06 Pediatrics in Review June20

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PediatricsinReview姞 Vol.31 No.6 June 2010
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223 Movement Disorders I: Tics and Stereotypies
Samuel H. Zinner, Jonathan W. Mink
Rochester, NY 14642
sydney_sutherland@urmc.rochester.edu
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234 Childhood Leukemia
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242 Periorbital and Orbital Cellulitis

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262 Toilet Training
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e40 North American Dimorphic Fungal

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Answer Key: 1. C; 2. C; 3. C; 4. B; 5. B; 6. B; 7. C; 8. E; 9. D;
10. C; 11. D; 12. E; 13. E; 14. A
Movement Disorders I: Tics and Stereotypies
Samuel H. Zinner and Jonathan W. Mink
Pediatr. Rev. 2010;31;223-233
DOI: 10.1542/pir.31-6-223
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Article neurology

Samuel H. Zinner, MD,*
Objectives After completing this article, readers should be able to:
Jonathan W. Mink, MD,
PhD† 1. Identify the important features of tics and stereotypies.
2. Recognize comorbid conditions and overlapping qualities with tics.
3. Describe treatment approaches for tic disorders.
Author Disclosure
Drs Zinner and Mink
have disclosed no Introduction
financial relationships Movement disorders involve impairment of appropriate targeting and velocity of voluntary
relevant to this movements, dysfunction of posture, the presence of abnormal involuntary movements, or
the performance of normal-appearing movements at inappropriate or unintended times.
article. This
The abnormalities of movement are not due to weakness or abnormal muscle tone but may
commentary does not
be accompanied by weakness or abnormal tone. By convention, movement disorders are
contain a discussion divided into two major categories. The first category is hyperkinetic movement disorders,
of an unapproved/ sometimes referred to as dyskinesias. This term refers to abnormal, repetitive involuntary
investigative use of a movements and includes most of the childhood movement disorders, including tics,
commercial product/ stereotypies, chorea, dystonia, myoclonus, and tremor. The second category is hypokinetic
movement disorders, sometimes referred to as akinetic/rigid disorders. The primary
device.
movement disorder in this category is parkinsonism, manifesting primarily in adulthood as
Parkinson disease or one of many forms of secondary parkinsonism. Hypokinetic disorders
are relatively uncommon in children. Although ataxia, weakness, and spasticity are char-
acterized by motor dysfunction, by common convention these entities are not included
among “movement disorders.”
This review of movement disorders consists of two parts. Part I focuses on the most
common movement disorders of childhood: tics and stereotypies. Part II examines chorea,
dystonia, myoclonus, tremor, and drug-induced movement disorders.
Most movement disorders in childhood arise from dysfunction in basal ganglia (cau-
date, putamen, globus pallidus, subthalamic nucleus, substantia nigra) and frontal cortex.
However, the accomplishment of normal movement requires a multifaceted network of
brain regions, including basal ganglia, frontal cortex, parietal cortex, thalamus, cerebellum,
spinal cord, peripheral nerve, and muscle. Recognition of the
multiple components of the nervous system involved in
motor control is important because the etiologic diagnosis
Abbreviations: often depends on localization.
ADHD: attention-deficit/hyperactivity disorder When faced with a movement disorder, the first step is to
CBIT: comprehensive behavioral intervention characterize the movement. Is the pattern of movements
for tics normal or abnormal? Are there excessive movements or is
CRT: competing response training there a paucity of movement? Is the movement paroxysmal
DSM-IV-TR: Diagnostic and Statistical Manual (sudden onset and “offset”), continual (repeated again and
of Mental Disorders, 4th edition – again), or continuous (without stop)? Has the movement
Text Revision disorder changed over time? Do environmental stimuli or
LD: learning disability emotional states modulate the movement disorder? Can the
OCD: obsessive-compulsive disorder movements be suppressed voluntarily? Is the abnormal
SSRI: selective serotonin reuptake inhibitor movement heralded by a premonitory sensation or urge? Are
TS: Tourette syndrome there findings on the examination suggestive of focal neuro-
logic deficit or systemic disease? Is there a family history of a
*Associate Professor of Pediatrics, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, Wash.
†
Professor of Neurology, Neurobiology, & Anatomy, Brain & Cognitive Sciences, and Pediatrics, University of Rochester School
of Medicine and Dentistry and Golisano Children’s Hospital at Strong, Rochester, NY.
Pediatrics in Review Vol.31 No.6 June 2010 223

neurology tics & stereotypies
Table 1. Phenomenologic Classification of Movement Disorders

