1C); and oxygen saturation, 100% on room air. Her weight is 36.4 kg (15th percentile), height is 153 cm (40th percentile), and body mass index is 15.1 (10th percentile). Physical examination reveals a soft, benign abdomen without any masses or organomegaly. Perianal examination is notable for gross external blood on the perianal skin without external ssures, hemorrhoids, lesions, uctuance, or palpable masses. There is no palpable stool in the rectal vault. The sacrum does not have any overlying skin changes or palpable masses. There is no other evidence of bleeding, bruising, or petechiae. The rest of the physical examination ndings are normal. Laboratory examination reveals a hemoglobin level of 10.5 g/dL (105 g/L) (mean corpuscular volume, 90.0 mm3; red blood cell distribution width, 13.8). The rest of her complete blood cell count was remarkable for a white blood cell count of 15,800/mL (15.8 109/L) (87% neutrophils and 10% lymphocytes) and platelet count of 261 103/mL (261 109/L).
Figure 1. Lymphoid hyperplasia throughout colon (arrows).
Author Disclosure Drs Srinath, Wendel, Bond, and Lowe have disclosed no nancial relationships relevant to this article. This commentary does contain discussion of unapproved/ investigative use of a commercial product/device.
*Pediatric Gastroenterology Fellow, Childrens Hospital of Pittsburgh, Pittsburgh, PA. Pediatric Resident, Childrens Hospital of Pittsburgh, Pittsburgh, PA. Assistant Professor in Transplant Surgery, Transplant Director, University of Pittsburgh, Pittsburgh, PA. x Chief, Division of Pediatric Gastroenterology, Childrens Hospital of Pittsburgh, Pittsburgh, PA.
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visual diagnosis
Because of her rectal bleeding, tachycardia, and mild anemia, the patient is admitted for observation and further evaluation. During the next 24 hours, she has one painless melanotic stool, and her hemoglobin level decreases 2 g/dL (20 g/L) to 8.5 mg/dL (85 g/L) (mean corpuscular volume, 89.4 mm3; red blood cell distribution width, 13.7). Further laboratory tests reveal a reticulocyte count of 1.2%, an international normalized ratio of 1.1, a partial thromboplastin time of 38.1 seconds, and negative von Willebrand study results. The patients albumin, erythrocyte sedimentation rate, and urinalysis results are normal. A Meckel scan is unremarkable. Subsequent endoscopy and colonoscopy document a attened rectum. However, gross blood in the rectum prevents optimal visualization of the mucosa. The rest of the colon is remarkable for lymphoid hyperplasia (Figure 1). Subsequent abdominal computed tomography (CT) (Figure 2) with contrast reveals the diagnosis.
Diagnosis: Rectal Duplication Cyst

A roughly 5-cm3 heterogeneous uid collection located anterior to the sacrum and posterior to the anal canal and pushing the anal canal anteriorly is discovered on
Figure 3. Axial view on pelvic magnetic resonance imaging. Evolving hematoma (arrow) posterior to the rectal lumen (dashed arrow). A[anterior; R[right; O[ovary. Courtesy of Virginia Kania, DO, and Sameh Tadros, MD, MSc, Department of Radiology, Childrens Hospital of Pittsburgh of University of Pittsburgh Medical Center.
CT examination. The presence of gas around and within the mass is concerning for bowel wall disruption (Figure 3). Follow-up pelvic magnetic resonance imaging (MRI) reveals a well-circumscribed, heterogeneous presacral mass in the pelvis that is contiguous with the rectal wall and compresses the rectum (Figure 4). There is also an incidental Tarlov cyst, which is a perineural cyst that contains cerebrospinal uid.
Discussion
Rectal duplications are congenital malformations of abnormally closed epithelium-lined cavities whose walls consist of colonic or anorectal mucosa. Rectal duplications are either continuous or contiguous with the rectum and have a muscular coat (smooth muscle in 2 layers) and an epithelial lining. Most rectal duplications are cystic, although they can be tubular, extrophic, or diverticular or occur with a cutaneous stula (25%40% of cases) to the perineum or anus. Rectal duplications are usually retrorectal. Their epithelial lining is most often colonic, although they also can have squamous epithelia, respiratory epithelia, gastric mucosa, or urothelial cells. The cause of rectal duplications is unclear. Because a great deal of embryologic activity occurs in the caudal
Figure 2. Abdominal-pelvic computed tomogram. Heteroge-
neous uid collection (blue arrow) anterior to sacrum and posterior to the anal canal. Locules of gas (red arrow) within uid collection raise concern for bowel wall disruption. B[bladder. Dashed arrow indicates the rectal lumen. Courtesy of Virginia Kania, DO, and Sameh Tadros, MD, MSc, Department of Radiology, Childrens Hospital of Pittsburgh of University of Pittsburgh Medical Center.
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presentation of rectal duplications depends on multiple factors, such as size, site, presence of infection, presence of gastric mucosa, and type of communication (internal to rectal lumen or external). In addition, rectal duplications can compress the rectum and adjacent viscera and lead to rectal prolapse. The presence of ectopic gastric mucosa could lead to bleeding, perianal stula, perianal irritation, or recalcitrant perianal infection. Rectal bleeding can also occur because of irritation or infection of the cyst itself, even without the presence of gastric mucosa. Potential complications of rectal duplications include secondary infection or rupture or carcinomatous degeneration. The incidence of carcinomatous degeneration is 12% to 18% in adults, with none reported to date in children.
Differential Diagnosis
Figure 4. Sagittal view on pelvic magnetic resonance imaging.
Evolving hematoma (red arrows) posterior to the rectal lumen (dashed arrows). Incidental Tarlov cyst (blue arrow). B[bladder; S[pubic symphysis. Courtesy of Virginia Kania, DO, and Sameh Tadros, MD, MSc, Department of Radiology, Childrens Hospital of Pittsburgh of University of Pittsburgh Medical Center.
region, multiple theories on abnormal development in this area have been proposed to explain their occurrence. The enteric bud theory hypothesizes that a part of the intestinal epithelium protrudes outwards but still maintains connection with the bowel lumen. Another theory proposes the embryonic gastrointestinal tract rapidly enlarges and outgrows the coelomic cavity; this occurrence is followed by recanalization of intestinal epithelia. Lastly, it is postulated that duplications develop from an aberration in cloacal division. None of these theories explain the potential presence of heterotopic gastric mucosa in rectal duplication cysts. Rectal duplications themselves are more prevalent in white females and comprise 1% to 8% of intestinal duplications. They can also be associated with other hindgut malformations, such as in the Currarino triadanorectal malformation, anterior sacral defect, and presacral mass (teratomas, meningoceles, dermoid cyst, and enteric cyst). Rectal duplications can be but are rarely associated with cardiac malformations. Rectal duplications can present at any age. They are often discovered before age 2 years but may not present until adulthood. The main clinical features include rectal pain, rectal discomfort, obstruction, a prolapsing rectal mass, bleeding, and/or sciatic pain. However, the clinical
The differential diagnosis for rectal duplications includes teratoma, dermoid cyst, anterior sacral meningocele, and hematoma. Rectal duplications can also be misdiagnosed as hemorrhoids, rectal prolapse, or polyps. The latter 3 conditions fall under the general differential diagnosis for lower gastrointestinal bleeding in an adolescentin addition to infectious enterocolitis, Meckel diverticulum, inammatory bowel disease, anal ssure, perianal streptococcal cellulitis, intussusception, rectal trauma, vascular malformation, and solitary rectal ulcer.
Diagnosis
The diagnosis of rectal duplication requires a high index of suspicion. On rectal examination, one may palpate a diverticular opening. Proctoscopy can aid in visualizing a diverticular opening. In addition, barium enema, stulogram, ultrasonography, CT, and MRI are helpful to delineate the anatomy and the extent of the duplication. Abdominopelvic CT is particularly helpful to rule out an anterior meningocele associated with a vertebral defect. Endoscopic ultrasonography may be helpful as well. Even if gastric mucosa is present, rectal duplications may have false-negative Meckel scan results because of either the sensitivity and specicity of the test itself or obscuration by physiologic tracer activity in the bladder.
Management
The treatment of rectal duplications depends on their site and presence or absence of infection. Surgical resection is the main treatment. The main risk of surgery includes anal sphincter injury from the rectal duplication lesion itself or from intraoperative retraction. This injury could lead to fecal incontinence.
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Patient Course
Surgical exploration identied a rectal duplication cyst surrounded by low-grade inammatory tissue. The cyst was incompletely excised because the cysts margins could not be clearly identied and the cyst was proximal to the anal sphincter. Pathologic examination of the cyst revealed colonic mucosa without ectopic mucosa within the cyst. Of note, the patients Tarlov cyst was left alone. A Tarlov cyst is a sac that contains cerebrospinal uid, located in the sacral region (S1-S4) of the spinal canal. The Tarlov cyst has an unclear origin and is usually asymptomatic if less than 1.5 cm in diameter. Although the patient tolerated surgery without complication, she later presented with an abscess at the surgical site and had to undergo a temporary sigmoidostomy after abscess drainage, with reanastamosis 6 months later. She is currently doing well and passes stool without difculty.
The diagnosis of a rectal duplication cyst requires a high index of suspicion. Conrming the diagnosis can be difcult based on the location of the cyst. Efforts to conrm the diagnosis include digital rectal examination, computed tomography, magnetic resonance imaging, ultrasonography, and Meckel scan. Surgical resection is the treatment of choice, especially because of the cysts potential for malignant transformation. Because of the cysts proximal location to the nerves innervating the anal canal and sphincters, surgical resection can lead to fecal incontinence.
Suggested Reading
Dahan H, Arriv L, Wendum D, Docou le Pointe H, Djouhri H, Tubiana JM. Retrorectal developmental cysts in adults: clinical and radiologic-histopathologic review, differential diagnosis, and treatment. Radiographics. 2001;21(3):575584 Knudtson J, Jackson R, Grewal H. Rectal duplication. J Pediatr Surg. 2003;38(7):11191120 Macpherson RI. Gastrointestinal tract duplications: clinical, pathologic, etiologic, and radiologic considerations. Radiographics. 1993;13(5):10631080 Rajah S, Ramanujam TM, Anas SR, et al. Duplication of the rectum: report of four cases and review of the literature. Pediatr Surg Int. 1998;13(56):373376 Salameh JR, Votanopoulos KI, Hilal RE, et al. Rectal duplication cyst in an adult: the laparoscopic approach. J Laparoendosc Adv Surg Tech A. 2002;12(6):453456 Thompson RJ, Charlton FG, Jaffray B. Acid-secreting rectal duplication cyst with associated peptic ulcer eroding through the anal sphincters. J Pediatr Surg. 2002;37(11):E37
Summary
Rectal duplication cysts are rare, thought to be due to defects in embryologic development, and often associated with other structural abnormalities. Clues to the existence of a rectal cyst are mainly due to bowel compression and presence of ectopic gastric mucosa within the cyst, leading to rectal bleeding.
Parent Resources from the AAP at HealthyChildren.org

English: http://www.healthychildren.org/English/health-issues/conditions/abdominal/Pages/Constipation.aspx Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/abdominal/paginas/constipation.aspx English: http://www.healthychildren.org/English/family-life/health-management/Pages/When-to-Call-Your-Pediatrician.
aspx
Spanish: http://www.healthychildren.org/spanish/family-life/health-management/paginas/when-to-call-your-
pediatrician.aspx
e14 Pediatrics in Review Vol.35 No.2 February 2014
Muscle Disease Chang-Yong Tsao Pediatrics in Review 2014;35;49 DOI: 10.1542/pir.35-2-49
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/35/2/49
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 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.
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Article
neurology
Muscle Disease
Chang-Yong Tsao, MD*
Educational Gaps
1. Duchenne muscular dystrophy (DMD) may be mistaken for liver disease because of elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Sometimes, especially in the early stage, when the child does not have obvious or progressive muscle weakness, the patient may occasionally be subjected to unnecessary liver biopsy or other gastrointestinal diagnostic procedures. When a preschool boy with delay in walking and difculty in running, as well as elevated ALT and AST levels, is seen, serum creatine kinase (CK) and g-glutamic transpeptidase (GGTP) are useful to perform. If elevated serum CK but normal GGTP levels are detected, muscle diseases are most likely. 2. In a boy younger than 5 years, if serum CK is at least 50 times normal, large calf muscles are present, and inherited pattern is consistent with X-linked recessive trait, DMD is the most likely diagnosis. Blood dystrophin gene mutation study will conrm the diagnosis of DMD if out-of-frame mutation is detected.
Author Disclosure Dr Tsao has disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Objectives
After completing this article, readers should be able to:
1. Know the clinical features of DMD. 2. Know the natural history and late complications of the muscular dystrophies. 3. Know the differential diagnosis of weakness and an increased serum creatine kinase level. 4. Know the laboratory studies available to diagnose muscle disease of childhood. 5. Formulate a differential diagnosis for a patient who has an acquired muscle disorder.
Case Study
A 4-year-old boy is seen in his pediatricians ofce for evaluation of toe-walking and delayed independent walking at age 2 years. On physical examination, he has hypertrophy of both calf muscles and pushes on the oor and his thighs to get up from the oor. His serum creatine kinase (CK) level is 20,000 U/L (reference range, 37430 U/L). His blood dystrophin gene mutation study reveals an out-of-frame deletion of exon 45. His maternal uncle also had calf muscle hypertrophy and muscle weakness and could not walk after age 10 years. The boy is diagnosed as having Duchenne muscular dystrophy (DMD).
Abbreviations
ALT: AST: BMD: CK: DMD: EMG: GGTP: alanine aminotransferase aspartate aminotransferase Becker muscular dystrophy creatine kinase Duchenne muscular dystrophy electromyography g-glutamic transpeptidase
Denition of Dystrophies
Muscular dystrophies consist of a group of genetic disorders characterized by progressive muscle degeneration, weakness, and atrophy. Among the muscular dystrophies, DMD is the most common severe childhood form. It is caused by dystrophin gene mutations and thus is classied as a dystrophinopathy. Most boys with DMD are unable to walk after age 12 years. Becker muscular dystrophy (BMD) is a mild allelic disorder compared with DMD, with loss of independent walking after age 16 years. Both DMD and BMD are
*Department of Clinical Pediatrics and Neurology, College of Medicine, The Ohio State University, Columbus, OH.
Pediatrics in Review Vol.35 No.2 February 2014 49
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inherited as X-linked recessive disorders Carrier mothers have a 50% chance of transmitting the DMD mutation in each pregnancy. The sons who inherit the mutation will be affected; the daughters who inherit the mutation are carriers, often have CK elevation, and may develop cardiomyopathy, muscle weakness, or muscle cramps.
Epidemiology of DMD and BMD

DMD and BMD are caused by mutations in the dystrophin gene located on Xp21.2, affecting 1 in 3,600 to 6,000 live male births. (1) The dystrophin gene is the largest human gene, contains 79 exons, and produces dystrophin protein (427 kDa). Most mutations are due to deletions (65%); other mutations include duplications and point mutations. One-third of new cases are induced by spontaneous mutations. The out-of-frame (also known as frameshift) mutations of the dystrophin gene in DMD typically disrupt the reading frame, result in absence of muscle dystrophin protein production, and cause severe muscle weakness. (2)(3) A milder dystrophin-decient muscular dystrophy, BMD is due to in-frame mutation of the dystrophin gene, which allows production of abnormal or semifunctional dystrophin, resulting in less severe muscle weakness. BMD occurs less frequently and has been reported to affect 1 in 18,450 live male births. (3)
Pathogenesis of DMD and BMD

Dystrophin localizes to the muscle membrane and is required for muscle membrane stability. It is part of the cytosolic protein complex (Figure) (dystrophin-glycoprotein complex), which also includes sarcoglycans and dystroglycans in the muscle membrane, and links the subsarcolemmal cytoskeleton to laminin-a2 protein in the extracellular matrix. With dystrophin gene mutations, there is a reduction or absence of dystrophin, sarcoglycans, and dystroglycans. The end result is membrane tears, muscle necrosis, and brosis, producing muscular dystrophy. Dystrophin expression is seen not only in the skeletal muscles but also in smooth and cardiac muscles and the brain. Therefore, boys with DMD or BMD may also develop problems in the heart, gastrointestinal system, and central nervous system.
Clinical Aspects of DMD and BMD

Patients with DMD often present with delayed walking and difculty in running. Before age 5 years, the affected boys walk with a broad-based, waddling, lordotic gait. When getting up from the oor, the patients turn to face the oor and use their hands to push up from the oor
50 Pediatrics in Review Vol.35 No.2 February 2014
and then the thighs to achieve a standing position (Gowers sign) due to proximal muscle weakness. The calf and thigh muscles are enlarged in the beginning because of true muscle hypertrophy, but later muscle necrosis occurs and muscle mass is replaced by fat and connective tissue. At approximately age 6 years, heel cord contractures frequently develop, resulting in toe-walking. Iliotibial band contractures often limit hip exion. Muscle weakness advances, disrupting independent ambulation at approximately age 12 years. Knee and elbow contractures occur when boys are conned to a wheelchair. Scoliosis rarely occurs before age 11 years; however, after loss of independent walking, progressive scoliosis rapidly develops. Progressive respiratory muscle weakness may also contribute to a restrictive and obstructive thoracic disorder, thus compromising pulmonary function. Respiratory failure and pneumonia often cause death of patients between the second and third decades of life. Cardiac involvement is usually asymptomatic in the early course; however, various electrocardiographic abnormalities, including short PR interval, tall right precordial R waves, and deep narrow Q waves in the left precordial leads, are often seen. (4) Sinus tachycardia, atrial and ventricular premature contractions, and other cardiac arrhythmias may be detected. Cardiomyopathy presents at a mean age of approximately 15 years, (5) and congestive heart failure is usually present in the late teens or early 20s and may cause death in 20% of DMD patients. Cardiac magnetic resonance imaging (6) and echocardiograms will detect cardiac abnormalities. Autopsy may demonstrate myocardial brosis in the posterobasal left ventricular wall. (3)(7) Acute gastric dilation with severe vomiting, abdominal pain, and distention sometimes may be seen in DMD patients because of gastric hypomotility, resulting from dystrophin deciency of the smooth muscle of the stomach. Intellectual impairment due to brain dystrophin abnormalities occasionally has been reported. Attention-decit/ hyperactivity disorder and learning disability can also be seen. (3) Reduced bone density and increased bone fractures of long bones and spine are also seen in DMD patients, especially when treated with corticosteroids. Patients with BMD present with proximal muscle weakness after age 5 years but can maintain independent walking after age 16 years. Patients with BMD also preserve antigravity strength of neck exor muscles, which allows differentiation from DMD patients who never have antigravity neck exor strength, even in the rst few years of life. Cardiomyopathy is common in BMD patients and may cause congestive heart failure and death. Age of death varies between the fourth and sixth decades of life.
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gene mutation study can conrm the diagnosis of DMD (out-of-frame mutation) or BMD (in-frame mutation). However, muscle weakness with an increased serum CK level in children can also be seen in other genetic muscle disorders, including type 1 myotonic dystrophy, congenital muscular dystrophies, limb-girdle muscular dystrophies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathies, periodic paralysis, myotonia congenita, and metabolic muscle disorders (glycogen storage diseases, lipid storage myopathies, and mitochondrial disorders) (Table 1). Among other genetic disorders that cause muscle weakness and an increased serum CK level in children, congenital myasthenic syndrome and spinal muscular atrophy should be included as well. Emery-Dreifuss muscular dystrophy is a rare, slowly progressive muscular dystrophy that initially causes muscle weakness and atrophy in humeroperoneal distribution; early contractures of elbows, ankles, and neck; and frequent cardiac arrhythmia, conduction defects, or severe cardiomyopathy. Serum CK levels may be normal or elevated up Figure. Schematic representation of the location of the various congenital muscular to 20 times normal. Emery-Dreifuss dystrophyrelated proteins in the muscle, sarcolemma, and extracellular matrix. muscular dystrophy can be inherited DG[dystroglycan; DYB[dystrobrevin; ER[endoplasmic reticulum; L4[domain 4; as X-linked disorders and caused by LE[domain E; LG[domain G; LN[domain N (lamin domain); SY[syntrophin. Figure EMD gene or FHL1 gene mutareproduced with permissions from Annals of Neurology. (6) tions; however, it can also be an autosomal dominant or recessive disease and caused by LMNA gene mutations. (3) Differential Diagnosis of Genetic Muscle Type 1 myotonic dystrophy is an autosomal dominant Diseases muscular dystrophy that may present as the congenital type A preschool boy with muscle weakness often seeks medwith severe generalized muscle weakness, facial weakness, ical attention from his primary care physician because clubfoot, feeding difculty, and severe respiratory distress of gross motor delay, toe-walking, difculty walking or that requires ventilator support. Classic type 1 myotonic climbing stairs, and falling. When proximal muscle weakdystrophy presents in later childhood with predominant distal muscle weakness in the hands, distal legs, neck, ness with an increased serum CK level that is at least 50 times normal occurs in a preschool boy and the inherited and face and myotonia. Serum CK levels may be normal pattern is consistent with X-linked recessive trait (only affects or mildly elevated. Type 1 myotonic dystrophy is caused male members on the maternal side), dystrophinopathy by expansion of a CTG trinucleotide repeat (>50 CTG re(DMD or BMD) is the most likely diagnosis. Dystrophin peats) in the noncoding region of the DMPK gene.
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Limb-girdle muscular dystrophies are a rare heterogeneous group of genetic muscular dystrophies, now consisting of 16 autosomal recessive subtypes and 8 autosomal dominant subtypes. They present as childhoodor adult-onset muscular dystrophies with progressive muscle weakness and atrophy, proximal greater than distal and varying from very mild to severe, and are caused by mutations of multiple genes other than dystrophin gene. Serum CK levels are usually mildly to highly elevated.
Muscle biopsy specimens are useful for histopathologic and immunolabeling studies for protein abnormalities, and DNA analysis is the gold standard to establish the specic form of limb-girdle muscular dystrophy. Limbgirdle muscular dystrophies are more commonly seen in children (Table 2). (8)(9) Congenital muscular dystrophies typically present at birth or early infancy with hypotonia, severe muscle weakness (proximal more than distal), and joint contractures
Table 1.
Key Features and Tests for Genetic Muscle Disorders