Movement Disorder Brief Description
Tics Stereotyped, intermittent, sudden, discrete, repetitive, nonrhythmic movements, most
frequently involving head and upper body.
Stereotypy Patterned, episodic, repetitive, purposeless, rhythmic movements.
Chorea Chaotic, random, repetitive, brief, purposeless movements that are rapid but not as
rapid as myoclonus.
Dystonia Repetitive, sustained, abnormal postures and movements; abnormal postures typically
have a twisting quality.
Myoclonus Sudden, brief, shocklike movements that may be repetitive or rhythmic.
Tremor Rhythmic oscillation about a central point or position involving any one or more
body parts.
Parkinsonism Hypokinetic syndrome characterized by rest tremor, slow movement (bradykinesia),
rigidity, and postural instability.
similar or related condition? Does the movement disor- The etiologic model shifted suddenly toward a neu-
der abate with sleep? rologic explanation in the early 1960s after neuroleptic
In clinical practice, the diagnosis of a movement dis- medication was discovered to diminish tic production in
order requires a qualitative appreciation of the move- patients who had TS. At that time, although tics them-
ment type and context. Classification of the disorder selves were viewed as common among school-age chil-
phenomenologically requires a description of the charac- dren, TS was viewed distinctively and grimly. Medical
teristics of the movements (Table 1). Even under the best journals of the era described TS in such terms as “mon-
circumstances, abnormal movements can be difficult to strous affliction,” offering prognostic statements that
define, and movement disorders may be difficult to char- described a uniformly poor outcome, often culminating
acterize. Chorea can resemble myoclonus. Dystonia can in personality deterioration or foreshadowing insanity,
resemble spasticity. Paroxysmal movement disorders schizophrenic psychosis, and certain commitment to
such as dystonia and tics may resemble other paroxysmal mental hospitals. So stigmatizing was the disorder that
neurologic problems, namely seizures. Movements in one author recommended avoiding use of the Tourette
some contexts may be normal and in others may indicate eponym because its pleasant sound was considered too
underlying disease. Movements that suggest a degener- incongruous with the presumed grave outcome. Experts
ative disorder in adolescents (myoclonus) may be com- of the era considered TS to be extremely rare, suggesting
pletely normal in an infant (benign neonatal myoclonus). that many physicians would never see a case. In a 1966
It can be difficult to diagnose a specific movement disor- report, the Mayo Clinic had made the diagnosis in just 7
der without seeing the abnormal movements. Thus, ob- of 1.5 million newly admitted patients over the preceding
taining video examples of the child’s movement may be 3 decades; another review reported only 4 cases among
essential to making a correct diagnosis. 59,000 admissions to a psychiatric clinic.
Today, TS and related disorders are viewed as com-
Tics mon, although the neurobiologic underpinnings remain
Background and Historical Overview poorly understood. It generally is agreed that TS has a
Tic disorders, including Tourette syndrome (TS), are genetic basis and that tics arise from basal ganglia-
among the most common of neurologic conditions. Sur- thalamocortical circuits. However, the specific causative
prisingly, however, they escaped significant scientific at- mechanisms are not known.
tention until recent decades, in part due to their protean
and evolving qualities. Although tic disorders, including Definitions
TS, no longer are considered rare, misconceptions per- Tics are nonrhythmic, repetitive, and intermittent mus-
sist, rooted in obsolete theories. For example, during the cle contractions resulting in “stereotyped” (ie, per-
era of the late 1800s, when Georges Gilles de la Tourette formed identically each time) movements. When these
first described the condition that later would bear his movements involve laryngeal-pharyngeal muscles and
name, “hysteria” and “neurosis” were the prevailing produce noise, tics are termed “phonic” or “vocal.” All
interpretations regarding cause; later interpretations sug- other tics are termed “motor,” although functionally,
gested tics to be representations of narcissism. phonic tics also are motoric. (For a video of a patient who
224 Pediatrics in Review Vol.31 No.6 June 2010

Table 2. Tic Classifications With Examples

General Type Simple Complex
Motor ● Sudden ● Slower and longer
● Brief ● “Purposeful” (head shaking, trunk flexion, scratching,
● “Meaningless” touching, gesturing such as waving or reaching, finger
● Isolated to muscle group: Facial and neck tapping, jumping, kicking, stomping, or vulgar gesturing
(blinking, eye movements, nose twitching, [“copropraxia”] such as giving the finger, touching
lip movements, grimacing, opening eyes forbidden body parts)
widely, neck jerks, jaw snaps, gaze shifts), ● Other possible features: Dystonic (sustained,
abdomen (tensing), extremities exaggerated, or distorted facial expressions or body
(clenching, jerking), or other body part postures), imitative (“echopraxic”), self-abusive (sudden
snapping back of neck, pulling of fingers, lip-licking
causing chapping)
Phonic ● Sudden ● Often sudden
● “Meaningless” ● “Meaningful” linguistic elements (syllables, words,
● Often “allergy”-like (grunting, sniffing, phrases, or obscenities [“coprolalia”] such as “shut up,”
throat clearing, coughing) profanities, or uncouth social observations)
● Sometimes nonvocal (voiceless expulsions ● May be imitative (“echoic”)
of air from mouth or nostrils, sucking, ● Speech atypicalities (changes in speech meter, pitch,
tongue-clicking, hissing) blocking one’s speech, or repeating one’s own speech
● Animal noises (barking, chirping, [palilalia])
whistling)
has Tourette syndrome demonstrating facial and vocal the presence of tics nearly daily or intermittently during
tics, see the Data Supplement.) the qualifying period of time.
Both motor and phonic tics can be characterized A departure from the original DSM-IV, published in
further as “simple” or “complex” (Table 2). Simple tics 1994, is the removal of the criterion that the disturbance
tend to appear meaningless, be anatomically isolated, or must cause marked distress or significant impairment in
be of brief duration but are excessive in frequency or social, occupational, or other important areas of func-
intensity. Complex tics may mimic a gestural or linguistic tioning. This distinction is noteworthy because the ab-
purpose, involve several muscle groups, or be more sus- sence of this criterion further supports the neurologic
tained, such as the holding of a posture. Other features of basis of tic disorders. When the presentation does not
complex tics can include socially unacceptable expres- completely fulfill the criteria in any of the three classifi-
sions, such as coprolalia (utterance of foul or other cations, a fourth classification, “tic disorder – not other-
inappropriate language) and copropraxia (making offen- wise specified,” can be chosen.
sive gestures), or a self-injuring action. The range of
possible tic manifestations is virtually infinite, however, Epidemiology
obscuring clear boundaries between simple and complex Tic disorders begin in childhood, usually emerging dur-
classifications. ing the first decade. Transient motor tics occur in as
The Diagnostic and Statistical Manual of Mental Dis- many as one in four children and may represent a normal
orders, 4th edition-Text Revision (DSM-IV-TR), pub- variant of childhood neurodevelopment. Because tics
lished in 2000, classifies tic disorders as “transient” (last- ordinarily are mild in severity and because of their com-
ing between 1 and 12 months) or chronic (lasting more monness, they often are overlooked entirely. The preva-
than 12 months). Chronic tic disorders are classified lence of TS today is recognized to be about 1%, a
further either as “chronic motor or vocal tic disorder” or dramatic increase from even very recent estimates. Boys
as “Tourette’s disorder,” the latter requiring the pres- are four times as likely as girls to have TS.
ence of both motor and phonic tics. Note that the term Most individuals who have chronic tic disorders expe-
“vocal” implies a laryngeal contribution, although some rience only mild and unambiguous tics, with simple
noise-producing tics involve only naso- or oropharyngeal motor tics, such as eye blinking, by far the most common
muscles, such as sniffing or tongue clicking, so the term and earliest manifestation. Complex tics are less common
“phonic” may be more precise. Additional criteria for all and are very unlikely to occur as the first tic, if at all.
tic disorders include tic onset prior to 18 years of age and However, among people who have chronic tic disorders,

tics often become more complex over time. Among with incomplete penetrance and possible polygenic and
those who have non-TS chronic tic disorders, phonic tics additive factors and environmental influences seems
are much less common than motor tics. When present, likely.
phonic tics are much more likely to be of the simple,
rather than complex, variety. Very few people who have Clinical Aspects
TS ever develop coprolalia, despite the disproportionate Transient tic disorders may be milder than chronic con-
media portrayals of this often startling feature and earlier ditions and are less likely to be associated with other
investigators’ expectations of a dismal unfolding of developmental and behavioral conditions. However, it is
symptoms. When chronic, tic severity usually peaks in the important to note that diagnostic criteria make no men-
preadolescent years, and most affected adolescents expe- tion of tic severity. Tics in TS may be mild and unrecog-
rience significant improvement or complete resolution nized by casual observers. When tics are chronic, they
into adulthood. typically change in anatomic location, frequency, type,
complexity, and severity or interference. New tics may
Pathogenesis replace older ones or add to a growing repertoire. Other
The pathogenesis of tic disorders is complicated and not important features of tic disorders include a waxing and
well understood, although a wealth of biomedical re- waning course, often observed as bouts of tics over
search strongly supports a defective filtering, or “sensor- periods of seconds, minutes, hours, days, weeks, months,
imotor gating,” mechanism, resulting in urges to per- or longer.
form elements of otherwise purposeful activity at Chronic tic disorders frequently are associated with
inappropriate times, intensities, or frequencies. The cen- one or more comorbid conditions (Table 3), and it is
tral concept focuses on the basal ganglia and their role these conditions, rather than the tics themselves, that
within brain-based circuits that also include the neocor- most often are the source of the greatest psychosocial and
tex and thalamus. Other key brain regions, such as the functional challenges. Children who have TS but no
midbrain, may be involved as well. When functioning comorbid conditions probably have a similar quality of
properly, the basal ganglia assist in the execution of life and function as children who have no TS. As de-
desired behaviors expressed by these circuits, but the scribed earlier, the feature of behavioral disinhibition in
basal ganglia also function to prevent the completion of tics is shared with some aspects of attention-deficit/
undesired behaviors. hyperactivity disorder (ADHD) as well as obsessive-
Many desired behaviors, when learned through repe- compulsive disorder (OCD) and obsessive-compulsive
tition, may become automatic or sequenced as “prepack- behaviors and may suggest common neurologic under-
aged and ready-to-use,” perhaps stored and reinforced in pinnings. In fact, ADHD occurs in at least 50% of clini-
these circuits. Imprecise regulation results in the expres- cally referred children who have TS, and OCD occurs in
sion of bits of these behaviors, such as tics. This model about 33%. Symptoms of ADHD usually precede the
also helps to explain related or comorbid conditions that, onset of tics in most individuals, often presenting during
like tics, share features of loss of behavioral inhibition, the toddler and preschool years.
such as compulsions or impulsive behaviors, and to ex-
plain why these behaviors often mimic purposeful activ-
ities.
Chronic primary tic disorders and many of their asso- Comorbid Conditions of
Table 3.
ciated conditions are strongly influenced genetically, al- Tourette Syndrome
though the inheritance pattern is unclear. Environmental
factors, such as sleep insufficiency, stress, and possibly in ● Attention-deficit/hyperactivity disorder
utero exposure to maternal smoking, also are important ● Obsessive-compulsive disorder and obsessive-
compulsive behaviors
as mediators of symptom severity. In 2005, the first
● Learning disabilities/learning difficulties
reported gene associated with TS was identified on chro- ● Anxiety disorders
mosome 13 in 3 of 174 patients, although subsequent ● Mood disorders
studies of this gene’s association with TS have yielded ● Oppositional defiant disorder
mixed findings. In 2007, strong linkage to chromosome ● Self-injurious behaviors
● Speech and language disorders (eg, hesitations,
2p was reported in a large genome scan. It is likely that
disfluency)
the genetics of TS are more complex than previously ● Intermittent explosive disorder/anger dysregulation
believed. An autosomal dominant mode of transmission