Key Features Progressive limb-girdle muscle weakness, onset before age 5 years, loss of ambulation after age 12 years, cardiomyopathy Progressive limb-girdle weakness, onset after age 5 years, walking after age 15 years, cardiomyopathy Congenital type: onset at birth, generalized weakness and hypotonia, respiratory insufciency Classic type: onset in later childhood; distal muscle weakness in hands, distal legs, neck, and face; myotonia Onset at birth or early infancy, hypotonia, severe generalized weakness, joint contractures, malformations of eyes, brain, cardiomyopathy, rigid spine Progressive limb-girdle muscle weakness, onset from early infancy to teenage Weakness of facial muscles and stabilizers of scapula or dorsiexors of feet, onset before age 20 years Progressive muscle weakness in humeroperoneal distribution; early contractures of elbows, ankles, and neck; cardiac arrhythmia; onset from childhood to teenage years External ophthalmoplegia, proximal muscle weakness, cardiomyopathy, sensorineural deafness, migraine, diabetes mellitus, ataxia, seizures; age onset from birth to all ages Generalized weakness and hypotonia, hypertrophic cardiomyopathy, respiratory failure, feeding difculty; onset from infancy to childhood Proximal muscle weakness, hypotonia, cardiomyopathy, onset in early childhood Muscle hypertrophy, myotonia, muscle weakness, onset from infancy to childhood Repeated accid paralysis of four extremities, muscle weakness, onset 120 years Severe generalized weakness, hypotonia, facial weakness, ophthalmoplegia, onset at birth or early infancy Test Dystrophin gene out-of-frame mutation Dystrophin gene-in-frame mutation CTG repeat >1000 in congenital type; CTG repeat 501000 in classic type Mutations of multiple genes of congenital muscular dystrophies Mutations of multiple genes of limb-girdle muscular dystrophies Contraction mutation of D4Z4: 110 repeat Mutations of EMD, FHL1, LMNA genes Mitochondrial DNA or nuclear DNA mutations Acid a-glucosidase gene mutations SLC22A5 gene mutation CLCN1 gene mutation Mutations of CACNA1S gene, SCN4A gene, KCNJ2 gene Mutations of MTM1 gene, RYR1 gene, DNM2 gene, BIN1 gene
Genetics Muscle Disease Duchenne muscular dystrophy Becker muscular dystrophy Myotonic dystrophy type 1
Congenital muscular dystrophies Limb-girdle muscular dystrophies Facioscapulohumeral muscular dystrophy Emery-Dreifuss muscular dystrophy Mitochondrial encephalomyopathy Pompe disease
Systemic primary carnitine deciency Myotonia congenita Periodic paralysis Congenital myopathy
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(LMNA and nesprin); and the SEPN1 gene in the endoplasmic reticulum. The congenital muscular dystrophies are inherited predomiLimb-Girdle nantly as an autosomal recessive trait Muscular but occur as a rare autosomal domDystrophy inant trait in LMNA-related and colType Gene Inheritance Protein lagen 6A1, 6A2, and 6A3related 2A CAPN3 Autosomal Calpain 3 congenital muscular dystrophies. Serecessive rum CK levels vary from normal to 2C SGCG Autosomal g-Sarcoglycan recessive moderately elevated. Muscle immu2D SGCA Autosomal a-Sarcoglycan nohistochemical staining may demrecessive onstrate specic protein deciencies 2E SGCB Autosomal b-Sarcoglycan and help guide gene mutation studies recessive for specic diagnosis. (10) 2F SGCD Autosomal d-Sarcoglycan recessive Facioscapulohumeral muscular 2G TCAP Autosomal Telethonin dystrophy is an autosomal domirecessive nant disorder and presents with 2H TRIM32 Autosomal Tripartite motif containing 32 weakness of facial muscles and stabirecessive lizers of the scapula or dorsiexors of 2I FKRP Autosomal Fukutin-related protein recessive the feet but without ocular and bulbar 2J TTN Autosomal Titin muscle weakness before age 20 years. recessive It is a slowly progressive muscular dys2K POMT1 Autosomal Protein O-mannosyltransferase 1 trophy and linked to contractions (1 recessive 10 repeat units vs 111100 on normal 2M FKTN Autosomal Fukutin recessive alleles) of the D4Z4 repeat array of 2N POMT2 Autosomal Protein O-mannosyltransferase 2 a specic haplotype of chromosome recessive 4q35. In this region, DUX4 has been 2O POMGNT1 Autosomal Protein O-mannose 1,2-Nproposed as the causative gene abnorrecessive acetylglucosaminyltransferase 1 mality, but additional studies more 2P DAG1 Autosomal Dystroglycan recessive accurately indicate that genetic 1B LMNA Autosomal Lamin A/C conditions are created that enable exdominant pression of DUX4 that activates a cas1C CAV Autosomal Caveolin-3 cade of myotoxic genes, including dominant P53 and PITX1 transcription factors involved in apoptosis and muscle atrophy. Serum CK levels vary from normal to 5 times normal (<1,500 IU/L). (11)(12) and may also present with malformations of the eyes Congenital myopathies consist of a group of rare musor brain, cardiomyopathy, and a rigid spine. Congenital muscular dystrophies, which are also less frequent than cle disorders with structural or developmental abnormalDMD and BMD, are caused by mutations of multiple ities but without dystrophic changes in the muscles and caused by different gene mutations, such as myotubular genes, including those that encode structural proteins myopathy (MTM1 gene), central core disease (RYR1 of the extracellular matrix and external sarcolemmal progene), and centronuclear myopathy (DNM2, BIN1, and teins (laminin-a2; collagen 6A1, 6A2, and 6A3; integrin RYR1 genes). They usually present at birth or early ina7; and integrin a9); genes that encode glycosyltransfancy with severe generalized muscle weakness and atroferases that affect the glycosylation of a-dystroglycan, phy, hypotonia, facial weakness, and ophthalmoparesis. which are associated with Fukuyama congenital muscular dystrophy, muscle-eye-brain disease, Walker-Warburg Most congenital myopathies are inherited as either autosyndrome, and other congenital muscular dystrophy varsomal dominant or recessive traits except the rare Xlinked form of myotubular myopathy. Serum CK levels iants (POMT1, POMT2, POMGNT1, FKTN, FKRP, and are normal or near normal. LARGE); genes that encode nuclear envelope proteins
Table 2.
Childhood Limb-Girdle Muscular Dystrophies
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Mitochondrial disorders are clinically and genetically heterogeneous groups of disorders that result from mitochondrial respiratory chain dysfunctions and are caused by mitochondrial or nuclear DNA mutations. Mitochondrial disorders may affect a single organ, such as eyes in Leber hereditary optic neuropathy, but most often affect multiple organs, especially those highly dependent on aerobic metabolism, such as heart, skeletal muscles, and brain. They may present at any age and may be syndromic, such as mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes, or nonsyndromic. Skeletal muscle biopsy specimens may reveal ragged red bers, ragged blue bers, or abnormal mitochondria, suggestive of a mitochondrial disorder. Mitochondrial disorders due to nuclear gene mutations are inherited as autosomal dominant or recessive traits; those due to mitochondrial DNA mutations are transmitted by maternal inheritance. Serum CK levels vary from normal to moderately elevated. Serum or cerebrospinal uid lactate levels are frequently elevated. Mitochondrial or nuclear DNA mutation studies are indicated of denitive diagnosis. Glycogen storage disorder type 2 (Pompe disease), an autosomal recessive disorder, due to acid a-glucosidase gene mutations, often presents in early infancy with generalized weakness and hypotonia, hypertrophic cardiomyopathy, respiratory failure, feeding difculty, and hearing loss but may also present with proximal muscle weakness and respiratory insufciency without cardiomyopathy in childhood or adulthood. Serum CK levels are increased up to 2,000 U/L. Muscle specimens reveal increased glycogen storage as lysosomal vacuoles of varying severity. Without enzyme replacement therapy, patients with infantile Pompe disease usually die in the rst year of life due to progressive left ventricular outow obstruction. Complete deciency of acid a-glucosidase is seen in infantile Pompe disease, whereas partial deciency of the enzyme is seen in late-onset Pompe disease. Lipid storage myopathy is characterized by increased lipid accumulation in the skeletal muscles. The most important type, systemic primary carnitine deciency, an autosomal recessive disorder, can present in early childhood with proximal muscle weakness, cardiomyopathy, and hypotonia, and early death occurs due to cardiac failure if not treated with carnitine supplementation. It is caused by an SLC22A5 gene mutation. Serum CK levels are increased, but total, free, and acylated carnitine levels are very low (<10% normal). Myotonia congenita is a rare childhood muscle disorder due to the chloride channel CLCN1 gene mutation. It is inherited as either an autosomal dominant or recessive trait. It is characterized by muscle stiffness due to
myotonia, which is relieved by brief exercise. The muscles are usually hypertrophic. Serum CK levels may be elevated up to 4 times normal. Sometimes proximal and distal muscle weakness may be seen. However, in contrast to type 1 myotonic dystrophy, early cataracts, cardiac conduction defects, and endocrine abnormality are not seen. Periodic paralysis is characterized by repeated episodes of accid paralysis of the 4 extremities, increased serum CK levels (sometimes up to 10 times normal), and serum potassium levels that vary from low to normal to elevated. Flaccid hypokalemic paralysis may last a few hours to a few days. Periodic paralysis often occurs after exercise and carbohydrate-rich meals. Some patients with hypokalemic periodic paralysis may develop persistent muscle weakness. Patients with hypokalemic periodic paralysis need to have their plasma thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels checked. If the thyroid-stimulating hormone level is low but free thyroxine and free triiodothyronine levels are high, hyperthyroidism due to thyrotoxic periodic paralysis would be the cause of hypokalemic periodic paralysis and patients should receive treatment for hyperthyroidism. Thyrotoxic periodic paralysis is thus distinct from genetic hypokalemic periodic paralysis. Hypokalemic periodic paralysis has been associated with mutations of the calcium channel CACNA1S gene and the sodium channel SCN4A gene. Hyperkalemic periodic paralysis is associated with sodium channel SCN4A gene mutations. It often occurs while eating potassium-rich food or during rest after exercise. Andersen-Tawil syndrome is characterized by accid paralysis, ventricular arrhythmia, prolonged QT interval, and facial dysmorphism, such as ocular hypertelorism, low-set ears, and small mandible. Mutations in the potassium channel KCNJ2 gene are associated with this syndrome. Congenital myasthenic syndrome is a rare genetic disorder of the neuromuscular junction and presents from birth to early childhood with fatigable muscle weakness, which may include facial weakness, ptosis, 4-extremity weakness, feeding difculty, or respiratory distress. Cardiac and smooth muscles are not affected. There are no antibodies to acetylcholine receptor and antimusclespecic kinase as seen in myasthenia gravis. In addition, there is no improvement with immunosuppressive therapy. Congenital myasthenic syndrome is inherited as an autosomal recessive or dominant trait. Serum CK levels vary from normal to 10 times normal. Multiple gene mutations encoding proteins in the neuromuscular junction are responsible for this disorder. Spinal muscular atrophy is characterized by progressive muscle weakness, more severe in the proximal than
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the distal muscles, due to degeneration of anterior motor neurons and brain stem nuclei and absence of deep tendon reexes. The SMN1 gene is the disease-causing gene; 95% to 98% of patients have homozygous deletion of SMN1, and 2% to 5% of patients are compound heterozygotes with an SMN1 deletion or truncation and an SMN1 intragenic mutation. Spinal muscular atrophy is a common autosomal recessive disorder of childhood. The onset of weakness varies from before birth to early childhood. Serum CK levels vary from normal to mildly elevated. Patients with spinal muscular atrophy type 1 can never sit unaided, and disease onset is before age 6 months. Patients with type 2 disease can sit well when placed in a sitting position but can never walk independently, and onset is usually between ages 6 and 12 months. Patients with type 3 disease can walk independently, and onset usually occurs after age 12 months during childhood. The patients with prenatal onset often have severe joint contractures (arthrogryposis), facial diplegia, and respiratory failure. Poor weight gain, scoliosis, pneumonia, and sleep problems are common complications of spinal muscular atrophy.
Differential Diagnosis of Acquired Muscle Disorders

Muscle weakness with an increased serum CK level in children also occurs in acquired disorders, including inammatory myopathies, and those associated with systemic
Table 3.
disorders, infections, critical illness myopathy, toxins, or drugs (Table 3). Juvenile dermatomyositis is the most common idiopathic inammatory myopathy in children; the mean age of onset is 7 years, but 25% of patients are seen before age 4 years. Juvenile dermatomyositis often presents with generalized muscle weakness (more severe in proximal muscles), red or purplish heliotrope rash over the eyelids, raised erythematous papules over the extensor joint surfaces (Gottron papules), and thrombi or hemorrhage in nailfold capillary loops. Serum CK levels vary from normal to 50 times normal. Currently, the origin is unknown, but genetic and environmental inuences play a role. It is a systemic disease that affects skeletal muscles, skin, the gastrointestinal tract, kidney, heart, lung, and other organs. Both humoral and cellular immunity are involved. A skeletal muscle biopsy specimen typically reveals perifascicular atrophy, perimysial brosis, perivascular inammation (B cells and CD4 T cells), and muscle degeneration and regeneration. Dystrophic calcication may be seen in the knees, elbows, digits, and buttocks in 30% of patients, causing skin ulcers, pain, local erythema, edema, and joint contractures. Vasculopathy of bowels may cause ulceration, bleeding, or perforation. In addition, dermatomyositis in adults carries a risk of an underlying malignant neoplasm, but this risk is either much lower or nonexistent among children. (13)
Key Features and Tests for Acquired Muscle Disease

Key Features Generalized weakness, heliotrope eyelid rash, Gottron papules, nail fold thrombi, onset in childhood Generalized weakness, no heliotrope rash or Gottron papules, onset in childhood. Muscle weakness with acute viral, bacterial, and other infections Limb weakness, difculty weaning from ventilator in intensive care unit patients (without heart or lung diseases) Muscle pain, weakness, myoglobinuria after exposure to drugs or toxins in patients without prior muscle disease Proximal muscle weakness in various endocrine disorders Dermatomyositis or polymyositis seen with other rheumatic disorders Muscle weakness seen with inammatory bowel diseases, sarcoidosis, lymphoma, leukemia, other cancers Test Perifascicular muscle atrophy, perivascular inammation (B cells and CD4D T cells) Endomysial inammation (CD8D T cells and macrophages) Serologic testing of specic infections Muscle myosin loss and necrosis Resolution or improvement after discontinuation or removal of toxins or drug therapy Specic endocrine tests for endocrine diseases Specic rheumatology studies Specic studies for malignant tumors or underlying inammatory disorders
Acquired Muscle Disease Juvenile dermatomyositis Juvenile polymyositis Infectious myositis Critical illness myopathy Toxic myopathy Endocrine myopathy Overlap myositis Other inammatory myopathies
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Juvenile polymyositis, another idiopathic inammatory myopathy, is seen much less frequently than dermatomyositis in children. Both infantile and childhood cases have been reported. Median age at diagnosis is 12 years. It presents with generalized muscle weakness, more severe in the proximal muscles, but without the heliotrope eyelid rash or Gottron papules. Serum CK levels are elevated, at least 5 to 10 times normal. Muscle biopsy specimens reveal prominent endomysial inammatory cells (predominantly CD8 T cells and macrophages) surrounding nonnecrotic muscle bers but without perifascicular muscle atrophy. Arthritis, contractures, and bowel involvement may also occur. (13)(14) Overlap myositis is diagnosed when juvenile dermatomyositis or polymyositis is seen with other rheumatic disorders, such as systemic lupus erythematosus, scleroderma, juvenile idiopathic arthritis, Sjgren syndrome, systemic vasculitis, mixed connective-tissue disease, and Behet disease. Serum CK levels may be mildly increased. (14) Other inammatory myopathies are seen in association with other inammatory disorders, such as inammatory bowel diseases, celiac disease, and sarcoidosis. Rarely, lymphoma, leukemia, or other cancers can be seen with inammatory myopathies. (14) Viral infections associated with acute myositis, such as inuenza virus, Coxsackie virus, Epstein-Barr virus, echovirus, cytomegalovirus, human immunodeciency virus type 1, parainuenza virus, and herpes simplex virus, have been reported with muscle weakness and elevated serum CK levels. Other infections also may induce muscle weakness and increase serum CK levels, including bacterial infection (such as staphylococcal and streptococcal myonecrosis), cysticercosis, trichinosis, toxoplasmosis, echinococcosis, Lyme disease, and systemic fungal infections, such as sporotrichosis. (14) Endocrine disorders, such as hypothyroidism, hyperthyroidism, hypoparathyroidism, hyperparathyroidism, acromegaly, Cushing syndrome, and diabetes mellitus, may be associated with proximal muscle weakness; patients with hypothyroidism, hypoparathyroidism, hyperparathyroidism, and acromegaly also have increased serum CK levels. (14) Critical illness myopathy is typically seen in critically ill patients, often with multiorgan dysfunction and failure. These patients receive steroids and neuromuscular blocking agents in the intensive care unit. Patients develop limb weakness or difculty weaning from the ventilator but do not have nonneuromuscular causes, such as heart and lung diseases. Elevated serum CK levels vary from
mild to very high. Muscle myosin loss and muscle necrosis can be seen. Early rehabilitation in the intensive care unit may improve the functional recovery and independence of patients. Drugs and other toxins also can cause muscle weakness and elevated serum CK levels. Toxic myopathy should be suspected when a patient without a preexisting muscle disease develops muscle pain, fatigue, weakness, or myoglobinuria, temporally connected to the administration of a drug or exposure to a myotoxic substance. Anticholesterol drug statins, though useful in lowering the low-density lipoprotein cholesterol and cardiovascular risks, are reported to cause muscle weakness, pain, tenderness, and more than 10 times serum CK levels in 0.5% of patients. Among different types of toxic myopathies, statins cause both necrotizing and inammatory myopathy, clobrate and alcohol cause necrotizing myopathy, glucocorticoids cause type 2 ber atrophy, emetine causes myobrillar myopathy, chloroquine and amiodarone cause lysosomal myopathy, colchicine and vincristine cause antimicrotubular myopathy, D-penicillamine and interferon alfa cause inammatory myopathy, and zidovudine causes mitochondrial myopathy. Cyclosporin and tacrolimus, when used with statins, also induce toxic myopathy. Recreational drugs, such as cocaine, heroin, amphetamine, and alcohol, are frequently used together and can cause rhabdomyolysis. L-tryptophan contaminants, diuretics, amphotericin B, and procainamide have also been associated with toxic myopathies. (14)(15)
Transient Neonatal Myasthenia Gravis

In addition, transient neonatal myasthenia gravis, a neuromuscular junction disorder, can present with muscle weakness that results from transplacental transfer of maternal receptor site antibodies, including acetylcholine receptor antibodies and muscle-specic kinase antibodies. The clinical features include generalized hypotonia and weakness, weak cry and sucking, swallowing difculty, and sometimes respiratory distress. It is usually evident in the rst 2 days of life and lasts for 2 to 4 months. Treatment with pyridostigmine or neostigmine before feeding usually is effective. Rarely, assisted ventilation, intravenous immunoglobulin, or exchange transfusion may be needed for severe cases.
Laboratory Tests of Muscle Diseases

General Tests
Serum CK measurement is the rst laboratory test to evaluate muscle diseases, whether genetic or acquired types. A patients CK level can vary from normal to more
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than 50 times normal. In DMD patients, the CK level is at least 10 times normal and often up to 100 times normal. In other muscle disorders, lesser increased CK levels are usually seen. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), aldolase, and lactate dehydrogenase also derive from the muscles and levels may be elevated in the muscle diseases; therefore, when they are elevated during an investigation of a patients disease, it is useful to measure both serum CK and g-glutamic transpeptidase (GGTP) levels. If elevated CK levels but normal GGTP levels are detected, muscle diseases are most likely, and liver diseases are not the causes of high ALT, AST, aldolase, and lactate dehydrogenase levels. Serum lactate levels may be elevated in mitochondrial disorder at rest. Serum and urine carnitine and acylcarnitine levels may be elevated in lipid myopathy. Serum thyroidstimulating hormone, thyroid hormones, and thyroid antibodies should be tested when muscle disorders are associated with hypothyroidism or hyperthyroidism. Erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, C3, and C4 may be needed if considering rheumatic diseases as a cause of muscle weakness. Serum electrolytes may reveal hypokalemia or hyperkalemia in periodic paralysis. Serum and urine myoglobin may be detected in metabolic muscle disorders or other slowly progressive muscle disorders, such as muscular dystrophies. Electromyography (EMG) may reveal myopathic changes but also may be normal in muscle disorders. The EMG ndings may include myopathic motor unit action potentials, abnormal insertional activity, positive waves, brillation potentials, myotonic discharges, and complex repetitive discharges. The myopathic EMG ndings are not specic and need to be combined with neurologic examinations and laboratory ndings for proper diagnosis. Nerve conduction studies are usually abnormal in neuropathy but normal in myopathies. Repetitive nerve stimulations are useful in the diagnosis of neuromuscular junction disorders, such as myasthenia gravis, infantile botulism, and myasthenic syndrome, but have normal results in muscle diseases. Muscle biopsy is indicated if the clinical and laboratory features suggest muscle disease. To demonstrate specic features of a muscle disease, moderately weak muscles are usually chosen for muscle biopsy, whereas severely weak muscles and recently traumatized muscles should be avoided. Muscle specimens can be studied for general histologic analysis, stains and histochemical reactions, specic enzyme quantitation, electron microscopy ndings, and specic gene mutations. Typical muscle biopsy specimens in various kinds of muscular dystrophies reveal variability in ber size, increased connective tissue
surrounding individual muscle bers, and evidence of necrotic and regenerative muscle bers. However, specic histochemical staining with antibodies to dystrophin, dystroglycans, sarcoglycans, laminin-a2, and other specic proteins can direct further specic gene mutation studies. Special histochemical studies also can be performed on muscle specimens for lipid storage myopathy, glycogen storage myopathy, and mitochondrial myopathy, followed by specic enzyme quantitation and gene mutation studies. Specic structural abnormalities can be identied for various congenital myopathies. Further specic gene mutation studies can be performed for specic congenital myopathies. Muscle biopsy specimens typically reveal perifascicular atrophy and perivascular inammation (B cells and CD4 T cells) in dermatomyositis and endomysial inammatory cells (predominantly CD8 T cells and macrophages) surrounding nonnecrotic bers without perifascicular atrophy in polymyositis.
Brain Imaging Studies

Brain magnetic resonance spectroscopy may be useful in the detection of increased lactic acid. Brain magnetic resonance imaging may demonstrate abnormalities in the cerebral gray matter or white matter, basal ganglia, thalamus, and brainstem suggestive of mitochondrial disorders. Cerebral white matter abnormalities are seen in congenital muscular dystrophies caused by laminin-a2 deciency. Various neuronal migration defects are seen in muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, and Walker-Warburg syndrome.
Genetic Studies
Molecular genetics are useful in the diagnosis of hereditary myopathies and can avoid many other traditional studies, such as EMG, nerve conductions, or even muscle biopsies in some muscle diseases. For example, DMD can be diagnosed from blood dystrophin gene mutations showing out-of-frame mutations and BMD from dystrophin gene in-frame mutations. Myotonic dystrophy type 1 can be established with blood CTG trinucleotide repeat expansion mutations greater than 50. Mitochondrial DNA mutations can be performed in the blood for common mutations, such as mitochondrial encephalomyopathy with lactic acidosis and strokelike syndrome (3243 A to G mutation) and myoclonic epilepsy with ragged-red ber (8344 A to G mutation).
Treatment of DMD
Prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) is recommended for the treatment of DMD in boys older
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than 5 years because of demonstrated benets on muscle strength and function, which can prolong independent walking from a few months to 2 years. Deazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone, is used in European and other countries but is not available in the United States. Adverse effects include weight gain, short stature, Cushingoid face, hirsutism, cataracts, and increased risk of fracture of vertebrae and long bones. (16)(17) Cardiomyopathy and cardiac arrhythmias occur in DMD and BMD patients. Because cardiomyopathy may develop years before clinical heart failure becomes evident and cardiac arrhythmias frequently occur in older DMD and BMD patients, a complete cardiac evaluation, including detailed history and physical examination, electrocardiogram, Holter monitoring, and echocardiogram, is recommended at age 10 years or whenever symptomatic. Some patients as young as 7 years have had cardiomyopathy present on echocardiography (5)(18) Treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be benecial in patients with cardiac abnormalities. (5) Continued cardiac evaluations are recommended. (2)(5)(18) Pulmonary management by a pulmonary specialist with experience in DMD and BMD for the associated restrictive, obstructive thoracic disorder is recommended. Pulmonary function tests, noninvasive assisted ventilation with nasal bilevel positive airway pressure, and other pulmonary interventions are required for these patients. Immunizations with 23-valent pneumococcal polysaccharide vaccine for patients 2 years and older, annual inactivated trivalent inuenza vaccine for patients 6 months and older, and other proper vaccinations are needed. (2)(3) Nasally inhaled live vaccine should be avoided because these patients are immunosuppressed from steroid treatment. Physical therapy is needed for improvement of motor function and prevention of contractures in DMD. Stretching of heel cords, iliotibial bands, and hip can be performed by parents and physical therapists to prevent contractures, and night splints can be used to delay heel cord tightness. Nutritional evaluation by a dietitian is recommended for proper nutrition and weight in DMD. Daily supplement of multivitamins, minerals, and vitamin D is recommended. Chewing and swallowing difculty may lead to aspiration. Evaluation of such difculties requires a videouoroscopic swallowing study and referral to an experienced speech and language pathologist for proper management of dysphagia. Constipation and gastroesophageal reux are frequently seen in DMD patients and require proper medical treatment. (2)(3) These boys tend to self-restrict uid intake to avoid frequent and
cumbersome urination. This habit should be discouraged in that renal stones can develop and hypotension, especially with angiotensin-converting enzyme inhibitor treatment, can occur. Scoliosis develops in many DMD patients, often with rapid progression after loss of ambulation, and requires regular follow-up with experienced orthopedic surgeons. Posterior spinal fusion can straighten the spine, slow further deformity, and lessen respiratory decline. Dualenergy x-ray absorptiometry for bone density study is recommended for DMD patients, especially for those undergoing long-term corticosteroid treatment, to detect osteoporosis. (2)(3) Evaluations by pulmonary specialists and cardiologists before operations to prevent postoperative complications are mandatory. When undergoing general anesthesia and surgery, DMD and BMD patients should not be given inhalational anesthetic agents, such as halothane, and depolarizing muscle relaxants, such as succinylcholine, to prevent malignant hyperthermia-like conditions or rhabdomyolysis. (2)(3)
Treatment of Other Muscle Disorders

For other muscular dystrophies, including BMD, myotonic dystrophy type 1, Emery-Dreifuss muscular dystrophies, facioscapulohumeral dystrophy, limb-girdle muscular dystrophies, or congenital muscular dystrophies, symptomatic treatments similar to those of DMD would be necessary, including cardiology and pulmonary evaluations and treatments, physical therapy, and nutritional evaluation. Proper use of ankle-foot orthoses, wheelchairs, or other assistive devices may be needed. For periodic paralysis, oral or intravenous potassium to normalize the serum potassium levels and to shorten the paralytic episode would be indicated in hypokalemic periodic paralysis. However, in thyrotoxic periodic paralysis, treatment of hyperthyroidism is necessary. For hyperkalemic periodic paralysis, muscle weakness may be prevented or aborted with mild exercise and oral intake of carbohydrates, inhalation of salbutamol, or intravenous calcium gluconate. Acetazolamide may be given for prevention of all types of periodic paralysis. (20) The Food and Drug Administration approved the use of alglucosidase alfa (Myozyme) for infantile Pompe disease in 2006. It is given by slow intravenous infusion at 20 to 40 mg/kg per dose every 2 weeks, which may reduce cardiac mass to varying degrees and improve the ejection fraction. For systemic primary carnitine deciency, 100 to 400 mg/kg daily of oral levocarnitine treatment can improve
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muscle weakness and cardiomyopathy and prevent metabolic decompensation. (19) For mitochondrial disorders, there is no clear evidence supporting the use of any intervention in mitochondrial disorders according to a 2012 Cochrane Database Systemic Review. For myotonia congenita, it is impossible to determine whether drug treatment is safe and effective in the treatment of congenital myotonia according to a 2010 Cochrane Database Systemic Review because of insufcient quality data and lack of randomized studies. For congenital myopathies, only symptomatic supportive treatments are available, including cardiology and pulmonary evaluations and treatments, physical therapy, nutritional evaluation, proper use of ankle-foot orthoses, wheelchairs, or other assistive devices. For inammatory myopathy, according to a 2012 Cochrane Database Systemic Review, corticosteroids are the principal treatment, but because of its adverse effects, there is a need for additional treatment with drugs that suppress the immune system (immunosuppressants) or modify it (immunomodulatory therapies) to improve patient outcomes. However, there is lack of high-quality randomized controlled trials that assess the efcacy and toxicity of immunosuppressants in inammatory myositis. Recently, the members of the Childhood Arthritis and Rheumatology Research Alliance have developed consensus treatment plans for inammatory myositis, including use of oral prednisone and methotrexate, the addition of intravenous methylprednisolone at treatment initiation in one consensus treatment, and the addition of intravenous methylprednisolone and intravenous immunoglobulin in another consensus treatment. (13) For endocrine myopathies, treating the underlying endocrine disorders is necessary and may improve the muscle weakness. (20) For critical illness myopathy, early rehabilitation in the intensive care unit may improve the functional recovery and independence of patients. (21) For drug myopathies, after the suspected drugs are withdrawn, clinical or biochemical signs of muscle involvement usually improve. Regarding statin myopathy (when myalgia and increased serum CK levels occur), statin therapy should be stopped and the patient should be monitored closely for myoglobinuria and deteriorating renal function. In most statin myopathy patients, there is progressive improvement in muscle symptoms. Complete recovery occurs 2 to 3 months after statin withdrawal. (15)
Summary
On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classied as a dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3) On the basis of some research evidence, cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory insufciency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7) On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17) Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be benecial in DMD patients with cardiac abnormalities. (2)(3)(5)(18) Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)
ACKNOWLEDGMENTS. The author would like to express his utmost appreciation to Jerry R. Mendell, MD for his critical review and helpful suggestions and to Ms. Abigail White for her secretarial assistance.
References
1. Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to
newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71(3):304313 2. Bushby K, Finkel R, Birnkrant DJ, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):7793 3. Darras BT, Miller DT, Urion DK. Dystrophinopathies. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, es. GeneReviews [Internet]. Seattle: University of Washington; 1993-. 4. Thrush PT, Allen HD, Viollet L, Mendell JR. Re-examination of the electrocardiogram in boys with Duchenne muscular dystrophy
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and correlation with its dilated cardiomyopathy. Am J Cardiol. 2009;103(2):262265. 5. Viollet L, Thrush PT, Flanigan KM, Mendell JR, Allen HD. Effects of angiotensin-converting enzyme inhibitors and/or beta blockers on the cardiomyopathy in Duchenne muscular dystrophy. Am J Cardiol. 2012;110(1):98102. 6. Hor KN, Wansapura J, Markham LW, et al. Circumferential strain analysis identies strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J Am Coll Cardiol. 2009;53(14):12041210 7. Muntoni F. Cardiac complications of childhood myopathies. J Child Neurol. 2003;18(3):191202 8. Rosales XQ, al-Dahhak R, Tsao CY. Childhood onset of limbgirdle muscular dystrophy [published correction appears in Pediatr Neurol. 2013;48(6):483]. Pediatr Neurol. 2012;46(1):1323 9. Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol. 2011;24(5):429436 10. Mercuri E, Muntoni F. The ever-expanding spectrum of congenital muscular dystrophies. Ann Neurol. 2012;72(1):917 11. Richard JLF, Lemmers RJLF, Miller DG, van der Maarel SM. Facioscapulohumeral muscular dystrophy. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews [Internet]. Seattle: University of Washington; 1993-.. 12. Tassin A, Laoudj-Chenivesse D, Vanderplanck C, et al. Article 1: DUX4 expression in FSHD muscle cells: how could such a rare protein cause myopathy? J Cell Mol Med. 2013;17(1):7689. 13. Huber A, Feldman BM. An update on inammatory myositis in children. Curr Opin Rheumatol. 2013;25(5):630635 10.1097/ BOR.0b013e3283635634
14. Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inammatory myopathies of childhood. Lancet. 2008;371(9631):22012212 15. Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry. 2009;80(8):832838 16. Moxley RT III, Ashwal S, Pandya S, et al; Quality Standards Subcommittee of the American Academy of Neurology; Practice Committee of the Child Neurology Society. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2005;64(1):1320 17. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008; (1):CD003725 18. American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005;116(6):15691573 19. El-Hattab AE. Systemic primary carnitine deciency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews [Internet]. Seattle: University of Washington; 1993-.. 20. Sternberg D, Tabti N, Hainque B, Fontaine B. Hypokalemic periodic paralysis. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, eds. GeneReviews [Internet]. Seattle: University of Washington; 1993-. 21. Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011;10(10):931941
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1. A 5-year-old boy presents with toe-walking after not walking until age 23 months. On examination, the boy has calf hypertrophy and struggles when rising from a prone position on the oor. The test most appropriate to help establish the childs diagnosis is: A. Brain magnetic resonance imaging. B. Electromyography. C. Serum creatine kinase measurement. D. Serum potassium measurement. E. Serum thyroid-stimulating hormone measurement. 2. You are following a 10-year-old boy undergoing steroid therapy for Duchenne muscular dystrophy. All the following are adverse effects of prednisone treatment for Duchenne muscular dystrophy except: A. Cataracts. B. Hirsutism. C. Hypoglycemia. D. Short stature. E. Reduced bone density. 3. You are counseling the parents of a 2-day-old girl with difculty sucking and hypotonia born to a mother with myasthenia gravis. Among the following, you are most likely to say: A. B. C. D. E. Mechanical ventilation should be instituted before the newborn deteriorates further. Transplacental transfer of maternal acetylcholine receptor antibodies led to transient weakness. Treatment with pyridostigmine is unlikely to be helpful. The child may experience weakness for 6 to 12 months. The child has inherited from the mother a gene mutation encoding a protein in the neuromuscular junction.
4. A previously well 6-year-old boy presents with 1 week of generalized weakness, more severe proximally. On examination, you note normal deep tendon reexes along with raised erythematous papules over the extensor joint surfaces. The most likely diagnosis is: A. B. C. D. E. Becker muscular dystrophy. Fascioscapulohumeral dystrophy. Hypothyroidism. Juvenile polymyositis. Simvastatin ingestion.
5. A newborn girl has respiratory failure, tongue fasciculations, and arthrogryposis. You suspect a diagnosis of spinal muscular atrophy. The gene most likely to be mutated on testing is: A. B. C. D. E. Acid a-glucosidase. Dystrophin. MTM1. SLC22A5. SMN1.
Muscle Disease Chang-Yong Tsao Pediatrics in Review 2014;35;49 DOI: 10.1542/pir.35-2-49
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The Clinician's Guide to Autism John W. Harrington and Korrie Allen Pediatrics in Review 2014;35;62 DOI: 10.1542/pir.35-2-62
Data Supplement at: http://pedsinreview.aappublications.org/content/suppl/2014/01/24/35.2.62.DCSupplementary_Data.htm l
Article
Developmental/Behavorial Issues
The Clinicians Guide to Autism

John W. Harrington, MD,* Korrie Allen, PsyD
Educational Gaps
1. Because 1% to 2% of children will be diagnosed as having an autism spectrum disorder, pediatricians need adequate training in screening and diagnosis, particularly with the changes presented in the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Initiating interventions for autism, both evidence-based and complementary, also requires the pediatrician to be familiar with available treatments. 2. Children with autism are likely to have a co-occurring mental health disorder that pediatricians should be able to recognize so that they can initiate treatment or provide timely referral. 3. Children with autism are less likely to have a medical home when compared with other children with special health care needs.
Author Disclosure Drs Harrington and Allen have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Objectives
1. Describe the signs and symptoms of an autism spectrum disorder and therefore be aware of the changes recently made to the DSM-5. 2. Be aware of appropriate screening devices for autism and how to use them effectively. 3. Consider a differential diagnosis and initiate an evaluation, as well as provide evidenced-based advice to a patient with newly diagnosed autism. 4. Recognize and provide screening devices for co-occurring mental health disorders in children with autism. 5. Become familiar with common complementary and alternative medicines and therapies. 6. Provide a more comprehensive medical home for children and families with autism.
Introduction
Autism spectrum disorder (ASD) includes a continuum of neurodevelopmental disorders characterized by decits in social communication and interactions, along with restrictive, repetitive patterns of behaviors, interests, and activities. (For this article, ASD and autism are used interchangeably.) Pediatric clinicians can signicantly affect the outcome of children with ASD by making an early diagnosis and providing referral for evidenced-based Abbreviations behavioral treatment. By recognizing the early signs and symptoms of autism and addressing common comorbid conAAP: American Academy of Pediatrics cerns, such as sleep problems, gastrointestinal problems, ABA: applied behavioral analysis seizures, and behavioral and psychiatric concerns, as well ADHD: attention-decit/hyperactivity disorder as being aware of complementary and alternative medicine ASD: autism spectrum disorder (CAM) therapies, clinicians can provide a more comprehenCAM: complementary and alternative medicine sive medical home for their patients and parents. DSM-IV: Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition M-CHAT: Modied Checklist for Autism in Toddlers DSM-5:
Epidemiology
Recent data from the National Survey of Childrens Health from 20112012, which estimates parent-reported ASD
*General Academic Pediatrics, Childrens Hospital of The Kings Daughters, Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA. Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA.
autism
diagnoses for school-aged children, placed the current prevalence of autism at 2%. (1) However, the Centers for Disease Control and Preventions Autism and Developmental Disabilities Monitoring Network, which requires more denitive diagnostic testing, estimates the prevalence of ASD in the United States at 1 in every 88 children. Because males outnumber females 4 to 1, this translates into an incidence of 1 in 54 males and 1 in 252 females. (2) This recent estimated prevalence rate represents an increase of 23% compared with the 2006 estimate of 1 in 110 children. With the steady increase during the past 2 decades, ASD has become an urgent public health concern. A recent study by Hallmayer et al (3) of the largest collection of fraternal and identical twins revealed that genetic and environmental factors likely have an equal effect on determining an autism diagnosis with sibling risk rates at or above 25%. The increase in diagnosis of autism during the last 20 years has raised public concern and questions on possible causes. Reasons for the increase include diagnostic substitution, broadening of the denition of ASD, and better screening and ascertainment. Diagnostic substitution assumes that children previously were diagnosed only as being developmentally delayed and/or intellectually disabled and not appropriately diagnosed as having an ASD. Monitoring networks have allowed multiple records (clinicians and schools) to be reviewed, which has led to better ascertainment of children diagnosed as having an ASD. In addition, concerted efforts by multiple sources (American Academy of Pediatrics, Autism Speaks, and FirstSigns.org) to improve screening at a younger age have had an effect. Finally, the broader denition of autism, now referred to as ASD has allowed more cases of ASD to be diagnosed. The most recent report from the Centers for Disease Control and Prevention indicates that the biggest increase in cases is among the higher-functioning patients with less severe disease and in African American and Hispanic populations. (1)(2)
ASD Symptoms and Signs