Learning disabilities (LDs) are another common co-

occurring problem, although children who have TS may Possible Causes of
Table 4.
face obstacles to effective learning due to reasons other
than LD, including ADHD, obsessive thoughts or com-
Secondary Tics
pulsions, and complications due to other comorbid con- ● Infections and postinfectious sources
ditions, such as anxiety, poor frustration tolerance, insuf- ● Drugs
ficient sleep, and executive function difficulties such as ● Toxins
poor organizational skills. Tics themselves can interfere ● Neurodevelopmental disorders (eg, pervasive
developmental disorders, intellectual disabilities)
with operations such as reading, writing, listening, and
● Chromosomal disorders (eg, trisomy 21)
speaking. In addition, tics can be distracting and some- ● Stroke
times physically challenging, further jeopardizing the ● Neoplasm
child’s ability to attend. ● Heredodegenerative disorders
Explosive anger and aggression, or episodic “rage – Huntington disease
– Neuroacanthocytosis
attacks,” are seen in 25% or more of referred patients who
– Pantothenate kinase-associated neurodegeneration
have TS, and parents overwhelmingly regard these events (PKAN)
as the most problematic feature. Their origin likely is – Wilson disease
multifactorial, related both to primary disorders and ● Neurocutaneous disorders
secondary consequences of having a chronic disorder. ● Head trauma
● Seizure disorders
These attacks may be related to comorbid conditions,
● Psychogenic factors
including aggressive obsessions or other anxieties, loss of
impulse control or other disinhibited urges, and hyper-
arousal.
Although tics often improve or resolve in adolescence ioral, learning, and developmental comorbid conditions
and young adulthood, it is not yet possible to predict a tic are essential in providing comprehensive care. When
course for individual patients. A growing identification of screening identifies concerns beyond the scope of general
endophenotypes, such as fine motor skills deficits, is primary care diagnosis or management, specific consul-
emerging that may suggest degrees of basal ganglia dys- tation or referral for more specialized medical, psycho-
function that could help serve as clues to predict greater social, or psychoeducational evaluations may be indi-
tic severity in adulthood. cated. An evaluation by a medical specialist, such as a
developmental/behavioral pediatrician, psychiatrist, or
Diagnosis neurologist, includes an assessment of past medical, fam-
Diagnosing tic disorders is clinical and usually straight- ily, and developmental history; a social and environmen-
forward, not requiring any laboratory or imaging studies. tal overview; a review of the onset and course of tics and
Most often, parents or patients self-diagnose and seek related problems; and a complete physical examination
confirmation from a specialist. Simple motor tics seldom with direct clinical observation. When screening suggests
pose diagnostic uncertainty; complex tics and phonic tics the presence of obstacles to optimal academic and social
may be more difficult to discern. Although tics may performance, psychosocial and psychoeducational assess-
resemble chorea or myoclonus in some cases, the pres- ments within the school district or the private domain are
ence of a premonitory sensory urge that is relieved by tics indicated.
and the ability to suppress tics voluntarily distinguish tics
from true involuntary movement disorders. Rarely, tics Management
can be symptomatic of other disorders (Table 4). In GENERAL PRINCIPLES. Management starts with edu-
those cases, there usually are other signs or symptoms to cation about tic disorders as neurologically based, which
distinguish such secondary tic disorders from primary tic often includes reversing long-held misconceptions and
disorders. A comprehensive history (including family myths. Solicitation of beliefs and concerns from patients
history of tics and associated problems) and physical and families can help guide educational approaches. For
examination can rule out most of these causes. If there is example, awareness that tics may be suppressible can
diagnostic uncertainty, referral to a neurologist is indi- mislead parents or teachers to assume that tics are delib-
cated. erate. Also, attention to the tics may be misplaced or
Additional screening and ongoing monitoring to as- overemphasized, and when overlooked, comorbidity
sess for the presence of any of the psychosocial, behav- may be a much more significant source of functional

difficulty. At the same time, comorbid challenging be- on the Tourette Syndrome Association web site provides
haviors may be regarded as an irremediable part of the a wealth of suggestions and guidance.
broad TS spectrum and not amenable to disciplinary
guidance, an assumption that is invalid. Comorbid prob- BEHAVIORAL APPROACH. Comprehensive behavioral
lems often accompany disruption in family and peer intervention for tics (CBIT) is a behavior-based strategy
relations, and effective intervention relies first and fore- that has shown preliminary evidence of efficacy; addi-
most on successful, positive parenting foundations. Pro- tional investigation is underway. The theoretical princi-
fessional family, individual, or parenting counseling may ple behind this strategy relies on the roles that internal
be considered. and external environmental influences contribute to pro-
moting tics and assumes that tics are, in part, negatively
reinforced learned behaviors. This interpretation means
EDUCATION. The first approach to managing tic dis- that tics are performed to some degree because they
orders should be providing education and reassurance. eliminate the negative experience of the premonitory
Parents, patients, educators, and peers may benefit from sensory urge, thereby providing temporary relief to the
education about tics and TS. An understanding of how TS sufferer, and the repetition of tics and their associated
symptoms of tics and comorbid problems affect the experiences of relief reinforce the tic behavior. Accord-
patient, family, and others can help to prioritize and ingly, CBIT employs an individualized “competing re-
establish a sensible direction and degree of intervention. sponse training” (CRT) with “functional analysis” to
In recent years, an abundance of new educational re- disrupt the urge-tic-relief cycle that, when successful,
sources on TS and related conditions has become avail- seems ultimately to weaken the urge. The nuts and bolts
able, owing, in part, to increased awareness and research of CRT involve strengthening the patient’s awareness of
as well as to a collaborative agreement between the the internal environment (ie, premonitory urge) so as to
Tourette Syndrome Association and the Centers for Dis- anticipate an impending tic and gradually replace it with
ease Control and Prevention. Some of these materials are a competing tic-incompatible behavior. The functional
listed at the end of the article under “DVD Educational analysis piece identifies and modifies reinforcements in
Programming.” the external environment that promote tics (eg, parents
When tics are chronic, anticipatory guidance can help inappropriately indulging a child’s wish not to do home-
avert needless interventions. In these cases, the basis of work to avoid anxiety and resultant tic exacerbation) as
management focuses on forming an identity separate well as those that reduce tics (eg, appropriately praising a
from the tic disorder and maintaining and supplement- child for practicing CRT).
ing the development of academic, organizational, and
interpersonal skills with an eye to ensuring a satisfying, Pharmacotherapy
independent adulthood. When tics cause impairment, A variety of psychotropic medications is available and
specific treatment of the tics may be indicated. It is potentially useful for the amelioration of behavioral and
important to establish clear treatment goals, with the psychosocial symptoms due to tics and comorbid condi-
expected outcome being the reduction rather than the tions. Medication management of patients who have TS
eradication of tics. For most, however, ongoing moni- usually addresses problems related to tics, ADHD, anxi-
toring and reassuring periodic reminders that chronic tics ety (including OCD), or a combination. Although each
usually improve during adolescence are adequate tic diagnostic condition must be considered individually
management. (“splitting”), contributions of self-esteem, parenting
Children who have special educational needs should practices, social milieus of family and community, learn-
be evaluated in this area and identified needs addressed ing or organizational barriers, temperament, and other
accordingly. Such needs may include complications due elements strongly influence functional outcomes in all
to tics. In 2006, the United States Department of Edu- aspects of the patient’s illness. Effective interventions rely
cation, Office of Special Education Programs, formally on the identification and monitoring of these modifiable
included TS as a condition in the category of “Other factors, a point that should be underscored and repeated.
Health Impairment,” eligible for special education ser-
vices under the Individuals with Disabilities Education TICS. Historically, even mild tics were treated medi-
Act. Additional information is available through the cally with “typical neuroleptics” (older-generation anti-
United States Department of Education at http:// psychotics), but today a more conservative approach is
idea.ed.gov. The “Education/Education Advocacy” link recommended. Features of tic severity, including fre-

Table 5. Medications Used for Tic Reduction decisions are informed largely by
results from trials of adults and by
Alpha-2-adrenergic Commonly prevailing practice patterns. Devel-
agonists ● Clonidine (0.025 to 0.4 mg/day divided 3 to 4 times/ opment of research units in pediat-
day) ric psychopharmacology has helped
● Guanfacine (0.5 to 4 mg/day divided 1 to 2 times/day)
to rectify these serious limitations,
Typical neuroleptics Commonly
● Haloperidol (0.25 to 4 mg/day divided 2 times/day)* and progress is ongoing but very
● Pimozide (0.5 to 8 mg/day divided 2 times/day)* slow.
Less Commonly The primary indication for treat-
● Fluphenazine (0.5 to 10 mg/day) ment is the extent to which tics
Atypical Commonly
bother the child. Tics of mild sever-
neuroleptics ● Risperidone (0.25 to 3 mg/day divided 2 times/day)
● Ziprasidone (10 to 100 mg/day divided 2 times/day) ity do not require pharmacologic
Less Commonly intervention. Medication may be
● Aripiprazole (2.5 to 20 mg/day divided 2 times/day) indicated for moderate-to-severe
● Olanzapine (2.5 to 12.5 mg/day divided 2 times/day) tics, but reasonable expectations
Benzodiazepine Less Commonly
must be understood. Table 5 pre-
● Clonazepam (0.125 to 1.5 mg/day divided 1 to
3 times/day) sents medications listed by class
Other Less Commonly that are used for tic reduction. Sca-
● Botulinum toxin hill and associates have prepared
*Approved by the United States Food and Drug Administration for use in children who have Tourette more detailed guidelines (see Sug-
syndrome. gested Reading). Some therapeutic
combinations can benefit both tics
and comorbid complications and
quency, functional interference, distraction, intensity, may help guide medication selection. For example,
self-injurious aspects, and social implications, help to alpha-2-adrenergic agonists can assist in tic reduction
guide decisions regarding treatment, and all approaches and may aid some in reducing symptoms of ADHD and
are individualized. No medication has been designed insomnia; atypical neuroleptics can be useful for tic re-
specifically for tic reduction, and none eliminates tics duction and comorbid aggression.
entirely. A reasonable goal is to reduce tic severity to a A conservative medication approach for moderate-to-
state of tolerable functional outcome that has acceptable severe tics begins with an alpha-2-adrenergic agonist.
adverse effects. Because tics tend to increase during times Families should be informed that these drugs may re-
of stress, it may be useful to provide reassurance and quire up to 2 months to achieve benefit. The neuroleptic
monitoring during such periods, rather than initiating or agents are the next option. As evidence grows for their
resuming medication control. In so doing, the child or efficacy in tic reduction in combination with atypical
adolescent may learn to “ride the wave” and recognize neuroleptics, this class commonly now is chosen over the
that successful relief from tics can come with patience, typical neuroleptics because the atypical agents are less
while also helping to build attitudinal tolerance to the likely to cause extrapyramidal effects such as restlessness
natural ebbs and flows of the disorder. It is important to or acute dystonic reactions. In addition, their risk for the
recognize that the waxing and waning pattern persists development of tardive dyskinesia is considered to be
during medication use. Therefore, changes in tic severity substantially less relative to typical neuroleptics. How-
or expression should not be assumed to be a result of the ever, adverse effects, including significant weight gain,
medication. sedation, “foggy” thinking, gynecomastia, and glucose
When it is decided to use medication, the most con- intolerance with the risk for diabetes mellitus, are fre-
sistently effective available tic-reducing agents work by quent and often poorly tolerated. Alternative classes of
blocking dopamine neurotransmission within regions of agents, such as benzodiazepines, are sometimes helpful.
the basal ganglia. Both typical and atypical neuroleptics Botulinum toxin can be useful for an isolated severe
are useful, although adverse effect profiles limit their tic when injected by a neurologist directly into the of-
selection as first-line agents. Research trials of children fending muscle group. Its therapeutic impact is limited
and adolescents investigating the safety and efficacy of to the injected anatomic region and lasts about 3
medications for tic reduction have been very limited, months. Of course, any desired function of the affected
despite a growing array of available treatments. Clinical muscle group also is curtailed by this intervention.