Communication, Social Reciprocity, and Repetitive or Restrictive Behaviors
Commonly, the rst sign that alerts a pediatric clinician to a child with possible autism is a decit in communication, manifested by a delay in or abnormal use of language, at approximately ages 18 to 24 months. A child with autism may initially be mute, have a signicant delay in language acquisition, or have a regression in language. If the child is speaking, he or she may only exhibit echolalia, repeating words and phrases previously heard. In some instances, children with autism may develop language normally and be
quite verbose, but they only speak tangentially about their specic interests without any concern about the listeners response. Children with autism may also have trouble modulating their vocal tone (ie, monotone), with little inection in their voice. Because of these decits in language and reciprocity, many children tend to have an inability to initiate or sustain a conversation with others. Social reciprocity is the give and take of social interaction and requires the child to have the ability to recognize another persons perspective. Children with autism have difculty with social reciprocity; thus, they have trouble establishing relationships with same-aged peers. This inability to socially share or reciprocate implies that a child with autism may not empathize well. These social decits impair ones ability to maintain joint attention (ability to attend to an activity with another person), read body language, and respond to nonverbal cues. A red ag for these difculties is an inability to point to a desired object at 18 months (protoimperative pointing), but even more important is whether the child uses pointing to draw something to the attention of another, referred to as protodeclarative pointing. Children with autism may pull their caregiver by the hand to a desired object by hand guiding. Direct eye contact may be difcult and avoided by children with autism. A study from Yale compared the eye gaze pattern of children with autism and neurotypical peers during a video simulation of play with an adult. Children with autism tended to spend more time looking at the adults mouth rather than the eyes, whereas the neurotypical peers spent little time looking at the mouth and most of the time looking at the eyes of the speaker. (4) The repetitive and restrictive behaviors noted in autism can be the most isolating symptoms of the disorder. Often children strongly desire a rigid routine and are extremely upset if there is deviation from the routine. This reliance on maintaining a nonfunctional routine to avoid conict can make a familys life stressed. Repetitive motor movements, such as hand apping or an intense preoccupation with parts of an object, like spinning wheels on a toy car, highlight these behaviors. Children with autism may also have difculty with onset or maintenance of sleep, as well as restricted food preferences, and hypersensitivity or hyposensitivity to any of the 5 senses. Repetitive and restrictive behaviors along with these sensory issues have gained new prominence and hallmark some of the classication changes recently implemented in the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
Understanding the DSM-IV to DSM-5 Changes

There had been some debate about the upcoming changes to the Diagnostic and Statistical Manual of
autism
Mental Disorders, Fourth Edition (DSM-IV). The newer DSM-5 was accepted and published in May 2013. The DSM-5 merges communication and social interaction behaviors into one symptom category and increases the importance of the repetitive and restrictive behavior into the requirements for a diagnosis of an ASD. The DSM-5 also allows the use of co-occurring diagnoses to exist with autism, whereas before a child under the DSM-IV could not have both autism and attention-decit/hyperactivity disorder (ADHD). To obtain more specics concerning the diagnostic features, differential diagnosis, and comorbidities, the reader is referred to the full publication of the DSM-5. The DSM-5 criteria are listed below (reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [Copyright 2013], American Psychiatric Association). To diagnose an ASD from the DSM-5, a child will need to meet the criteria in A, B, C, D, and E: A. Persistent decits in social communication and social interaction across multiple contexts, as manifested by the following; currently or by history (examples are illustrative, not exhaustive): 1. Decits in social-emotional reciprocity; ranging, for example, from abnormal social approach and failure of normal back and forth conversation; to reduced sharing of interests, emotions, or affect, to failure to respond to social interactions. 2. Decits in nonverbal communicative behaviors used for social interaction; ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or decits in understanding and use of gestures; to a total lack of facial expression and nonverbal communication. 3. Decits in developing, maintaining, and understanding relationships, ranging, for example, from difculties adjusting behavior to suit various social contexts; to difculties in sharing imaginative play or in making friends; to absence of interest in peers. Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Table 1). B. Restricted, repetitive patterns of behavior, interests, or activities as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive):
1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or ipping object, echolalia, idiosyncratic phrases). 2. Insistence on sameness, inexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior (e.g., extreme distress at small changes, difculties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat same food every day). 3. Highly restricted, xated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests). 4. Hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of environment (e.g. apparent indifference to pain/temperature, adverse response to specic sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement). Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Table 1). C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). D. Symptoms cause clinically signicant impairment in social, occupational, or other important areas of current functioning. E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level. Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Aspergers disorder, or pervasive developmental disorder not otherwise specied should be given the diagnosis of autism spectrum disorder. Individuals who have marked decits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder. Once the diagnosis of ASD is made, the DSM-5 provides a severity level rating that can be used to help grade
autism
Table 1.
Severity Levels for Autism Spectrum Disorder

Social Communication Severe decits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches. Marked decits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and who has markedly odd nonverbal communication. Without supports in place, decits in social communication cause noticeable impairments. Difculty initiating social interactions, and clear examples of atypical or unsuccessful responses to social overtures of others. May appear to have decreased interest in social interactions. For example, a person who is able to speak in full sentences and engages in communication but whose toand-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful. Restricted, repetitive behaviors Inexibility of behavior, extreme difculty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difculty changing focus or action.
Severity Level Level 3: Requiring very substantial support
Level 2: Requiring substantial support
Inexibility of behavior, difculty coping with change, or other restricted/ repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. Distress and/or difculty changing focus or action.
Level 1: Requiring support
Inexibility of behavior causes signicant interference with functioning in one or more contexts. Difculty switching between activities. Problems of organization and planning hamper independence.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (Copyright 2013). American Psychiatric Association. All rights reserved.
the level of functioning for the child. As stated in the criteria for diagnosis, the severity level rating is based on both social communication impairments and restricted, repetitive patterns of behavior but should be rated separately. This process is outlined in Table 1. It may be tempting to use this severity grading of function to determine eligibility of services for children; however, severity may vary over time and in certain situations, and therefore providing services should be decided on an individual level. Table 2 summarizes specic changes to the DSM-IV in the DSM-5. The changes in the DSM-5 may help to clarify the diagnostic process for autism, but some opponents to this change are worried that it will decrease the overall incidence by only recognizing the most severely affected,
thus overlooking children who may benet from autism services. Proponents believe that this will not happen. However, in recent studies using the DSM-5 criteria vs the DSM-IV, up to 48% fewer toddlers would be diagnosed as having autism. (5) Reconciling the new changes to the DSM will be challenging in the next few years, when considering that the previous increase in the incidence of autism during the last 2 decades is still not completely understood.
ASD Possible Causes and Vaccine Concerns

It is well known that certain genetic disorders (eg, fragile X syndrome, neurobromatosis, and tuberous sclerosis) are more likely to be associated with autism and should
autism
Table 2.
Comparison of Changes in the DSM-IV and DSM-5 for ASD

DSM-V Changes for ASD 1. Rett disorder is eliminated because it is considered a genetic disease 2. These 3 disorders will now ofcially be called ASD 3. Unusual sensory behaviors will be added to the criteria 4. 2 symptom categories (decits in social communication and social interaction combined, and repetitive and restrictive behaviors) but more criteria required per category
DSM-IV for ASD 1. Rett disorder 2. Pervasive developmental disorder not otherwise specied, Asperger disorder, and childhood disintegrative disorder 3. Unusual sensory behaviors not part of the criteria. 4. 3 symptom categories (impairment in social interaction, impairment in communication, and repetitive and restrictive behaviors)
ASDautism spectrum disorder; DSM-IVDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition; DSM-5Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
be considered when making a diagnosis of ASD (Table 3). In addition, with rened genetic techniques, such as comparative genomic hybridization microarrays, whole genome linkage, and gene association studies, researchers have found hot spots on almost every chromosome that can coincide with either a specic singlenucleotide polymorphism or copy number variant. (6) Interestingly, it is not always the gene but the intervening sequences between genes (introns) and how they are methylated that play a critical role in how genes are turned on and off. However, even with an advanced ability to view up to 10,000 base pairs on the genome, approximately 75% of children diagnosed as having autism have no measurable genetic abnormality when rigorously tested. (7) Without a consistent genetic association for autism, a search for a possible environmental cause has led some to consider implicating vaccines because these are given throughout early infancy and at the same time when children are diagnosed as having autism. Initially, the measlesmumps-rubella vaccine was linked as a cause of autism through a small, poorly conceived case series by a British gastroenterologist named Andrew Wakeeld. This report was later retracted by Lancet when it was found to be tainted by inappropriate recruitment and bias. When the measles-mumps-rubella vaccine link was disproven, a recycled theory concerning mercury as a preservative (thimerosal) in multidose vial vaccines became popular as a cause of autism, which was also subsequently disproven. Furthermore, the manufacturers removed thimerosal from their vaccines. Unfortunately, some parents and antivaccine websites still try to manipulate temporal data into causality. It is therefore important for pediatric clinicians to be aware of this misguided information and to be able to counter this argument with the multitude of
studies that have disproven any causal association between vaccines and autism. (8) It is important to make parents aware of the risks of not vaccinating. If a parent is steadfastly against vaccinating their child for fear of causing autism, even after an exhaustive use of evidenced-based data to the contrary, then the American Academy of Pediatrics (AAP) recommends that they ll out a refusal to vaccinate form (http://www2.aap.org/immunization/pediatricians/pdf/RefusaltoVaccinate.pdf). Historically, certain exposures and environmental factors were associated with an increased risk of autism: rubella infection, exposure to thalidomide or valproic acid in the rst trimester, and untreated phenylketonuria. A search for additional environmental factors was launched in California in 2000, called the Childhood Autism Risk from Genetics and Environment. Some factors that have been established as incurring risk include prematurity, twins or multiple pregnancy, and advanced maternal or paternal age at conception. A recent study from Denmark also suggested a possible immune response based on prolonged fever in mothers during pregnancy. (9) Currently, no denitive environmental factors can predict diagnosis; therefore, the pediatric clinicians ability to screen children early for autism becomes extremely important.
Screening
The AAP in 2007 recommended to pediatric clinicians that all 18- and 24-month-old children be screened for an ASD. Providing an early diagnosis of autism allows parents to access intensive behavioral treatments (ie, applied behavioral analysis [ABA]) that can ultimately improve a childs overall outcome in language, adaptive behaviors, academic performance, and IQ. Research has conrmed that the diagnosis of an ASD can reliably be made in the
autism
Table 3.
Syndromes Associated With Autisma

Physical Examination and/or History Findings Ash leaf spots, adenoma sebaceum, shagreen patches, tubers, seizures, and intellectual disability 2 criteria of the following: 6 cafe au lait spots, 2 neurobromas or 1 plexiform, axillary or inguinal freckling, optic glioma, 2 Lisch nodules, sphenoid dysplasia or tibial pseudoarthrosis, rst-degree relative with neurobroma type 1 Language and Intellectual decits, seizures, hypermotoric and ataxic movements, paroxysms of laughter, and happy disposition Inconsistent physical examination ndings, microcephaly and macrocephaly, large jaw, large hands, macro-orchidism Regression in development, hand-wringing behavior, female, microcephaly Associated Gene(s) TSC1 and TSC2 Patients With Syndrome Who Have Autism, % 20-40 Patients With Autism Who Have Syndrome, % 1 Testing to Consider MRI, ophthalmology, cardiac and renal evaluation
Autism-Related Syndrome Tuberous sclerosis
Neurobromatosis
NF1
40-50 in some studies
0.3
Ophthalmology consultation, MRI, spinal examination for scoliosis, cardiac for murmurs, and blood pressure for hypertension
Angelman syndrome
UBE3A
50
Rare
FISH or microarray testing for 15q11.2-q13, EEG, MRI
Fragile X syndrome
FMR1
25 (males) and 6 (females)
1-2
Fragile X testing looking for CGG repeats >200 EEG, MECP2 gene testing
Rett syndrome
MECP2
All females, but with DSMV will be considered separate disorder
Rare
EEGelectroencephalography; FISHuorescent in situ hybridization; MRImagnetic resonance imaging. a Other disorders associated with autism are as follows: 15 q duplication, 16p11 deletion, 22q deletion, cortical dysplasia-focal epilepsy syndrome, Joubert syndrome, Potocki-Lupski syndrome, PTEN hamartoma tumor syndrome, Smith-Lemli-Opitz syndrome, trisomy 21, and Timothy syndrome. (5)
second year of life, but the overall predictive reliability and stability of a diagnosis at this age are lower. Children suspected of having an ASD through screening must be further evaluated as soon as possible. The AAP developed Caring for Children with Autism Spectrum Disorders: A Resource Toolkit for Clinicians or more simply the
Autism Toolkit (www.aap.org) as a helpful guide for pediatric clinicians to screen, identify, and treat children with ASDs. The toolkit presents different practical items (clinician fact sheets and parent handouts) that help a primary care physician maintain a medical home for children with autism, discusses autism screening and identication, and
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provides the following 3 screening tools (also available separately online) used at different ages (Table 4): 1. Children younger than 18 months can be screened with the Communication and Symbolic Behavior Scales and Developmental Prole. 2. Children age 18 to 30 months can be screened using the Modied Checklist for Autism in Toddlers (MCHAT). 3. For Preschool and Elementary school children the screen suggested is the Childhood Autism Screening Test. The Infant Toddler Checklist, also known as the Communication and Symbolic Behavior Scales and Developmental Prole, uses 24 total questions grouped into developmental milestones and social communication. There is also a nal free-text question that asks, Do you have any concerns about your childs development? (http://rstwords.fsu.edu/pdf/checklist.pdf). The checklist has been studied as a broad-based screener for developmental problems and identied problems in 56 of 60 children ultimately diagnosed as having autism from a large population sample. (10) However, it could not easily distinguish between children with autism from children with other communication delays. The M-CHAT was developed from the previous British version called the CHAT. The M-CHAT uses 23 yes/no questions that expand on the previous CHAT. The difcult aspect of the M-CHAT is that it requires the practitioner to do an M-CHAT follow-up interview questionnaire orally (http://www2.gsu.edu/wpsydlr/Diana_L. _Robins,_Ph.D..html) for screens with positive results, which can happen in 1 of 10 screens. This second-level screen for a positive M-CHAT result was studied by using follow-up telephone calls, which can eliminate 5 of 6 as not requiring referral. (11) This 2-step screening process has
been combined and integrated into an online screening at www.m-chat.org. Unfortunately, the M-CHAT is unreliable in children older than 3 years. Therefore, a validated screening tool for autism at older than 3 years and especially in school-aged children is needed. Children who meet DSM criteria for ASD are often diagnosed by age 2 to 3 years. However, identifying subtler cases of ASD may take longer. Most subtle cases occur in children with minimal intellectual dysfunction and better language skills. Difculties with functioning may not be noticeable until school-age, when social demands become greater. Recognizing older children with ASD can be challenging for the practicing clinician, educator, and parent. The use of the Childhood Autism Screening Test may prove helpful. This test provides yes/no questions with 1 point scored for each ASD-relevant response to questions related to social abilities and interest in being around other people. There are 37 total questions with a maximum score of 31. The cutoff for a positive screen is 15 or greater. This is only a screening test, but it can be helpful when responding to concerns by teachers and parents or, if the result is positive, to consider a second-level diagnostic test, such as the Autism Diagnostic Observation Schedule. Some children, who may have not been diagnosed as having ASD by the time they reach elementary school, may have been labeled with behavioral concerns or co-occurring problems, such as hyperactivity, inattention, aggressiveness, mood disturbances, or learning disorders. Alternatively, a child may have been diagnosed as having ASD when in fact another disorder may explain the reason for their symptoms. In addition, some children with an initial ASD diagnosis may no longer t ASD criteria over time naturally or as a result of therapy. Sometimes the diagnostic process may not be straightforward, and consideration of a differential diagnosis, along with targeted diagnostic testing, may be indicated.
Table 4.
Screening Tools for Autism Spectrum Disorder

Acronym ITC CSBS-DP Age Range 9-24 mo Description Designed to screen for communication delays but recently has tested well for early autism screening (http://rstwords.fsu.edu/pdf/checklist.pdf) 23-Item yes/no questionnaire (www.rstsigns.org and www.m-chat.org) (online free versions with scoring) Has some research toward use as a universal screening device (http://www.autismresearchcentre.com/ project_9_cast) (public domain)
Measure Infant and Toddler Checklist also called Communication and Symbolic Behavior Scales and Developmental Prole Modied Checklist for Autism in Toddlers Childhood Autism Screening Test
M-CHAT CAST
16-30 mo 4-11 y
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Initial Workup and Differential Diagnosis

All children being assessed should undergo a complete physical examination, specically noting any neurologic abnormalities (macrocephaly and hypotonia) or oddities, such as toe-walking, dysmorphic features suggestive of any syndromes, and neurocutaneous skin ndings consistent with neurobromatosis or tuberous sclerosis, such as caf au lait or ash leaf spots (Table 3). In addition, the practitioner should review the medical and family histories, focusing on developmental and behavioral issues. Children younger than 3 years with developmental delays should be immediately referred to an early intervention program whether or not the clinician is certain about a diagnosis of autism. If the child is older than 3 years, referral to the special education department at the local school should occur. Generally, the assessment teams for these services will have a speech-language pathologist, physical therapist, and an occupational therapist. Having multiple therapists and evaluations helps clarify the diagnosis and treatment planning. Children with communication problems and/or language delay should undergo audiology testing. This can be difcult and may ultimately require a sedated auditory brainstem response or a brainstem auditory evoked response test. Deciding on laboratory or diagnostic testing will be guided by a physical examination and medical history. For children diagnosed as having autism, testing for lead exposure, fragile X syndrome, and a comparative genomic hybridization array should be standard; moreover, the use of neuroimaging, electroencephalography, or metabolic testing should be reserved if indicated from physical examination or historical ndings. Diagnostic dilemmas can occur when certain disorders are paired together and can simulate a diagnosis of autism, such as having a language disorder with ADHD or having an intellectual disability and visual impairment. In addition, when considering the differential diagnosis of a child with signicant developmental delays, it is important to remember that harsh psychosocial conditions can elicit a response that may briey mimic autism and other developmental delays. These disorders can include posttraumatic stress disorder, reactive attachment disorder, and child abuse. Generally, these disorders can be diagnosed over time after repeated evaluations, counseling, and therapy. This may require several months, and a diagnosis of autism may be withheld until the childs environment is evaluated for safety and stability. Mandated reporting of child abuse or neglect should be immediate when suspected, and follow-up communication with authorities is important.
After conrming the diagnosis of autism, it is important to help the family identify a treatment strategy to provide the most effective therapy for their child. Intensive psychological and educational interventions are currently the primary treatments for addressing the core decits in children with autism. The assessment and diagnostic process is often stressful for the family and the child; treatment and clinical care can be stressful too. Engagement of parents after the diagnostic process should be geared toward providing education, obtaining resources, and accessing supports. Autism Speaks is one of the largest advocacy and science organizations dedicated to the needs of individuals and families struggling with autism. They provide 2 useful parent toolkits: one that addresses children with lower functioning autism (http://www.autismspeaks.org/docs/ family_services_docs/100_day_kit.pdf) and another for children with minimal intellectual disability and higher functioning (http://www.autismspeaks.org/docs/family_services_ docs/AS-HFA_Tool_Kit.pdf). As mentioned earlier, the AAP provides helpful handouts from the Autism Toolkit, including the educational booklet Understanding Autism Spectrum Disorders, which helps parents navigate the consequences of an initial diagnosis of autism. Another helpful learning tool for residents and practitioners is Autism Case Training: A DevelopmentalBehavioral Pediatrics Curriculum (http://www.cdc.gov/ ncbddd/actearly/act/class.html).
Evidence-Based Treatments
Because of the rapid increase in the prevalence rate of ASD, many treatment services are not readily available, and treatment burden falls on clinicians. Families often look initially to the pediatric clinician for guidance to make treatment and educational decisions. Children with an ASD have high service use rates because of the complexity and early onset of the disorder, lifelong prevalence, and associated impairments. Many children also have co-occurring disruptive behaviors (eg, aggression, tantrums, and self-injury), which are common reasons for referral to medical and mental health services. There are several established behavioral and educational therapies and treatments available to treat the core symptoms of autism. Previously known as behavior modication, ABA is a behavioral treatment approach designed to increase socially appropriate behavior and decrease the severity and/or emergence of challenging behaviors. Widely recognized as an effective treatment for autism, ABA has been endorsed by a number of state and federal agencies, including the US Surgeon General. (12) ABA
autism
focuses on identifying the function of problem behavior and building skills to improve such behaviors. To facilitate appropriate behavior, ABA focuses on teaching specic behaviors in a systematic manner in the context of repeated trials. The therapy is tailored to meet the needs of the individual and requires support of the family. Research has demonstrated that ABA results in improvements in communication, social relatedness, and decreasing repetitive behaviors; however, these skills require additional training to generalize to environments and situations. ABA is extremely labor intensive and expensive and may be needed for several years. As ABA has evolved, several treatment approaches have been developed that use the ABA framework to improve behaviors associated with autism. In addition, many children with ASD require additional therapy to address issues such as speech and language delays and sensory problems (Table 5).
Co-occurring Diagnoses
Up to half of children with an ASD have an intellectual disability as measured by standard testing. However,
Table 5.
many of these children may have strengths in visual spatial skills that are difcult to test. Many children with autism are rst recognized by their language delay. In addition, impaired pragmatic and semantic language skills create learning difculties for children with ASD. Children with an ASD are either in special education classrooms or the regular classroom with an individual education plan or 504 plan. Children with autism may have common medical problems, such as sleep disorders, constipation, and irritability, that a clinician may feel comfortable treating. However, addressing the common comorbid mental health issues, such as anxiety, ADHD, and disruptive behaviors, may be more challenging. Because of the complexity of ASD, it is important to take into account all possible diagnoses to be able to address the needs of the child and family. As the child gets older, these cooccurring mental health disorders could become the problematic aspect or the dening diagnosis in some cases. A helpful website to review and download tests for co-occurring diagnoses can be found at http://www2.massgeneral. org/schoolpsychiatry/screeningtools_table.asp. However,
Additional Interventional Therapies for Autism

Description This method is a data-driven approach designed to improve language and social, behavioral, and play decits common among children with ASD. This method focuses on comprehensive services across the lifespan that are specic to the individual and their personal environment, skills decits, and unique family situations. Parents play an integral role in the treatment process. Education strategies are established individually to assess the potential for acquisitions of learning abilities, rather than decits. An assessment called the Psycho Education Prole is used to identify areas where skills are deemed passing, not developed yet, or where the skill is emerging. The DIR model is an intensive program that requires parents to work with their children across multiple settings and sessions throughout the day, often for 20 minutes or longer at each session. At the core of the DIR model is Floortime, where the caregiver literally gets down on the oor to interact with the child, one-on-one, for 20 minutes in child-directed play or interactions. The purpose of speech and language therapy is to improve verbal and nonverbal communication through didactic and naturalistic behavior methods. This also may include sign language and augmentative communication techniques, such as the Picture Exchange and Communication System. Occupational therapy is designed to improve ne motor decits and improve academic and self-care skills. In addition, the therapy will address issues with the integration of sensory of information.
Treatments Pivotal Response Training Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH)
Developmental, individual-difference, relationshipbased model (DIR)/Floortime
Speech and language therapy
Occupational therapy
autism
these screening tools are not specic to screening children with ASD. ANXIETY AND PHOBIAS. Anxieties and phobias can be found in up to half of all children diagnosed as having an ASD. Many children may have more than one phobia and/ or anxiety related to objects or situations. Screening with the Spence Childrens Anxiety Scale can help discern whether a child has separation and generalized anxiety, along with social phobia and panic disorders (http:// www.scaswebsite.com/). The Self-report for Childhood Anxiety Related Disorders screens for 5 factors: general anxiety, separation anxiety, social phobia, school phobia, and physical symptoms of anxiety (http://psychiatry.pitt. edu/research/tools-research/assessment-instruments). Medication is rarely required in clinical practice unless the anxiety is debilitating. However, being able to recognize a mild anxiety disorder is helpful for parents when explaining how to modify these maladaptive behaviors. OBSESSIVE-COMPULSIVE DISORDER. Obsessive-compulsive disorder is considered the second most common cooccurring condition with ASD and many times de nes some early behaviors in children based on their unwillingness to change routines. More than one-third of children with an ASD continue with some type of obsession or compulsion that will limit their ability to interact socially. These behaviors are fairly easy to ask parents about and may not require any speci c screening. Treatments with low doses of selective serotonin reuptake inhibitors have been administered in small trials with mixed success. Interestingly, a recent Cochrane review of selective serotonin reuptake inhibitor use in children with autism found no evidence of effect for either anxiety or obsessive-compulsive disorder. (13) ADHD. ADHD is another common co-occurring condition in children with ASD. Use of the inclusive denition of all types of ADHD (inattentive, hyperactive, and combined) can encompass approximately two-third of all children with ASD. Children may be diagnosed as having and treated for ADHD with stimulants such as methylphenidates and amphetamines before a diagnosis of ASD is ever made. Some studies have suggested that ADHD may actually be considered somewhere along the continuum of the autism spectrum. (14) Screening and follow-up for ADHD can be accomplished with the Vanderbilt forms (http://www.pampapediatrics. com/client_images/File/vanderbilt-forms.pdf). The important caveat for children with autism who have ADHD is that they may be more sensitive to the
medications and can have adverse effects and irritability at lower doses than children without ASD. Therefore, the mantra is to start low and go slow with medications. A therapeutic model for assessment and treatment of ADHD in a child with autism is provided (Figure). (15) DEPRESSION. Generally, depression can be seen in children with ASD as they get older and perhaps become more aware of their diagnosis. In middle school the pressure to conform is strong, and there is a low tolerance for being different. Children with ASD are likely to get teased and taunted or bullied and nd it difcult to t in. This may increase their social withdrawal and cause sadness, crying spells, and depression that may require medical treatment and counseling. The Pediatric Symptom Checklist is sometimes useful as a global screen when there may be more than one co-occurring disorder. The Pediatric Symptom Checklist has a short form (Pediatric Symptom Checklist 17) or longer form ( Pediatric Symptom Checklist 35) (http://www.brightfutures.org/ mentalhealth/pdf/professionals/ped_sympton_chklst.pdf). DISRUPTIVE BEHAVIOR. Disruptive behavior may escalate to aggression, causing suspension from school and injury to siblings or parent. Behavioral therapy that targets these emotional outbursts can sometimes sufce, but many times the decision to start use of antipsychotic medications, such as risperidone or aripiprazole, may be necessary. It is important to perform a comprehensive evaluation to identify and assess target behaviors before launching into pharmacologic management. A comprehensive table, provided in the article by Myers et al, (16) that reviews the clinical approach before initiating pharmacologic management should be reviewed (Table 6). BIPOLAR DISORDER. Occasionally, children with ASD may cycle rapidly through periods of depression and a decreased need for sleep with maniclike activity. If concerned about a bipolar diagnosis, it is best to refer to a psychiatrist for assessment and support. Anticonvulsant mood stabilizers, such as carbamazepine or valproic acid, or an atypical antipsychotic agent, such as risperidone or aripiprazole, are sometimes used. Use of psychotropic medications as a treatment of acute symptoms of irritability or disruptive behaviors tends to occur as children get older and if the children have increased intellectual disability when placed in a more restrictive educational environment. It is therefore important to use combined therapies of parent training programs with medication in treating children with ASD and challenging behaviors. (17)
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Figure. A therapeutic model for assessment and treatment of attention-decit/hyperactivity disorder in a child with autism. (15) Reprinted with permission from Mahajan R, Bernal MP, Panzer R, et al. Clinical practice pathways for evaluation and medication choice for attention-decit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012;130(suppl 2):S125S138.
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CAM Therapies for Autism

There is a high use of CAM among children with ASD. Parents often use CAM therapies along with conventional treatments for their child with autism, a combination of treatments often referred to as integrative medicine. (18) Parents appear to be more likely to use CAM therapies if their child has a coexisting gastrointestinal issue, seizure, or behavioral disorder. It is important to be familiar with and provide an open and nonjudgmental approach when discussing CAM therapies with parents. Unfortunately, some CAM therapies receive media attention (eg, secretin and hyperbaric oxygen) and become fads that are used by parents that may or may not have disposable income. Regrettably, many of these therapies have not been rigorously studied, and vulnerable parents develop false hopes that each new treatment may provide a cure for their child with autism. The following guidelines may be useful for parents who are interested in trying biomedical and/or CAM therapy: 1. Research the medication or therapy as much as possible. Seek information from the clinician and share perspectives on the efcacy and safety of the treatment. 2. Know the behavior to be improved. Is treatment directed to improving disruptive behaviors or increasing speech production? 3. Start only one new treatment at a time. Do not introduce 2 or 3 interventions at once; this will make it difcult to know which treatment is or is not working. 4. Understand that a child with autism over time will move forward in development, although the forward rate may be slow. 5. Keep in mind that a child with autism may naturally have good weeks and bad weeks. 6. Be observant of other factors that may affect treatment outcome (eg, life transitions, parental separation, and birth of a new sibling). 7. Assess poor sleep habits by removing electronic devices from the bedroom and maintain a consistent bedtime routine. Consider obstructive sleep apnea if a child diagnosed as having autism snores loudly, appears to stop breathing while sleeping, or has daytime sleepiness. Remember, insufcient sleep can negatively affect mood and cause disruptive behaviors, inattentiveness and hyperactivity, and ritualistic behaviors. The types of CAM therapies marketed to parents include nutrition, immunomodulation, biochemical and metabolic therapies, detoxication, manipulative and
body-based practices, sensory integration therapy, music and other expressive therapies, and additional therapies, such as dolphin swim therapy, hippotherapy (horseback riding), and hyperbaric oxygen. NUTRITION. Gluten-free and casein-free diets are common, as is the use of vitamins B6 and magnesium, vitamin C, carnosine, v3 fatty acids, and combined hypervitamin therapies. IMMUNOMODULATION. Antifungals and antibiotics, along with the use of prebiotics and probiotics, are popular based on the unproven hypothesis that children with autism may have underlying immunodeciencies. BIOCHEMICAL AND METABOLIC THERAPIES. Abnormalities have been proposed in metabolic pathways, and use of precursors and coenzyme factors are thought to be helpful (eg, dimethyl glycine, trimethyl glycine, and vitamin B12 shots). DETOXIFICATION. Parents may have nonstandardized hair analysis or serologic testing performed. The results of these unregulated tests may lead parents to believe that their child has heavy metal poisoning that requires chelation. Some clinicians offer chelation therapy, and parents should be advised that deaths have occurred from improper use of chelation protocols for children with autism. (19) MANIPULATIVE AND BODY-BASED PRACTICES. These practices include chiropractic manipulation, craniosacral massage, massage therapy, and therapeutic touch. SENSORY INTEGRATION THERAPY. This is sometimes grouped with occupational therapy but really refers to practices such as auditory integrative therapy, which purports to retrain the childs auditory reexes. MUSIC AND OTHER EXPRESSIVE THERAPIES. Generally, music and other expressive therapies involve listening or moving to music, along with using art, drama, and other theatrical activities. For the clinician, a general ethical principal, developed by Cohen et al, (20) provides guidance using a simple 2 2 table philosophy that asks a yes/no question of safety and efcacy of CAM therapies. The 4 outcomes of these questions can look like this: 1. If a CAM therapy is safe and effective then recommend. 2. If a CAM therapy is safe but effectiveness is unknown then tolerate. 3. If a CAM therapy has a concern for safety but is effective then monitor closely. 4. If a CAM therapy is unsafe and not effective then advise against.
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A CAM therapy that might be considered safe and effective would be using melatonin for sleep. Alternatively, something that is known to be unsafe and unlikely to be effective, such as chelation for presumed heavy metal poisoning, should be advised against. Other therapies that are generally safe, such as message therapy and most
dietary supplements, may be tolerated but should be monitored for targeted behavior improvement and safety. Part of providing a medical home involves understanding that parents are likely to consider using the different CAM therapies and being aware of the different CAM therapies that are available.
Table 6.
Clinical Approach to Psychopharmacologic Management
(16)
Identify and assess target behaviors Parent or caregiver interview Intensity Duration Exacerbating factors or triggers (eg, time, setting or location, demand situations, denials, and transitions) Ameliorating factors and response to behavioral interventions Time trends (increasing, decreasing, or stable) Degree of interference with functioning Consider baseline behavior-rating scales and/or baseline performance measures or direct observational data Include input from school staff and other caregivers Assess existing and available supports Behavioral services and supports Educational program, rehabilitative therapies Respite care, family psychosocial supports Search for medical factors that may be causing or exacerbating target behavior(s) Consider sources of pain or discomfort (eg, infectious, gastrointestinal, dental, and allergic) Consider other medical causes or contributors (eg, sleep disorders, seizures, and menstrual cycle) Complete any medical tests that may have a bearing on treatment choice Consider psychotropic medication on the basis of the presence of the following: Evidence that the target symptoms are interfering substantially with learning or academic progress, socialization, health or safety (of the patient and/or others around him or her), or quality of life Suboptimal response to available behavioral interventions and environmental modications Research evidence that the target behavioral symptoms or coexisting psychiatric diagnoses are amenable to pharmacologic intervention Choose the medication on the basis of the following: Likely efcacy for the specic target symptoms Potential adverse effects Practical considerations, such as formulations available, dosing schedule, and cost and requirement for laboratory or electrocardiographic monitoring Informed consent (verbal or written) from parent or guardian and, when possible, assent from the patient Establish plan for monitoring of effects Identify outcome measures Discuss time course of expected effects Arrange follow-up telephone contact, completion of rating scales, reassessment of behavioral data, and visits accordingly Outline a plan regarding what might be tried next if there is a negative or suboptimal response or to address additional target symptoms Change to a different medication Add another medication to augment a partial or suboptimal therapeutic response to the initial medication (same target symptoms) Add a different medication to address additional target symptoms that remain problematic Obtain baseline laboratory data if necessary for the drug being prescribed and plan appropriate follow-up monitoring Explore the reasonable dose range for a single medication for an adequate length of time before changing to or adding a different medication Monitor for adverse effects systematically Consider careful withdrawal of the medication after 6-12 mo of therapy to determine whether it is still needed
Reprinted with permission from Myers SM, Johnson CP; American Academy of Pediatrics, Council on Children With Disabilities. Management of children with autism spectrum disorders. Pediatrics. 2007;120(5):1162-1182.
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Medical Home
In the physician survey performed in 2009 by Golnik et al (21) concerning children with autism, primary care practitioners reported a lack of self-perceived competency, a desire for education, and a need for improvement in providing primary care to children with autism. Outlined below are the 6 major attributes that a medical home should have for a family dealing with autism.
Accessibility
As the number of children diagnosed as having an ASD increases, there is a need for pediatric clinicians to become comfortable handling the complexity of their care. Designing a scheduling system that allows staff to provide an early morning appointment or a larger block of time for patients with autism is critical. Currently, many parents still consider their pediatric clinician for just illnesses and well visits, not developmental or behavioral concerns. Pediatric clinicians need to be open-minded and understanding about discussions on the use of CAM therapies.
outside the home should be available and current. An available list should include subspecialist physicians, psychologists, dentists, community mental health agencies, therapists (speech therapists, occupational therapists, and physical therapists), advocacy centers, and early intervention and special education programs. Parents may require letters or other communication with camps, sports teams, and recreational clubs outlining important aspects of their childs care. Less rule-oriented sports, such as swimming and track, and the development of nonverbal talents, such as music, dance, and karate, should be encouraged. When possible, ASD children should be integrated with neurotypical children to improve social skills. However, no data are available to support the theory that such integration provides better outcomes. (22) The medical home should have direct connections with the schools, listing teacher names and perhaps the e-mail addresses or telephone numbers of the parents with the parents consent. Care should include the ability to recognize mental health concerns in both the parent and child.
Family-Centered Care
A child with ASD changes the dynamics of the whole family, siblings as well as relatives. Education and treatment options are not easily obtained and, if not offered by the local school, may be denied by insurance. Clinicians should be cognizant to ask parents what they want (resources and information) and not assume what they want (respite care) and speak in people-rst language when discussing their child with autism and not their autistic child.
Compassionate Care
Children with autism appear physically normal, so when they have a public meltdown parents are often blamed for raising an undisciplined child. Parents may be embarrassed and could still be mourning the loss of their hoped-for perfect child. Counseling should focus on what their child can do and not on what others think of their child. A medical home should be open-minded about treatments and therapies suggested by parents and should provide support and concern. Not all parents require or want respite care for their child; however, it is important to mention Medicaid waivers and access to social programs. Although a medical home should emphasize therapy strengths, it should not offer false hopes or unrealistic goals. Safety issues should be addressed, including elopement, reported to occur in up to 50% of children with autism. (23) In such situations, leg or armband global positioning devices (http://www.projectlifesaver.org/) that can be used by law enforcement and rst responders should be recommended.
Continuous Care
Transitions or changes in the environment are extremely difcult for the child and family, so such events should be managed proactively if possible. Behavioral conditioning and consistent parenting are always necessary, especially during times of high stress, such as household moves, transition from childhood to adolescence, and marital discord or divorce. Regressions and/or prolonged plateaus in development should be red ags that indicate hidden stress and medical or mental health concerns and the need for intervention. Discussing the transition from adolescence to adulthood should start early (end of middle school) so parents can prepare their child for community-living options, guardianship and alternatives to guardianship, and possible postgraduate studies.
Culturally Sensitive Care

Different cultures have varying perceptions regarding social acceptability of certain behaviors and blame related to the cause of ASD. Parents may have different literacy levels, and autism screening tools may not be appropriate for different languages. Immigrant families are more likely to be uninsured, may be unaware of local resources for autism, and may be more likely to consider alternative
Comprehensive and Coordinated Care