COMORBID ADHD. When present, ADHD often im- unique advantages. Their effectiveness may be enhanced
poses more severe functional interference than do tics. when used in combination with CBIT, particularly expo-
Stimulant medications are the first-line agents in the sure and response prevention. Second-line agents, such
treatment of ADHD, even when comorbid with tic dis- as clomipramine, may be chosen when patients fail
orders. Until recently, the presence of TS contraindi- two SSRI trials. Families must be made aware of the
cated the use of stimulants for the treatment of ADHD in United States Food and Drug Administration “black
clinical practice, and the Physicians’ Desk Reference con- box” warning regarding the use of antidepressants in
tinues to list motor tics and family history or diagnosis of children and adolescents. Useful support for families
TS among their contraindications. The assumptions of and practitioners has been prepared by The American
tic induction or exacerbation with stimulant use have Psychiatric Association and the American Academy of
been reinforced by case reports dating to the 1970s as Child and Adolescent Psychiatry and is available at http:
well as by the natural time courses for the emergence of //ParentsMedGuide.org.
symptoms of ADHD (prior to age 7 years) and tics
(around age 7 years), respectively. As such, the concom- Prognosis
itant introduction of stimulant medication in a patient at Long-term prognosis in TS has not been well studied, in
approximately the time that she or he might otherwise large part because the condition was considered rare until
have been destined to develop tics or perhaps during a very recently. However, available data and clinical expe-
natural waxing phase reinforces the impression of causal- rience reveal that chronic tic disorders wax and wane
ity. regardless of intervention and most often improve sub-
In addition, stimulant medications work by increasing stantially or resolve entirely in mid-to-late adolescence.
dopamine neurotransmission, and because dopamine- The likelihood of the patient experiencing ongoing se-
blocking agents decrease tics, it is reasonable to assume vere tics in adulthood is low. The greater prognostic risks
that stimulants increase tics. However, data from recent for continued challenges and disability are seen not in tics
placebo-controlled studies simply do not support this but rather in comorbid conditions, such as ADHD,
prohibition for most patients. Nevertheless, it is a sensi- OCD, LD, anxiety, depression, and poor anger control.
ble and safer practice to alert families to the possibility of Competent interpersonal and coping skills with effective
tic appearance or exacerbation in children who have tics. behavioral and emotional self-control afford tremendous
For some children, tics increase and may not decrease, as support toward a positive psychosocial outcome, irre-
can be the nature of tic disorders. Families must under- spective of disease severity or course. Therefore, identi-
stand this, and counseling should emphasize that stimu- fying and building these qualities should form the back-
lants do not cause tics de novo or permanently increase bone of any management design.
tic severity. Reminding families of the natural waxing and
waning feature of tics as well as raising awareness of Stereotypies
predictable environmental influences that may increase Stereotypies are patterned, repetitive, purposeless, invol-
tics, such as stresses imposed by excitement, a holiday, or untary movements that also are rhythmic and continual
the beginning of a school year, may help to assuage and tend to change little over time. In contrast, tics are
apprehensions during inevitable upsurges. nonrhythmic and discrete, typically change in location
Standard stimulant dosing schedules and customary and type over time, and wax and wane in frequency and
medical precautions apply. Nonstimulant medications severity. Examples of stereotypies include body rocking,
also are available for the treatment of ADHD, including head nodding, walking in circles, hand flapping or clap-
alpha-2-adrenergic agonists, tricyclic antidepressants, ping, finger wiggling, and facial grimacing. Some stereo-
and newer antidepressants. For some patients, combined typed movements may occur in the setting of object
treatment with a stimulant and alpha-2-adrenergic ago- manipulations, including spinning or twirling items, but
nist may provide improved outcomes relative to either manipulation of objects is not required for stereotypies to
agent alone. There now is some evidence that treating be identified as such. Other terms have been used to
ADHD with the selective norepinephrine reuptake in- describe stereotypies, including “rhythmic habit pat-
hibitor atomoxetine may reduce tic severity. terns,” “gratification phenomena,” “self-stimulation,”
and “motor rhythmias.”
OCD. The selective serotonin reuptake inhibitors Stereotypies are associated most commonly with au-
(SSRIs) are the first-line agents for the treatment of tism and other developmental disabilities. Indeed, ste-
comorbid OCD. Currently, no specific SSRI shows reotypies are present in most autistic children. Stereotyp-