Information about local support groups and medical and recreational resources in the area that provide treatment and activities specic to children with autism inside and
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therapies. Information on autism should be available in more than one language.
References
1. Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu
MC. Changes in Prevalence of Parent-Reported ASD in School-aged US Children: 2007 to 20112012. National Health Statistics Report No. 65. Hyattsville, MD: National Center for Health Statistics; 2013. 2. Centers for Disease Control and Prevention, Autism and Developmental Disabilities Monitoring Network. Identied Prevalence of Autism Spectrum Disorders. 2012. http://www.cdc.gov/ ncbddd/autism/data.html. Accessed September 10, 2013 3. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):10951102 4. Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946954 5. Matson JL, Kozlowski AM, Hattier MA, Horovitz M, Sipes M. DSM-IV vs DSM-5 diagnostic criteria for toddlers with autism. Dev Neurorehabil. 2012;15(3):185190 6. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9(5): 341355 7. Miles JH. Autism spectrum disordersa genetics review. Genet Med. 2011;13(4):278294 8. Gerber JS, Oft PA. Vaccines and autism: a tale of shifting hypotheses. Clin Infect Dis. 2009;48(4):456461 9. Atladttir HO, Henriksen TB, Schendel DE, Parner ET. Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study. Pediatrics. 2012;130(6):e1447e1454 10.1542/peds.2012-1107 10. Wetherby AM, Brosnan-Maddox S, Peace V, Newton L. Validation of the Infant-Toddler Checklist as a broadband screener for autism spectrum disorders from 9 to 24 months of age. Autism. 2008;12(5):487511 11. Robins DL. Screening for autism spectrum disorders in primary care settings. Autism. 2008;12(5):537556 12. Satcher D. Mental Health: A Report of the Surgeon General. Washington, DC: US Dept of Health and Human Services; 1999: 163164 13. Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2010;8(8):CD004677 14. Reiersen AM, Constantino JN, Volk HE, Todd RD. Autistic traits in a population-based ADHD twin sample. J Child Psychol Psychiatry. 2007;48(5):464472 15. Mahajan R, Bernal MP, Panzer R, et al; Autism Speaks Autism Treatment Network Psychopharmacology Committee. Clinical practice pathways for evaluation and medication choice for attentiondecit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012;130(suppl 2):S125S138 16. Myers SM, Johnson CP; American Academy of Pediatrics Council on Children With Disabilities. Management of children with autism spectrum disorders. Pediatrics. 2007;120(5):11621182 17. Frazier TW, Youngstrom EA, Haycook T, et al. Effectiveness of medication combined with intensive behavioral intervention for reducing aggression in youth with autism spectrum disorder. J Child Adolesc Psychopharmacol. 2010;20(3):167177 18. Vohra S, Surette S, Mittra D, Rosen LD, Gardiner P, Kemper KJ. Pediatric integrative medicine: pediatrics newest subspecialty? BMC Pediatr. 2012;12:123
Conclusion
Providing a medical home to children and families dealing with an ASD can be both challenging and rewarding. Screening tools and improved diagnostic skills help identify and treat children earlier for the best outcomes. Improving awareness and evaluating for co-occurring problems are important adjuncts to providing comprehensive care to ASD families. Familiarity with the evidence-based treatments, openness to discussing CAM therapies, and maintaining a current set of local autism resources and health care practitioners are critical to optimal care of patients with ASD. The pediatric clinician who takes the time to help families navigate the multiple interventions and issues surrounding the care of a child with autism will be rewarded with fullling a childs potential for a more independent and productive life.
Summary
On the basis of the most recent epidemiologic research, Autism Spectrum Disorder (ASD) affects approximately 1% to 2% of all children. (1)(2) On the basis of some research evidence and consensus, the Modied Checklist for Autism in Toddlers is a helpful tool to screen for autism in children between ages 16 and 30 months. (11) The Diagnostic Statistical Manual of Mental Disorders, Fourth Edition, changes to a 2-symptom category from a 3-symptom category in the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5): decits in social communication and social interaction are combined with repetitive and restrictive behaviors, and more criteria are required per category. The DSM-5 subsumes all the previous diagnoses of autism (classic autism, Asperger syndrome, and pervasive developmental disorder not otherwise specied) into just ASDs. On the basis of moderate to strong evidence, the use of applied behavioral analysis and intensive behavioral programs has a benecial effect on language and the core decits of children with autism. (16) Currently, minimal or no evidence is available to endorse most complementary and alternative medicine therapies used by parents, such as dietary changes (gluten free), vitamins, chelation, and hyperbaric oxygen. (16) On the basis of consensus and some studies, pediatric clinicians should improve their capacity to provide children with ASD a medical home that is accessible and provides family-centered, continuous, comprehensive and coordinated, compassionate, and culturally sensitive care. (20)
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19. Baxter AJ, Krenzelok EP. Pediatric fatality secondary to EDTA chelation. Clin Toxicol (Phila). 2008;46(10):10831084 20. Cohen MH, Kemper KJ, Stevens L, Hashimoto D, Gilmour J. Pediatric use of complementary therapies: ethical and policy choices. Pediatrics. 2005;116(4):e568e575 21. Golnik A, Ireland M, Borowsky IW. Medical homes for children with autism: a physician survey. Pediatrics. 2009;123(3):966971 22. Foster EM, Pearson E. Is inclusivity an indicator of quality of care for children with autism in special education? Pediatrics. 2012; 130(suppl 2):S179S185 23. Anderson C, Law JK, Daniels A, et al. Occurrence and family impact of elopement in children with autism spectrum disorders. Pediatrics. 2012;130(5):870877
Suggested Readings
Harrington JW. Are we overmedicating our children? Pediatrics. 2008;122(1):211-212 Levy SE, Giarelli E, Lee L-C, et al. Autism spectrum disorder and co-occurring developmental, psychiatric, and medical conditions among children in multiple populations of the United States. J Dev Behav Pediatr. 2010;31(4):267275
Levy SE, Hyman SL. Complementary and alternative medicine treatments for children with autism spectrum disorders. Child Adolesc Psychiatr Clin N Am. 2008;17(4):803820, ix McEachin JJ, Smith T, Lovaas OI. Long-term outcome for children with autism who received early intensive behavioral treatment. Am J Ment Retard. 1993;97(4):359391 Research Units on Pediatric Psychopharmacology Autism Network. Risperidone treatment of autistic disorder: longer-term benets and blinded discontinuation after 6 months. Am J Psychiatry. 2005;162(7):13611369 Robins DL, Fein D, Barton ML, Green JA. The Modied Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord. 2001;31(2):131144 Schall CM, McDonough JT. Autism spectrum disorders in adolescence and early adulthood: characteristics and issues. J Vocat Rehabil. 2009;32:8188 Sinzig J, Walter D, Doepfner M. Attention decit/hyperactivity disorder in children and adolescents with autism spectrum disorder: symptom or syndrome? J Atten Disord. 2009;13(2): 117126

English: http://www.healthychildren.org/English/health-issues/conditions/developmental-disabilities/Pages/Diagnosing-
Autism.aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/developmental-disabilities/paginas/diagnos-
ing-autism.aspx
English: http://www.healthychildren.org/English/health-issues/conditions/developmental-disabilities/Pages/Early-Signs-
of-Autism-Spectrum-Disorders.aspx
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autism-spectrum-disorders.aspx
autism

1. A 30-month-old girl presents for a health care maintenance visit. Which of the following is the most appropriate screening tool for this girl for autism spectrum disorder (ASD)? A. Autism Diagnostic Observation Schedule. B. Childhood Autism Screening Test. C. Communication and Symbolic Behavior Scales and Developmental Prole. D. The Infant Toddler Checklist. E. Modied Checklist for Autism in Toddlers. 2. A 2-year-old boy presents with severe language delay. Which of the following tests should be administered rst? A. B. C. D. E. Audiology testing. Comparative genomic hybridization array. Fragile X syndrome testing. Lead level. Metabolic testing.
3. A 5-year-old boy previously diagnosed as having ASD fullls the criteria for attention-decit/hyperactivity disorder (ADHD). His pediatrician prescribes a beginning dose of methylphenidate. Which of the following caveats is most appropriate for therapy of ADHD for this child? A. Higher dosage of methylphenidate than children with ADHD and faster medication dosage increase because of his ASD. B. Lower dosage of methylphenidate than children with ADHD and slower medication dosage increase because of his ASD. C. Slightly higher dosage of methylphenidate than children with ADHD because of his ASD. D. Slightly lower dosage of methylphenidate than children with ADHD because of his ASD. E. Usual dosage of methylphenidate as used for other children with ADHD. 4. Parents of a 4-year-old girl diagnosed as having ASD want to know the best, most accepted complementary and alternative therapies for their childs disorder. Which of the following therapies is best accepted in this category? A. B. C. D. E. Chelation for heavy metal poisoning. Hyperbaric oxygen therapy. Massage therapy. Melatonin therapy. Vitamin B12 shot therapy.
5. Parents of a 9-year-old diagnosed as having ASD inquire about what extracurricular activities would be best for their child. Which of the following sports activities would be best for a child with this diagnosis? A. B. C. D. E. Baseball. Football. Gymnastics. Soccer. Swimming.
The Clinician's Guide to Autism John W. Harrington and Korrie Allen Pediatrics in Review 2014;35;62 DOI: 10.1542/pir.35-2-62
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musculoskeletal disorders
Congenital Muscular Torticollis and Positional Plagiocephaly

Alice A. Kuo, MD, PhD,* Sophie Tritasavit, DPT, John M. Graham Jr, MD, ScD
Educational Gap
The incidence of torticollis is as high as 16% in a normal newborn population. Torticollis is vastly underreported in infants with positional plagiocephaly. Early identication of torticollis and referral to early intervention services by a physical therapist could result in complete correction of torticollis and positional plagiocephaly and prevent the need for cranial orthoses or surgery.
Author Disclosure Drs Kuo, Tritasavit, and Graham have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Objectives
1. Understand the prevalence of congenital muscular torticollis (CMT) and its association with positional plagiocephaly. 2. Counsel parents on the importance of tummy time in the treatment of CMT and prevention of positional plagiocephaly. 3. Guide parents on strategies to treat CMT and prevent positional plagiocephaly. 4. Refer appropriately to a physical therapist for treatment of CMT.
Introduction
The term torticollis refers to the postural positioning that occurs when the head is twisted and turned to one side. Prenatally acquired congenital muscular torticollis (CMT) is the most common type of torticollis and is due to asymmetric length and/or strength of the sternocleidomastoid (SCM) muscles on each side of the neck. Congenital muscular torticollis is believed to be due to fetal head descent or abnormal intrauterine fetal positioning during the third trimester, resulting in trauma to the SCM muscle and occasional associated deformations of the back, hips, and feet. Alternative, but potentially concomitant, theories of the origin of CMT include brosis of the SCM muscle, resulting from venous occlusion due to intrauterine persistent lateral exion and rotation of the neck, or trauma to the SCM muscle during difcult deliveries.
Differential Diagnosis of Torticollis

Although CMT is the most common type of torticollis, other causes of abnormal posturing of the head and neck should be considered. Sandifer syndrome is a combination of hiatal hernia and abnormal posturing of the head and neck. The abnormal posturing has been attributed to the attempt to decrease the pain of esophagitis, resulting from gastroesophageal reux and hiatal hernia. In children with this syndrome, after treatment of the hiatal hernia with fundoplication, the torticollis will often resolve itself, with return of normal motion and appearance of the head and neck. Some cases of torticollis are associated with ocular abnormalities, such as weakness of the superior oblique or lateral rectus muscles or the presence of nystagmus. Surgical correction of extraocular muscles will often result in the resolution of the ocular torticollis. Congenital vertebral Abbreviations anomalies may cause abnormal positioning of the head, such as seen in Klippel-Feil syndrome. Posttraumatic infecCMT: congenital muscular torticollis tions and inammation of adjacent structures, neoplastic SCM: sternocleidomastoid conditions, and rare structural and functional neurologic
*Departments of Pediatrics and Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA. Early Start Pediatric Physical Therapy, Los Angeles, CA. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
torticollis
conditions may also cause torticollis in childhood. Paroxysmal torticollis is an unusual self-limiting condition that consists of intermittent spasms of the SCM muscle, often sporadically involving both sides. Treatment is ineffective and usually resolves by age 2 or 3 years.
Pathophysiology and Clinical Features of CMT

Examination of the histologic features of affected SCM muscle tissue in CMT patients demonstrates that the muscle has been replaced by dense brous tissue. Magnetic resonance imaging studies of affected tissue suggest that CMT may be caused by intrauterine or perinatal SCM muscle compartment syndrome. Ischemia and edema within the SCM muscle compartment can result from exion with lateral bending and rotation of the head and neck, leading to SCM muscle trauma. Interstitial brosis of the muscle is sometimes palpable as a fusiform brous mass or tumor that becomes evident in the rst 3 weeks after birth and reaches maximum size by age 1 month. This mass comprises myoblasts, broblasts, myobroblasts, and mesenchyme-like cells that usually mature and differentiate. Myoblasts can be mechanically stimulated to undergo hypertrophy and hyperplasia in vitro by intermittent stretching and relaxation, and the proper orientation of the skeletal bers during myogenesis is maintained by rhythmic contractions. Thus, there is good physiologic justication for early initiation of neck physical therapy to prevent muscle brosis. (5) Clinically, in infants with CMT, the head is typically tilted toward the side of the affected muscle and rotated toward the opposite side (although infants with CMT could have ipsilateral tilt and turn, the differential diagnosis for ipsilateral tilt and rotation should include causes other than CMT, such as congenital vertebral malformation, intracranial tumor, ocular abnormality, infection, or malignant tumor). In CMT, skull and facial asymmetry (in addition to plagiocephaly) may be present. Jaw asymmetry with mandibular hypoplasia may be the rst indication that CMT is present, and some mothers notice that infants with CMT have difculty breastfeeding equally well from both breasts. Ears are asymmetric as well, with the ear on the side of the torticollis, or affected SCM muscle, often smaller and the ear opposite the torticollis displaced forward with the contralateral occipital attening. The ipsilateral eye is often smaller, and the ipsilateral frontal area attens as a result of forces from the contralateral parietal occipital attening (Figure 1). In addition to facial asymmetry that occurs with CMT, atypical postural and gross motor development results from the persistent head tilt and the infants perception of his or her environment. Young infants rely on neckrighting responses to manage antigravity movements and generate stabilizing postural control. Congenital muscular torticollis can alter the balanced base of support
Epidemiology, Plagiocephaly Association

The extent to which torticollis is present at birth is not well known, although older studies quote rates of torticollis of less than 1%. Many clinical studies have demonstrated that infants with CMT have an increased incidence of other deformations, such as metatarsus adductus and developmental dysplasia of the hip, to the degree that many authors recommend screening for developmental dysplasia of the hip in children with torticollis. (1) In more recent studies, rates of torticollis of 0.3% to 3.92% have been reported in infants with more severe neck involvement or presence of an SCM muscle tumor. One recent prospective study by Stellwagen et al (2) identied that as many as 16% of newborns have evidence of torticollis at birth, making CMT the most common congenital musculoskeletal abnormality. The increase in multiple births due to advanced fertility treatments has resulted in an increase in CMT incidence. (3) Several risk factors have been associated with the development of positional plagiocephaly (symmetrical or asymmetrical occipital attening), including torticollis. After the implementation of the Back to Sleep campaign in 1992, the number of infants with positional plagiocephaly increased markedly. It is commonly believed that supine positioning is the major cause of occipital attening, but most infants who sleep on their backs do not develop clinically signicant occipital attening. Another theory postulated that the deformation began in utero and the congenitally at area is the surface on which the infant would prefer to lie; however, no correlation between cranial asymmetry at birth and subsequent occipital attening has been found. The most common associated nding in infants with positional plagiocephaly is torticollis. In a recent prospective case series, Rogers et al (4) determined that although more than 90% of infants with positional plagiocephaly were noted to have preferential head positioning with head rotational asymmetry (ie, torticollis), only 24% of infants had been previously diagnosed as having or treated for torticollis, indicating that the incidence of torticollis is underreported and underdiagnosed in infants with positional plagiocephaly.
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Figure 1. Features of asymmetry related to plagiocephaly in a 4-month-old infant.
or the interaction between deep and supercial muscle groups. The postural abnormalities with infants with CMT include shoulder hiking and lateral side bending on the shortened side. Visual gaze is often oriented toward the side of head turning, further reinforcing the head turning toward the affected side. For infants with developmental delays, plagiocephaly and associated CMT are more common because they are not able to move normally to prevent attening and the perpetuation of positioning preference. One associated hypothesis suggests that muscle mechanics are altered in the presence of CMT. The oblique abdominal muscles act as rib stabilizers to assist shoulder girdle and arm stability and function. Shoulder girdle muscles that take their origins from the rib cage require a stable base to function normally. The shoulder girdle and rib cage complex, as the insertion point for many major neck groups, including the clavicular portions of the SCM muscle, contributes to and is affected by poorly coordinated neck muscular activity. (6) On the basis of studies that have found an association between CMT and gross motor delays, another theory suggests that some infants with CMT have hypotonia or low muscle tone, which may have predisposed them to poor intrauterine positioning in the rst place. Other areas of development have been noted to be delayed in some infants with CMT, including problem solving, personal-social interaction, ne motor control, and communication. This effect could be due to the inability of infants with CMT with weaker truncal strength to access their environment and stimulate all the realms of development or another underlying cause of global
developmental delay. In older children and adults with uncorrected CMT, craniofacial deformities may persist, resulting in obvious facial asymmetry. Facial bone asymmetry starts to appear at age 5 years, at which time mandibular and occlusal abnormalities are observed. Deformity of the orbits and maxilla occur at an older age, characterized by the deviation and decreased vertical height on the affected side. The severity of the observed deformities may increase with age. Older children with uncorrected CMT have been noted to have more school problems and require more special education services, although the reason for this association is unclear. The most often identied concern by parents of these children relates to the childs craniofacial appearance and the possibility that he or she will be teased, embarrassed, or otherwise stigmatized because of the condition. It is possible that the childs psychological development is affected by the condition and results in poorer academic performance. In adults with untreated CMT, the resultant facial asymmetry has sometimes led to attempts at corrective surgery by plastic surgeons or maxillofacial surgeons. These attempts have led to improvement of the facial asymmetry but have rarely resulted in complete correction. Although descriptions of adults with untreated CMT have focused largely on the cosmetic issue of facial asymmetry, extrapolating from the gross motor decits identied in childhood, one could postulate that adults with untreated CMT have more neck and upper body truncal motor issues, such as weakness or stiffness, which may result in postural or alignment dysfunction and can lead to chronic neck and back issues.
Assessment of CMT in the Primary Care Ofce

In the primary care ofce, the child health practitioner should have a high index of suspicion for CMT if the birth history is remarkable for difcult labor or delivery, decreased fetal movement, oligohydramnios, large infant birthweight, breech position, or multiple births (usually affecting the infant who is bottom-most in the uterus). (7) In infants with CMT, the mothers often report that the fetus stayed in one position during the pregnancy and that the back was always on the same side. On physical examination, the asymmetric sequelae of CMT may be more obvious than the limited range of motion of the neck, particularly in newborns with short necks. Plagiocephaly should be examined from the top of the head and will manifest as a mild attening of the forehead on one side and of the occiput on the opposite
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Figure 2. Characteristic features of torticollis. In the picture on the right, the tilting of the lower jaw and gum line are evident on physical examination. In this infant, the tilting of the lower jaw resulted in breastfeeding problems, prompting a visit to the pediatrician. Illustration, left: Copyrighted 2014. Advanstar. 107408:114AT. Image, right: Wall V, Glass R. Mandibular Asymmetry and Breastfeeding Problems: Experience From 11 Cases. J Hum Lact. 2006;22(3):328-34. 2006 by SAGE Publications. Reprinted by Permission of SAGE Publications.
side (Figure 1). Misalignment of the eyes, asymmetry of the ears, attening of the mandible, and tilting of the lower jaw and gum line (more obvious when the lower gum line is compared with the upper one) are all characteristic features of torticollis (Figure 2). A small number of infants with CMT may present a diagnostic dilemma if they have bilateral torticollis. These infants present with range of motion impairments on both sides, one side being worse than the other. This diagnosis is often missed because infants with bilateral torticollis usually do not present with an obvious head tilt. In these cases, the discrepancy between right and left is not so large because both are limited. These do not present with obvious plagiocephaly but may present with brachycephaly (attening and widening of the back of the head) instead. For example, if the infant has limited end-range rotation on both sides, the head will function more or less positioned midline, with perhaps a slight bias toward mildly rotating to one side (Figure 3).
Many child health practitioners miss the diagnosis of CMT because if it appears the child can generally look both ways, it is concluded that they do not have torticollis. In fact, most infants who have torticollis can look both ways to some degree, and the typical impairment in CMT is lacking full range of motion on one side. Child health practitioners should be aware that the range-of-motion norms for infants and children younger than 3 years differ from older children and adults. In older children and adults, full cervical passive range of motion in rotation is 90 (chin to shoulder); however, in children from birth to age 3 years, full passive range of motion in rotation is 100 to 110 (the degree to which someone else can rotate the infants chin 10 to 20 past the shoulder). In older children and adults, full cervical passive range of motion in lateral exion is 45; however, in children between birth and age 3 years, it is between 65 and 75 (in general, the top of the ear should be able to touch the ipsilateral shoulder). If decreased range of motion persists despite several weeks of physical therapy, imaging studies may be considered.
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Figure 3. Measurements of a 4-month-old infant with bilateral torticollis greater on the right side than the left side. This infant presents with bilateral impairments in active and passive range of motion. The primary impairments are limited right rotation and left lateral exion, both of which correlate with restriction of the right sternocleidomastoid muscle. AROM[active range of motion; Lrot[left rotation; Lsb[left side bend; PROM[passive range of motion Rrot[right rotation; Rsb[right side bend.
Initial Management of CMT

Most cases of CMT can be successfully treated conservatively with neck-stretching exercises if diagnosed early enough. These exercises include encouraging the infant to visually regard objects on the less preferred side, placing the infant in the crib so that the door is on the less
preferred side, and holding the infant in such a way so that facing outward is the less preferred side. Most child health practitioners are adept at giving parents such strategies. Passive neck-stretching exercises are more difcult for child health practitioners to demonstrate to parents and equally difcult for parents to perform successfully at home. The recommendation for effective neck-stretching exercises is to hold each stretch for 30 to 60 seconds, to do 3 repetitions of each stretch, and to do the series of stretches 6 to 8 times a day. Ideally, a stretching period should take approximately 5 to 10 minutes, depending on the cooperative ability of the infant. Engagement with the infant is crucial for making the stretching exercises effective and enjoyable for the caregiver to perform. Many times, child health practitioners and even some physical therapists hand parents a worksheet of instructions and expect parents to gure out how to do the exercises themselves. Many parents are intimidated by the level of protest of the infant and are concerned that the exercises might be painful. In addition, many parents do not carry out the exercises effectively for fear of injuring the infant. A physical therapist experienced in treating CMT will be able to provide proper guidance so that parents can implement the exercises effectively and safely, while engaging with the child in a positive manner. In the cases of infants who are in child care, nonparental caregivers should be educated to conduct the exercises as well. These exercises are much easier to perform in younger infants and infants who are engaged with the caregiver performing the exercises. As infants grow bigger and have more desire for independent movement, it can be challenging for parents to perform the exercises effectively and as frequently as recommended. The stretching exercises should be performed to stretch the appropriate SCM muscle and should be based on physical examination to identify the specic muscle impairments, not parents subjective reports of tilt or turning preferences. However, in cases with unilateral SCM muscle restriction, the unaffected side may have excessive exibility. For this reason, child health practitioners should not default to instructing parents to perform exercises to both sides of the neck because this could cause a larger discrepancy in the exibility of the 2 SCM muscles, thus resulting in a more severe tilt. Because of the challenges of teaching parents how to do the exercises appropriately and giving general positioning advice that could possibly worsen plagiocephaly or result in new head deformities, early referral to physical therapy, even for a brief period, is prudent.
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It is commonly observed that infants with CMT who are undergoing a stretching exercise program may have periods of regression after observed progress. These periods of regression appear to be associated with growth spurts. It is hypothesized that the SCM muscle on the affected side may not grow or develop at the same rate as on the uninvolved side, creating a risk of return of contracture. During periods of illness, teething, and acquisition of new motor functions, regression to the torticollis posture could also occur. Child health practitioners in the primary care ofce must also counsel on sleep positioning and tummy time as part of the treatment for CMT. Given the strong association between prone sleep positioning and sudden infant death syndrome, it is advisable to position infants on their backs for sleep, except in cases of prematurity, gastroesophageal reux, or obstructive sleep apnea. The key to effective management is to position infants in the supine position, with regular variation in the position of the infants head to avoid undue attening. Encouraging tummy time when infants are awake and under observation may help to minimize these differences in normal motor development by strengthening the infants neck muscles and facilitating prone motor activities. Because most supine-sleeping infants are unused to viewing their world from the stomach, they need this visual experience to facilitate their motor development. Giving infants adequate tummy time while they are awake is also important to facilitate development of head turning while prone as a key protective mechanism in case the infant turns from supine to prone during sleep. Infants with CMT may have a more difcult time with tummy time because of slower gross motor development or overall neck muscle tightness and/or weakness. Parents should be counseled to encourage tummy time despite infant protests and put infants in a prone position frequently throughout the day for as short as 1 to 2 minutes at the beginning. Parents who are concerned about head positioning may inquire about various sleep positioners or other positioning or pillow products on the market. Often, these are shaped like donuts and claim to take the pressure off of the at spot so your babys head can round out as it grows. Although the Food and Drug Administration and the Consumer Product Safety Commission have warned against the use of infant sleep positioners because of suffocation risk, use of these products inherently misses the point that infants should be spending awake hours in the prone position under adult supervision. In addition, many parents now use car seats that
also serve as infant carriers, many of which fasten directly into strollers and swings without having to remove the infant from the seat, resulting in infants who spend prolonged periods in one position. For infants at risk for CMT or plagiocephaly, car seats should be used only for safety reasons in moving vehicles rather than convenience.
Referral to Physical Therapy

Early intervention is crucial for successful treatment of both CMT and resulting positional plagiocephaly. The earlier infants are identied and treated with effective stretches and strategies, the shorter the duration of treatment necessary to achieve full range of motion of the neck and resolution of the plagiocephaly. The goal is to avoid expensive or invasive interventions, such as cranial orthotics (helmets) or surgery. Several studies have documented the effectiveness of physical therapy in treating CMT and plagiocephaly and avoidance of cranial orthotics or surgery (Figure 4). The challenge of the primary care ofce in effectively treating CMT is the inability to quantitate progress with stretches and strategies by parents. Often, parents will not disclose that they are not doing the exercises as frequently (or at all) as recommended by the child health practitioner, or parents do not want to subject their young infant to exercises and think that waiting until the infant is older or bigger is better. Early referral to a physical therapist can institute effective stretching of the affected SCM muscle by a trained and experienced professional. In addition to ensuring that the infant is getting effective stretching for at least
Figure 4. Correction of plagiocephaly with positioning techniques in a 6-week-old infant who was identied and referred to an infant specialist physical therapist. In 5 weeks, signicant cosmetic improvement is achieved without the use of a cranial orthotic.
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some period, the physical therapist can also demonstrate and teach the caregiver how to perform the exercises so that the exercises at home are more effective as well. In addition, given the likelihood of additional motor delays associated with the diagnosis of CMT, involvement of a physical therapist can address these issues as well. Child health practitioners should try to identify a physical therapist who has experience working with infants. General physical therapists who work primarily with adults or even pediatric physical therapists who tend to work with school-aged children with sports injuries or neurologic problems may not have the expertise to treat CMT in infants. If CMT persists after 6 months of physical therapy, then additional workup should be considered to evaluate for other potential causes, such as congenital vertebral malformations. Such a workup may include anteroposterior and lateral plain radiographs of the cervical spine and the lateral skull, ophthalmologic examination, and magnetic resonance imaging of the cervical spine (as well as renal ultrasonography and echocardiography if congenital vertebral anomalies are being considered).
Botulinum Toxin Injections and Surgical Treatment of SCM Muscles

Botulinum toxin (Botox) has been used to enhance the effectiveness of stretching on the side of the contracture and allow strengthening of overstretched and weakened muscles on the opposite side of the neck. In severe cases of CMT that are refractory to conservative management with stretching exercises or cases of CMT that were identied or treated in older infants or toddlers, surgical intervention of the SCM muscles may be necessary. Surgery is indicated if symptoms persist after age 1 year despite conservative treatment. An alternative criterion for surgical intervention is the presence of residual deficits in rotation range of greater than 15 of rotation after at least 6 months of controlled manual exercises. Surgical techniques to lengthen tight SCM muscles include unipolar release, bipolar release, endoscopic release, and subperiosteal lengthening. Postoperative physical therapy consisting of range-of-motion exercises is recommended after surgical release of the SCM muscles.
to the infant when he or she tilts in the preferred direction, thus prompting a neuromuscular response to correct for the tilt. Neither therapy tool should be used until it is determined by a physical therapist that the child is demonstrating age-appropriate signs of motor readiness to respond to it optimally. Some infants with CMT have coexisting deformational plagiocephaly severe enough to warrant use of a cranial remolding orthosis. The duration of treatment with a cranial remolding orthosis could be longer if the torticollis has not resolved and the infant has residual limitations in cervical range of motion. However, until recently, many parents had difculty getting cranial orthotics covered by insurance because of lack of appropriate billing codes and the misperception that plagiocephaly was a cosmetic (and not medical) condition. The average cost of a cranial remolding orthosis is several thousand dollars, and not infrequently, infants will require more than one orthosis as the head grows during the time of remolding. The use of cranial orthoses for the treatment of plagiocephaly remains somewhat controversial in both overall effectiveness and cost-effectiveness of this intervention. No prospective randomized controlled trials have yet been conducted comparing the efcacy of cranial orthoses to repositioning and physical therapy.
Summary
On the basis of observational studies, child health practitioners in primary care settings should consider the diagnosis of congenital muscular torticollis (CMT) in infants with risk factors from birth history for intrauterine malpositioning or constraint (C). On the basis of observational studies, CMT is often associated with other conditions, including positional plagiocephaly and gross motor delays from weakened truncal muscles and/or lack of head control in early infancy (C). On the basis of observational studies, child health practitioners should counsel parents that infants should be on their stomachs frequently whenever they are awake and under direct adult supervision to develop their prone motor skills (C). On the basis of consensus, early identication of CMT (with or without positional plagiocephaly) and prompt referral to a physical therapist experienced in the treatment of CMT should be considered to avoid more costly or invasive treatments, such as cranial orthoses or surgery (D).
Cranial Orthotics and Other Devices

For children with CMT whose lateral tilt does not resolve with exercises alone, 2 treatment adjuncts exist: tubular orthosis for torticollis collar and elastic therapeutic tape. These therapy tools provide increased sensory feedback
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ACKNOWLEDGMENTS. The authors would like to thank Mina Kang, MD, and Christopher Thrash, MD for their thoughtful review of the manuscript.
4. Rogers GF, Oh AK, Mulliken JB. The role of congenital muscular torticollis in the development of deformational plagiocephaly. Plast Reconstr Surg. 2009;123(2):643652 5. Graham JM Jr. Congenital muscular torticollis. In: Recognizable Patterns of Human Deformation. 3rd ed. Philadelphia, PA: Elsevier; 2007:130-140. 6. Hylton N. Infants with torticollis: the relationship between asymmetric head and neck positioning and postural development. In: Karmel-Ross, ed. Torticollis: Differential Diagnosis, Assessment and Treatment, Surgical Management and Bracing . New York, NY: Haworth Press; 1997: 91-117. 7. Littleeld TR, Kelly KM, Pomatto JK, Beals SP. Multiplebirth infants at higher risk for development of deformational plagiocephaly, II: is one twin at greater risk? Pediatrics. 2002; 109(1):1925
References
1. von Heideken J, Green DW, Burke SW, et al. The relationship between developmental dysplasia of the hip and congenital muscular torticollis. J Pediatr Orthop. 2006;26(6):805808 2. Stellwagen L, Hubbard E, Chambers C, Jones KL. Torticollis, facial asymmetry and plagiocephaly in normal newborns. Arch Dis Child. 2008;93(10):827831 3. Littleeld TR, Kelly KM, Pomatto JK, Beals SP. Multiple-birth infants at higher risk for development of deformational plagiocephaly. Pediatrics. 1999;103(3):565569

English: http://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Positional-Skull-
Deformities-and-Torticollis.aspx
English: http://www.healthychildren.org/English/ages-stages/baby/Pages/Positional-Skull-Deformities-in-Infants-Audio.aspx English: http://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Head-Tilt.aspx Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/head-neck-nervous-system/paginas/head-tilt.aspx
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1. At her 2-month health maintenance examination, you note the head of your patient is turned to the right, and her occiput tilts toward her left shoulder. Her remaining examination ndings are normal. The MOST LIKELY explanation is: A. B. C. D. E. Cervical vertebral anomaly. Hiatal hernia. Injury to the sternocleidomastoid muscle. Intrauterine nystagmus. Weakness of the extraocular muscles.
2. A 5-month-old boy has a somewhat attened left occiput and a slightly asymmetric skull when you look down from above. These ndings are MOST LIKELY explained by: A. Back to Sleep campaign. B. Cervical vertebral anomalies. C. Congenital muscular torticollis. D. Hiatal hernia. E. Intrauterine deformation of the skull. 3. The MOST RELIABLE diagnostic feature of congenital muscular torticollis in a 4-month-old infant is: A. B. C. D. E. Asymmetry of the skull from above. Deformity of the orbit. Inability to turn head both ways. Leg length discrepancy. Occlusal abnormality.
4. A 2-month-old infant has mild positional plagiocephaly. Aside from recommending enhanced tummy time while awake, the MOST APPROPRIATE therapy at this time would also involve: A. Botulinum toxin injection. B. Elastic therapeutic tape. C. Neck-stretching exercises by parents. D. Prescription of a cranial orthotic. E. Tubular orthosis for torticollis. 5. A 4-month-old infant has moderate positional plagiocephaly that has so far not responded to tummy time and neck stretching exercises by his parents. At this time, the MOST APPROPRIATE intervention would be: A. Botulinum toxin injection. B. Continued neck stretching exercises by parents alone. C. Referral to a craniofacial surgeon. D. Referral to an experienced physical therapist. E. Tubular orthosis for torticollis.
Index of Suspicion Hana Niebur, Erjola Balliu, Marian Kim, Javeed Akhter, Rachel Boykan, Maribeth Chitkara, Ayse Bag-Ozbek, Ruba K. Azzam and Joseph Hageman Pediatrics in Review 2014;35;88 DOI: 10.1542/pir.35-2-88
Data Supplement at: http://pedsinreview.aappublications.org/content/suppl/2014/01/24/35.2.88.DCSupplementary_Data.htm l
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Case 1: Feeding Difculties and Failure to Thrive in an Infant Case 2: Right Upper Quadrant Pain in a 17-Year-Old Girl Case 3: Conjugated Hyperbilirubinemia in an 11-Month-Old Boy
Case 1
The reader is encouraged to write possible diagnoses for each case before turning to the discussion.
Presentation
The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire rst by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu.
Author Disclosure Drs Niebur, Akhter, Balliu, Bag-Ozbek, Boykan, Chitkara, Kim, Azzam, and Hageman have disclosed no nancial relationships relevant to this article. This commentary does not contain discussion of unapproved/investigative use of a commercial product/device.
A 3-month-old African American girl presents with new-onset irritability and a 1-month history of nonbloody, nonbilious emesis. She also has persistent thrush despite treatment with oral application of nystatin. Her mother is concerned because the infant has lost weight during the past month. The girl was born vaginally at term after an uncomplicated pregnancy with birth weight at the 50th percentile. Her birth was complicated by suspected fetomaternal hemorrhage, and she required a blood transfusion. After hospital discharge, she continues to be anemic and is taking a multivitamin with iron. She has received her 2-month immunizations, including rotavirus vaccine. Family history is noncontributory. She lives at home with her parents and older half-sister and does not attend daycare. Physical examination reveals a very thin, fussy, but consolable infant. The vital signs are within normal limits for age, but weight is below the fth percentile. White plaques with an erythematous base are observed on the tongue, gingiva, and oral mucosa. The remaining physical examination ndings are normal. Laboratory testing reveals normal values for complete metabolic panel, amylase, and lipase. Complete blood cell count reveals normocytic anemia with a hemoglobin level of 7.3 g/dL (73 g/L) and a hematocrit of 23.1% (0.23). Platelet counts are elevated at 712 103/mL (712 109/L). Total white blood cell count is normal,
but the differential reveals lymphopenia, with an absolute lymphocyte count of 1,400/mL (1.4 109/L). The girl is hospitalized for further evaluation. An upper gastrointestinal tract series demonstrates esophageal lumen irregularity. Further procedures and laboratory evaluation reveal the diagnosis.
Case 2
Presentation
A 17-year-old girl presents with a 5day history of right upper quadrant (RUQ) pain, sharp and colicky in nature, radiating to the back and shoulders. There is no history of fever, cough or cold symptoms, vomiting, diarrhea, dysuria, frequency, or hematuria. Medical history is unremarkable. Menarche was at age 10 years. The patient is sexually active with one partner. Medications include oral contraceptive pills. Immunizations are up to date. Family history is signicant for nephrolithiasis. On physical examination she is alert and in mild distress, secondary to pain. Vital signs are as follows: temperature, 99.7F (37.6oC); heart rate, 98 beats per minute (baseline, 60 beats per minute); blood pressure, 139/65 mm Hg (baseline, 100/60 mm Hg); respiratory rate, 18 breaths per minute; and oxygen saturation, 100% on room air. On abdominal examination, she has marked RUQ tenderness, no costovertebral angle tenderness, and negative Murphy, psoas, and obturator signs. Pelvic examination reveals a nulliparous cervix without discharge or cervical motion tenderness, nontender fundus, and
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nontender and nonpalpable adnexa. The ndings of the rest of her examination are normal. Results of initial investigations, including chest radiograph, RUQ ultrasonography, and computed tomography of the abdomen and pelvis, are normal. Complete blood cell count, complete metabolic panel, and serum amylase and lipase levels are normal. Serum b-human chorionic gonadotropin test result is negative. Urine analysis reveals large ketones, trace blood and protein, excess of 180 white blood cells per high-power eld, and 4 red blood cells per high-power eld. The patient is treated with intravenous uids and ceftriaxone for a presumptive diagnosis of pyelonephritis. Despite this treatment, her pain continues, requiring parenteral analgesics. The urine culture result is negative. Subsequent urine analysis reveals persistence of pyuria. A subsequent ultrasonogram and the results of pending studies reveal the diagnosis.
has moderate ascites. His muscle mass appears thin. Laboratory results include the following: hemoglobin, 9.7 g/dL (97 g/L); mean corpuscular volume, 82 mm (82 fL); platelet count, 246 103/mL (246 109/L); prothrombin time, 17 seconds; international normalized ratio, 1.3; albumin, 3.1 g/dL (31 g/L); total bilirubin, 12 mg/dL (205 mmol/L); direct bilirubin, 7.9 mg/dL (135 mmol/L); alanine aminotransferase, elevated at 204 U/L; aspartate aminotransferase, elevated at 325 U/L; and g-glutamyl transpeptidase, elevated at 115 U/L. Abdominal ultrasonography reveals the diagnosis.
Case 1
Discussion
Case 3
Presentation
An 11-month-old Middle Eastern boy is referred to our clinic for evaluation. He has a history of jaundice beginning at age 2 days. The pregnancy and perinatal course were unremarkable. He has been evaluated at the referring center beginning at age 3 months and has a long, complicated clinical course. There is no family history of liver disease. Physical examination reveals a boy who appears small for age, with a weight below the third percentile and both length and head circumference at the 10th percentile. He has scleral icterus and yellow discoloration of the skin. His abdomen is soft but distended with a rm and enlarged liver (6 cm below the costal margin) and palpable spleen (also at 6 cm below the costal margin). He
The differential diagnosis of failure to thrive encompasses a broad spectrum of disease processes and psychosocial issues. However, when failure to thrive is accompanied by recurrent or opportunistic infections, immunodeciency disorders must be considered. In this case, the upper gastrointestinal tract series was followed by esophagogastroduodenoscopy, which visualized diffuse esophagitis with erosions and white plaques. Brushings of the lesions conrmed esophageal candidiasis, an opportunistic infection frequently due to T-cell dysfunction. Immunologic evaluation included serum quantitative immunoglobulin levels, which revealed normal IgG and low IgA and IgM levels for the girls age, and tests for human immunodeciency virus (enzyme immunoassay and DNA PCR), which had negative results. Lymphocyte subset analysis by ow cytometry demonstrated absent T lymphocytes with normal numbers of B and natural killer (NK) cells, suggestive of a T-cell immunodeciency, such as complete
DiGeorge syndrome or severe combined immunodeciency (SCID). Genetic testing revealed a mutation in the interleukin 7a receptor, conrming the diagnosis of SCID. Primary immunodeciency diseases comprise a spectrum of phenotypes based on the part of the immune system affected. The immune system is composed of 2 main branches: the innate and adaptive immune systems. The innate immune system is the rst line of defense against pathogens, whereas the adaptive immune system can tailor and retain its response against specic microbes to provide specicity and memory. The innate immune system includes NK cells, neutrophils, macrophages, and complement. It reacts to common microbial motifs and products of tissue injury without specicity or memory for a particular antigen. Defects result in difculty with clearing and containing bacterial and fungal infections. Abscesses, granulomas, and poor wound healing are frequent complications of phagocytic defects. Complement deciencies often result in recurrent sinopulmonary infections or sepsis with encapsulated bacteria. Adaptive immunity has 2 components: humoral and cellular immunity. Adaptive immunity generates lymphocytes capable of gene rearrangement to elicit stronger immune responses and transformation into long-lived memory cells that are capable of quick reactivation on reexposure to the same antigen. B lymphocytes produce antibodies against specic antigens. However, B cells depend on T-cell help to mount a robust response. In addition to contributing to humoral immunity, T lymphocytes destroy cells infected by intracellular bacteria, viruses, and fungi as part of cellular immunity. Although defects in B cells can result in severe bacterial infections, T-cell abnormalities affect cellular and humoral
index of suspicion
immunity, resulting in serious bacterial, fungal, and viral illnesses.
incorporate SCID screening into mandatory newborn screening.
The Condition
SCID occurs in approximately 1 in 30,000 to 1 in 70,000 live births. Boys are more often affected than girls because of the high incidence of X-linked inheritance. Autosomal recessive inheritance and de novo mutations also occur. SCID results from absence or impaired function of T lymphocytes and may involve B- and/or NK-cell absence or dysfunction. In SCID, both the cellular and humoral immune systems are affected, predisposing the patient to a variety of serious infections, including persistent or recurrent pneumonia, otitis media, and sepsis. Those affected are also at risk of opportunistic infections with Candida, Pneumocystis jiroveci, and viruses. Affected individuals often have failure to thrive. Family history may include siblings who died in infancy. Evaluation must be performed in conjunction with a clinical immunologist. Lymphocyte subset analysis by ow cytometry can determine whether T, B, and NK cells are present. Immune function must also be examined. T-lymphocyte function may be studied using in vitro proliferation assays and NK-cell function determined by cytotoxicity assays. The serum IgG level is an indicator of B-cell function only after age 3 to 6 months because of placental transfer of maternal antibody during the third trimester. For infants older than 6 months, isohemagglutinins can be tested to verify specic antibody production. In vaccinated children, antibody titers to diphtheria, tetanus, and Haemophilus inuenzae type b are reliable measures of B-cell function. Genetic testing can conrm suspected mutations. Identication of affected infants before serious infections is possible as more states
Management
Initial treatment for SCID involves prophylaxis against infections, typically with acyclovir, azole antifungals, intravenous immunoglobulin, and pentamidine or trimethoprimsulfamethoxazole for Pneumocystis. Protective isolation is encouraged, and vaccination with live viruses is avoided. Vaccination of family members and avoidance of sick contacts are important. Daycare may pose a signicant risk of exposure to infections and should be avoided. Hematopoietic stem cell transplantation is potentially curative and can reconstitute the immune system, especially when HLA-identical, related donors are available. However, early recognition of SCID is imperative because survival decreases when transplantation is performed at an older age or during therapy for serious infections. Gene therapy and enzyme replacement therapy are also potential treatments. Without treatment, SCID is usually fatal by age 2 years. Our patient received intravenous uconazole with gradual improvement of her emesis and thrush. She was also prescribed prophylaxis with acyclovir, pentamidine, and intravenous immunoglobulin. She and her family underwent HLA typing, but no related donor was found. In the meantime, she had one episode of sepsis from a central catheter infection but recovered. She eventually underwent transplantation using HLA-matched umbilical cord blood and is doing well.
Common initial ndings include recurrent infections, failure to thrive, and lymphopenia. Prophylaxis, protective isolation, aggressive treatment of infections, and preparation for denitive therapy in conjunction with a multidisciplinary team are mainstays of treatment. Diagnosis of SCID before infections is crucial for improved outcomes. (Hana Niebur, MD, and Javeed Akhter, MD, Advocate Childrens Hospital-Oak Lawn Campus, Department of Pediatrics, Oak Lawn, IL)
Case 2
Discussion
Given the location of the patients pain, pyuria, and positive family history, she was initially suspected of having nephrolithiasis with pyelonephritis. After 3 days with no improvement in symptoms and persistent pyuria despite negative urine culture results, the concern for perihepatitis secondary to a sexually transmitted infection was raised and doxycycline therapy was started empirically. A subsequent sonogram revealed a perihepatic and pericholecystic uid collection and right pleural effusion. On the third hospital day, polymerase chain reaction assay of cervical uid was performed, and the results were positive for Chlamydia trachomatis. A clinical diagnosis of Fitz-Hugh Curtis syndrome (FHCS) was made. The patients pain resolved after starting treatment with doxycycline, and she was discharged home.
The Condition
Incidence and prevalence of FHCS are difcult to determine because of the varied clinical presentations and confusion with other diagnoses, most frequently cholecystitis and cholangitis. FHCS is thought to be a complication of pelvic inammatory disease (PID) in anywhere from 4% to 27% of
Lessons for the Clinician