ies also may be seen in children who have sensory typies last for many years in most children. In some
impairments, specifically in blind or deaf children. Fur- children, they disappear over time; in others, they persist
thermore, stereotypies may occur in children subjected into adulthood. There may be an increased incidence of
to severe environmental deprivation or restriction. How- ADHD or LD among children who have stereotypies.
ever, stereotypies also occur in children who have no
developmental disabilities, sensory impairments, or social
deprivation. Treatment
When approaching the treatment of stereotypies in any
Natural History child, the first question should be whether to treat. If the
Unfortunately, few data exist on the natural history of behaviors are not causing discomfort, injury, or social
stereotypies. Stereotyped, repetitive, rhythmic move- impairment, it may be preferable not to treat them. If
ments are common and, indeed, characteristic of infants they are causing difficulty, treatment may be indicated.
and toddlers. Particular types of stereotypy develop in Treatments include pharmacologic and behavioral ap-
correlation with motor development. In most children, proaches.
such movements decrease and ultimately cease. Stereo- Many pharmacologic treatments have been reported
typies typically are present before 3 years of age in both in single cases or in small series. However, most are small,
autistic and nonautistic children. As children get older, open-label designs subject to the usual problems of such
stereotypies may diminish but can persist into adulthood studies, that is, placebo effect and observer bias. Clomi-
in both autistic and nonautistic children. pramine, risperidone, and fluoxetine have been shown to
reduce repetitive behaviors in children and adolescents
Neurobiology who have autism. However, there has been no systematic
The neurobiologic mechanisms underlying stereotypies study of pharmacologic therapy in nonautistic children.
are not known. However, there are reasons to think that Our clinical experience is that pharmacotherapy with
like most other involuntary movements, they arise from available agents is of limited use in the treatment of
the basal ganglia or from cortical-basal ganglia- stereotypies. The evidence for behavioral treatment with
thalamocortical circuits. There may be important roles habit reversal therapy and differential reinforcement of
for dopamine and serotonin in the maintenance of ste- other behaviors is a bit stronger, but still is preliminary
reotyped repetitive behaviors as well. (see Miller and associates in Suggested Reading).
Physiologic Stereotypies
Stereotypies are associated most commonly with devel-
opmental disabilities. However, it has been estimated Summary
that stereotypies occur in up to 7% of nondisabled chil-
● Tics and stereotypies are among the most commonly
dren. The term “physiologic stereotypies” has been sug-
seen movement disorders in childhood.
gested when the movements occur in otherwise healthy ● Tics and stereotypies share several features, including
children. Typical stereotypies include repeated, recurrent stereotyped appearance of each movement, repetitive
raising and lowering of the arms, flapping, waving, wrist nature, and involuntary production.
rotation, and finger wiggling. Such motions often are ● Important distinguishing features include typical age
of onset, presence or absence of premonitory “urge,”
accompanied by facial movements or grimacing. Physio-
association with other symptoms, and response to
logic stereotypies may be present in any setting but occur medication.
most commonly when the child is excited, mentally ● For both types of disorders, education and
engaged, stressed, or bored and may increase with fa- reassurance may be sufficient. For tics, effective
tigue. A hallmark of stereotypies is that they usually cease pharmacologic and behavioral therapy is available.
For stereotypies, consistently effective treatment has
when the child is distracted or engaged in a new activity.
not been described.
Most children appear to be unaware of the stereotypies. ● Transient tics are the most common form of tic
The typical age of onset for physiologic stereotypies is disorder.
younger than 2 years. These motions are more common ● Tourette syndrome is characterized by the chronic
in boys (almost 2:1). Unlike tics, stereotypies tend not to presence of motor and phonic tics.
● In general, tic disorders and stereotypies improve as
change in anatomic location or complexity over time.
individuals enter adulthood, but this is not a uniform
Stereotypies are not preceded by an urge or thought, as is occurrence.
common with tics or compulsions. Physiologic stereo-

Suggested Reading Tourette Syndrome Association and the National Center on Birth
Mahone EM, Bridges D, Prahme C, Singer HS. Repetitive arm and Defects and Developmental Disabilities at the Centers for Dis-
hand movements (complex motor stereotypies) in children. ease Control and Prevention. Diagnosing and Treating Tourette
J Pediatr. 2004;145:391–395 Syndome. 2004. Two-disc set available from: The Tourette
Miller JM, Singer HS, Bridges DD, Waranch HR. Behavioral Syndrome Association, 42-40 Bell Boulevard, Bayside, NY
therapy for treatment of stereotypic movements in nonautistic 11361-2820, Phone: (718) 224-2999, Fax: (718) 279-9596,
children. J Child Neurol. 2006;21:119 –125 Web site: http://www.tsa-usa.org
Scahill L, Erenberg G, Berlin CM, et al. Contemporary assessment Tourette Syndrome Association and the National Center on Birth
and pharmacotherapy of Tourette syndrome. NeuroRx. 2006; Defects and Developmental Disabilities at the Centers for Dis-
3:192–206 ease Control and Prevention. TSA Youth Ambassador Program.
Woods DW, Piacentini JC, Walkup JT. Treating Tourette Syndrome 2006. Available from: The Tourette Syndrome Association,
and Tic Disorders – A Guide for Practitioners. New York, NY: 42-40 Bell Boulevard, Bayside, NY 11361-2820, Phone:
The Guilford Press; 2007 (718) 224-2999, Fax: (718) 279-9596, Web site: http://
www.tsa-usa.org
DVD Educational Programming