Severe combined immunodeciency (SCID) is an immunologic emergency that requires prompt recognition and treatment.
index of suspicion
patients, depending on the diagnostic criteria used. Fitz-HughCurtis syndrome involves inammation of the liver capsule associated with genital tract infection in females; it is postulated that adolescents less mature anatomy may make them particularly susceptible to infection. The pathogenesis of FHCS is not well understood. The spread of bacteria from the genital tract to the liver capsule likely results from the circulation of abdominal uid over the right paracolic gutter to the subphrenic space and hepatic surface. However, lymphatic and hematogenous spread of bacteria may also occur. FitzHughCurtis syndrome has also been reported in men. Previously, Neisseria gonorrhoeae was thought to be the main causative agent. However, cases of FHCS due to C trachomatis infection now outnumber those due to N gonorrhoeae infection by almost 5:1. Most commonly, FHCS presents as sharp, pleuritic RUQ pain. Other symptoms include lower abdominal or epigastric pain; fever and/or vaginal discharge may or may not be present. On physical examination, signs of PID, such as cervical motion tenderness and adnexal or uterine tenderness, increase the suspicion for FHCS but are not always present. The differential diagnosis includes pyelonephritis, nephrolithiasis, cholecystitis, cholangitis, appendicitis, tubo-ovarian abscess, and perinephric and renal abscess. Perihepatitis can be denitively distinguished from other causes of RUQ pain only by directly visualizing the liver by laparoscopy or laparotomy. However, in most cases the diagnosis is established by clinical examination and identication of a pathogen, most commonly from cervical uid. Rectal, urethral, or pharyngeal uids can be tested as well. Culture is the gold standard, although nucleic acid amplication tests are becoming increasingly
popular because of their high sensitivity and specicity, rapid turnaround time, and ease of use. Liver enzyme levels are usually normal or only slightly elevated, which can help rule out hepatitis. Erythrocyte sedimentation rate has not been found to be useful in the diagnosis. White blood cell count may be normal or elevated. Imaging studies are not needed to diagnose FHCS but may be performed to clarify an otherwise ambiguous diagnosis. Ultrasonography is the study of choice for evaluating the gallbladder and liver and can exclude cholecystitis, cholelithiasis, and tubo-ovarian abscess. Certain ultrasonographic abnormalities support a diagnosis of FHCS, including perihepatic adhesions with associated uid in the abdominal cavity and an increase in the width of anterior extrarenal tissue due to inammation. Enhancement of the liver capsule on contrast computed tomography can also support the diagnosis. Surgical or laparoscopic exploration to visualize perihepatic adhesions is warranted only if symptoms do not resolve with therapy.
for 14 days, with or without metronidazole. If symptoms do not resolve after 72 hours of oral therapy or the therapy is not tolerated, the patient should be hospitalized. Recommended inpatient regimens include cefotetan or cefoxitin plus doxycycline or clindamycin plus gentamicin. There are alternatives recommended by the Centers for Disease Control and Prevention. Patients started on parenteral therapy may be transitioned to oral therapy on resolution of symptoms.
Complications
Most cases of FHCS resolve with proper treatment. Long-term complications of FHCS are similar to those of PID. In a recent study of adolescent and adult women with PID, followed up for 84 months, 42.7% of patients experienced chronic abdominal pain, 18.6% experienced infertility, and 21.3% had recurrent PID.

For sexually active females with right upper quadrant (RUQ) pain, Fitz-HughCurtis syndrome (FHCS) should be considered in the differential diagnosis. The diagnosis is usually made clinically by eliminating other causes of RUQ pain and isolating the pathogen. Computed tomography and RUQ ultrasonography may aid in diagnosis. Other laboratory studies are generally not helpful. With response to treatment with appropriate antibiotics, no further workup is indicated. The diagnosis of FHCS provides an opportunity for education and counseling about safe sex and should prompt the clinician to screen for other sexually transmitted diseases. (Erjola Balliu, Rachel Boykan, Maribeth Chitkara, Department of Pediatrics, Stony Brook Long Island Childrens
Management
The management of FHCS is similar to that of PID. Most patients can be treated as outpatients, although hospitalization is recommended if the patient is pregnant; a potential candidate for surgery; severely ill with nausea, vomiting, or high fever; or has a tubo-ovarian abscess. Immunocompromised patients and those unable to tolerate oral medications should also be hospitalized. Antibiotics must be directed against C trachomatis and N gonorrhoeae, as well as anaerobic pathogens, because PID and FHCS are often polymicrobial. For patients with mild to moderate symptoms, parenteral and oral therapies appear to work equally well. Outpatient treatment consists of a single dose of ceftriaxone plus doxycycline
index of suspicion
Hospital, Stony Brook, NY; Ayse BagOzbek, Department of Medicine, Columbia University Medical Center, New York, NY)
Case 3
Discussion
Abdominal ultrasonography revealed a choledochal cyst. The patient was diagnosed as having end-stage liver disease with biliary cirrhosis secondary to obstructive choledochal cyst. When we reviewed his medical history, we found that at his initial presentation at the referring center at age 3 months he had infrequent medical care for jaundice and acholic stools. He had a poor diet and slow weight gain. He had bowel movements 4 times a day, and his stools were clay colored and pasty. His jaundice was persistent. He had severe itching, and his neurobehavioral development was slow. There was no history of fever, hematemesis, or melena. His initial laboratory evaluation revealed conjugated hyperbilirubinemia (direct bilirubin, 4.3 mg/dL [74 mmol/L]). At age 4 months, a liver biopsy specimen revealed proliferation of the ducts and stage 3 to 4 brosis. A hepatobiliary iminodiacetic acid scan, which may be helpful in determining patterns of excretion and identifying obstructive disease, was inconclusive for uptake and excretion in our patient. A small choledochal cyst was missed on the abdominal ultrasonogram, and the gall bladder looked contracted. The results of tests for progressive familial intrahepatic cholestasis, a rare autosomal recessive liver disease, were negative. At age 6 months he had 2 episodes of melena. He had multiple episodes of worsening ascites, which were treated with albumin and diuretics. He also had bacteremia and peritonitis at age 8 months. Subsequently, cirrhosis led to portal hypertension and esophageal varices,
which were treated with sclerotherapy procedures. He underwent living related donor (mother) liver transplantation. Pathologic evaluation of the liver explant revealed type 4a choledochal cyst with involvement of the extrahepatic and hilar intrahepatic ducts (Figure).
The Condition
Choledochal cyst is a rare condition that involves congenital dilatation of the intrahepatic and/or extrahepatic biliary tree. The incidence has been estimated to be 1 in 13,000 to 1 in 2,000,000 live births in western countries; most cases have been reported in Japan, where the incidence is as high as 1 in 1,000 live births; and it is found more commonly in females (4:1). A choledochal cyst may be detected at any age and in any portion of the bile duct. Cysts are present in up to 2% of infants with obstructive jaundice. The cause is unclear, but the most commonly accepted theories include failure of the biliary tree to canalize during fetal development and reux of pancreatic enzymes into the common bile duct, causing injury and dilation. There are 5 types of choledochal cysts, originally described by Vater
in 1723, categorized by Alonzo-Lej in 1959, and modied by Todani in 1977. Type 1 involves dilation of the extrahepatic biliary tree and is most common, followed by type 4, which involves intrahepatic and/or extrahepatic dilatation of the biliary tree. The classic clinical presentation includes RUQ pain, abdominal mass, and jaundice, but this triad is rarely seen. Jaundice is the most common presenting symptom in neonates, whereas abdominal pain is more common in older children. Neonates may also be asymptomatic or have a clinical picture similar to biliary atresia (prolonged jaundice, cholestasis, pale colored stools, and dark urine). Prolonged obstruction results in biliary cirrhosis and portal hypertension.
Diagnosis
Neonates and infants with persistent, direct hyperbilirubinemia require prompt evaluation for anatomical causes of biliary tract obstruction. The spectrum of obstructive neonatal biliary tract conditions ranges from extrahepatic biliary atresia to cystic changes in the extrahepatic and/or intrahepatic biliary tract. Ultrasonography can conrm the clinical suspicion of choledochal cysts by
Figure. Gross pathologic evaluation of the liver reveals green tubular structures that represent choledochal cysts.
index of suspicion
providing information about size, shape, and location of the cyst, although small cysts may be difcult to visualize. Antenatal ultrasonography has been useful in early diagnosis and for arranging immediate neonatal surgical intervention and can detect choledochal cysts as early as the second trimester. The classic ultrasonogram ndings for a choledochal cyst include biliary ductal dilatation and cysts. Magnetic resonance cholangiography may help better delineate the biliary tree and the choledochal cyst characteristics. Delayed diagnosis has been attributed to misdiagnosis as hepatitis, incomplete investigation of abdominal pain or pancreatitis, and indeterminate ultrasonographic ndings. A delay in diagnosis may lead to cholangitis, pancreatitis, biliary cirrhosis, cyst rupture, malignant degeneration, or other complications as seen in this patient. There is a well-established association between choledochal cyst and malignant tumor, with an incidence as high as 30%, typically adenocarcinoma of the bile duct, and less commonly cholangiocarcinoma.
In cases with complete cyst excision, the cancer risk is nearly zero. Therefore, early recognition and appropriate surgical treatment that includes complete cyst excision are imperative.
may occur in up to 15% of patients after surgery, although in other cases early liver brosis may resolve and liver function may improve after surgery.

Prolonged jaundice in an infant demands a prompt and thorough evaluation. Although relatively rare, choledochal cyst is important to be considered in the differential diagnosis of prolonged jaundice. Early detection by ultrasonography and prompt referral to a pediatric gastroenterologist and surgeon can have a signicant effect on outcomes. (Marian Kim, MD, and Ruba K. Azzam, MD, University of Chicago, Comer Childrens Hospital, Chicago, IL; Joseph Hageman, MD, Evanston Hospital, North Shore University Health System, Evanston, IL) To view Suggested Reading lists for these cases, visit http://pedsinreview. aappublications.org and click on the Index of Suspicion Link.
Management
Complete excision of the choledochal cyst mucosa with reconstruction to provide biliary drainage via a Roux-en-Y choledochojejunostomy is generally considered the therapy of choice, when possible. Choledochal cyst surgery in infants and asymptomatic patients is considered safe. Because progressive changes have been found to take place as early as the rst days of life, immediate surgical repair has been recommended to halt the progression of disease and avoid complications related to cyst infection and progressive liver disease. In addition, the average operating time for neonates is shorter, with a lower complication rate than in older children. Prognosis depends on early diagnosis, complete excision of the cyst, and surgical reconstruction. Cholangitis

Case 1: Feeding Difculties and Failure to Thrive in an Infant
English: http://www.healthychildren.org/English/ages-stages/baby/feeding-nutrition/Pages/Signs-of-Feeding-Difculties.aspx Spanish: http://www.healthychildren.org/spanish/ages-stages/baby/feeding-nutrition/paginas/signs-of-feeding-difculties.
aspx
English: http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Failure-to-Thrive.aspx Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/chronic/paginas/failure-to-thrive.aspx
Case 3: Conjugated Hyperbilirubinemia in an 11-month-old Boy

English: http://www.healthychildren.org/English/news/Pages/AAP-Issues-Guidelines-for-Care-of-Infants-in-Planned-
Home-Births.aspx
Answer Key for February 2014 Issue: Muscle Disease: 1. C; 2. C; 3. B; 4. D; 5. E. Autism: 1. B; 2. A; 3. B; 4. D; 5. E. Torticollis: 1. C; 2. C; 3. A; 4. C; 5. D.
Index of Suspicion Hana Niebur, Erjola Balliu, Marian Kim, Javeed Akhter, Rachel Boykan, Maribeth Chitkara, Ayse Bag-Ozbek, Ruba K. Azzam and Joseph Hageman Pediatrics in Review 2014;35;88 DOI: 10.1542/pir.35-2-88
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Mastoiditis Maya Bunik Pediatrics in Review 2014;35;94 DOI: 10.1542/pir.35-2-94
in brief
In Brief
Mastoiditis
Maya Bunik, MD, MSPH University of ColoradoDenver, Aurora, CO mechanism of spread to mastoid air cells is by direct erosion of bone or through the mastoid emissary veins. Impaired air cell drainage in this context causes mastoiditis. Incidence is low and varies, depending on geographic areas and the rate of treated bacterial otitis media. It is most common in children younger than 2 years. Clinical presentation most predictive of mastoiditis includes symptoms of ear pain, fever, and signs of postauricular swelling, tenderness, and erythema. A uctuant mass can cause anterior displacement of the auricle. Duration of symptoms, before diagnosis and treatment, averages 10 days. More than 80% of children have a bulging or perforated tympanic membrane by otoscopic visualization. Diagnosis is made by recognizing the clinical constellation above along with a radiologic evaluation most commonly by computed tomography but also by magnetic resonance imaging. Some common radiologic ndings are the loss of denition of the bony septae that dene the mastoid air cells along with soft tissue swelling. Pediatric patients most often have laboratory evidence on complete blood cell count of an elevated white blood cell count with an increase in immature neutrophils (a left shift). The most common bacterial cause remains Streptococcus pneumoniae, even in the postpneumococcal conjugate vaccine era. Other organisms include Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pyogenes, and Haemophilus inuenzae. Treatment usually includes both systemic antibiotics and surgical drainage. In terms of antibiotics, rst choice for those without a history of chronic otitis should be intravenous ceftriaxone plus clindamycin, pending culture. More than 50% of children have been taking antibiotics, usually for otitis, at the time of admission. If the child has had a history of recurrent otitis media then ceftazidime, cefepime, or piperacillin-tazobactam should replace ceftriaxone for added Pseudomonas coverage. Cultures obtained perioperatively from the middle ear or mastoid should continue to guide antibiotic therapy during the hospitalization. Surgical treatment is usually required and ranges from myringotomy to more extensive surgery. Recently, more conservative management, consisting of retroauricular puncture and aspiration, has been studied as an alternative to traditional mastoidectomy. Preliminary results demonstrate that the retroauricular puncture has the advantage of a shorter hospital stay than with mastoidectomy. Complications of mastoiditis occur in approximately 17% of cases at the time of presentation and include conductive hearing loss, facial palsy, and intracranial complications, such as sinus thrombosis, subdural and epidural abscesses, and meningitis. Comments: Although there is a constellation of symptoms and physical ndings commonly found in mastoiditis, there is a lack of consensus of the criteria. The incidence of mastoiditis has decreased with improved availability and use of antibiotics. Of note, the introduction of the pneumococcal 7-valent vaccine has not resulted in a further decrease in incidence, although the sample sizes of this study were small. As mentioned by Dr Bunik, S pneumoniae remains the most common organism in acute disease, whereas Pseudomonas is the most common pathogen in
Author Disclosure Dr Bunik has disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
Conservative Management of Acute Mastoiditis in Children. Bakhos D, ` re S, Pondaven S, Trijolet JP, Morinie Al Zahrani M, Lescanne E. Arch Otolaryngol Head Neck Surg. 2011; 137(4):346350 Mastoiditis in a Paediatric Population: A Review of 11 Years Experience In Management. Pang LH, Barakate MS, Havas TE. Int J Pediatr Otorhinolaryngol. 2009;73(11):15201524 Pediatric Mastoiditis in the Pneumococcal Conjugate Vaccine Era: Symptom Duration Guides Empiric Antimicrobial Therapy. Roddy MG, Glazier SS, Agrawal D. Pediatr Emerg Care. 2007;23(11): 779784 A Systematic Review of Diagnostic Criteria for Acute Mastoiditis in Children. van den Aardweg MT, Rovers MM, de Ru JA, Albers FW, Schilder AG. Otol Neurotol. 2008;29(6):751757
Acute mastoiditis in children includes infection of the temporal bone associated with otitis media of less than 3 weeks duration. Even with adequate availability of and treatment with antibiotics, mastoiditis can evolve quickly and cause cranial complications, with periosteal abscess being the most common. The
in brief
chronic infections. Intracranial imaging by computed tomography or magnetic resonance imaging has been suggested in patients with neurologic signs, continued fever after 2 to 3 days of treatment, symptoms of vomiting, or lethargy. If magnetic resonance imaging is available, this modality is preferred because of higher sensitivity, less invasiveness, and no radiation. The decision of
whether to operate has been evolving with more recent evidence. Immediate surgery is needed if intracranial complications are apparent. Most common surgical approaches have included mastoidectomy and tympanostomy tube placement. A new surgical strategy of retroauricular puncture with a tympanostomy tube has been proposed and in a small study demonstrated equal
cure rates but a shorter hospital length of stay when compared with mastoidectomy. Clinicians must remain alert to the diagnosis of mastoiditis and initiate appropriate antibiotic administration with consultation with an otolaryngologist. Janet Serwint, MD Consulting Editor, In Brief
Mastoiditis Maya Bunik Pediatrics in Review 2014;35;94 DOI: 10.1542/pir.35-2-94
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12-Year-Old Girl With Constipation And Rectal Bleeding

Figure 1. Lymphoid hyperplasia throughout colon (arrows).

Pediatrics in Review Vol.35 No.2 February 2014 e11

Diagnosis: Rectal Duplication Cyst

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Differential Diagnosis of Acquired Muscle Disorders

Key Features and Tests for Acquired Muscle Disease

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The Clinicians Guide to Autism

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