Home Box Office, Inc. and the Tourette Syndrome Association. I Internet Resources
Have Tourette’s But Tourette’s Doesn’t Have Me. 2005. Available Parents Med Guide. http://ParentsMedGuide.org
from: The Tourette Syndrome Association, 42-40 Bell Boule- Tourette Syndrome Association, 42-40 Bell Boulevard, Bayside,
vard, Bayside, NY 11361-2820, Phone: (718) 224-2999, Fax: NY 11361-2820, Phone: (718) 224-2999, Fax: (718) 279-
(718) 279-9596, Web site: http://www.tsa-usa.org 9596, Web site: http://www.tsa-usa.org

PIR Quiz
Quiz also available online at: http://pedsinreview.aappublications.org.
1. A 9-year-old boy presents for evaluation of stereotypic movements noted over the past year by his teacher.
Among the following, the most common chronic tic disorder is:
A. Coprolalia.
B. Copropraxia.
C. Eye blinking.
D. Sniffing.
E. Tongue clicking.
2. All of the following are commonly comorbid with chronic tics except:
A. Anxiety disorder.
B. Attention-deficit/hyperactivity disorder.
C. Hypersomnia.
D. Obsessive-compulsive disorder.
E. Rage attacks.
3. A mother seeks treatment for her 9-year-old son, who is bothered by tics that are moderately disruptive in
the classroom. Of the following, the most appropriate first-line pharmacologic approach is:
A. Aripiprazole.
B. Clonazepam.
C. Guanfacine.
D. Haloperidol.
E. Risperidone.
4. In counseling the father of a boy who has chronic tics and attention-deficit/hyperactivity disorder, the
most appropriate statement is that:
A. Atomoxetine should be avoided.
B. Combined treatment with methylphenidate and clonidine may improve outcome.
C. Selective serotonin reuptake inhibitors should be considered.
D. Stimulant medications can increase tic severity permanently.
E. Waxing and waning of tics is rare.
5. The mother of a 3-year-old boy who has autism seeks evaluation for the boy’s repetitive, purposeless, and
rhythmic movements. Of the following, the movement most likely to represent a stereotypy is:
A. Blinking.
B. Hand flapping.
C. Masturbating.
D. Spitting.
E. Trichotillomania.

Samuel H. Zinner and Jonathan W. Mink
Pediatr. Rev. 2010;31;223-233
DOI: 10.1542/pir.31-6-223
Updated Information including high-resolution figures, can be found at:

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/6/223
Supplementary Material Supplementary material can be found at:

/DC1
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pedsinreview.aappublications.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
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Childhood Leukemia
John J. Hutter
Pediatr. Rev. 2010;31;234-241
DOI: 10.1542/pir.31-6-234

Article blood/neoplasia
Childhood Leukemia
John J. Hutter, MD*
1. Discuss the potential roles of genetic and environmental influences in causing

Author Disclosure leukemia, including congenital disorders that carry an increased risk for developing
Dr Hutter has leukemia.
disclosed no financial 2. Explain why proliferation of leukemic cells and the subsequent reduction in production
relationships relevant of normal blood cells contribute to clinical manifestations of leukemia.
to this article. This 3. Recognize the importance of a bone marrow aspiration or biopsy procedure in
commentary does not establishing the diagnosis of leukemia.
contain a discussion 4. Delineate current initial remission rates and 5-year survival rates achievable for chil-
of an unapproved/ dren who have acute lymphoblastic leukemia and who reside in developed countries.
investigative use of a 5. Describe potential problems that may occur in some children who have leukemia after
commercial product/ completion of therapy, including recurrence of leukemia in extramedullary sites and
device. long-term treatment complications.
Case Study
A 6-year-old boy who has Down syndrome presents with a 2-day history of fever (temperature
to 39.0°C) and a painful limp and favoring of his right leg. During the past 2 weeks, he has
had decreased appetite, increased pallor, and increased bruises on his upper and lower
extremities. Physical examination reveals pallor and multiple ecchymoses on his arms, legs, and
trunk. Bilateral cervical and supraclavicular lymph nodes are palpable; the nodes are firm,
nontender, and 1 to 2 cm in size. The liver is palpable 3 cm below the right costal margin, and
the spleen is palpable 2 cm below the left costal margin. Tenderness is elicited over the right
distal femur. Radiographs of the right distal femur reveal osteopenia plus a small lytic lesion.
A chest radiograph shows normal results with no mediastinal mass or pulmonary infiltrate.
His white blood cell count is 2.8⫻103/mcL (2.8⫻109/L) with 10% neutrophils, 5% monocytes,
85% lymphocytes, and no blasts. His hemoglobin measures 8.2 g/dL (82 g/L) and platelet
count is 38⫻103/mcL (38⫻109/L). Due to the presence of severe neutropenia with fever,
intravenous broad-spectrum antibiotics are administered after blood cultures are obtained.
The child is referred to a pediatric hematologist/oncologist, and a bone marrow aspirate and
biopsy demonstrate more than 90% lymphoblasts. The patient is enrolled in a Children’s
Oncology Group clinical trial for treatment of acute lymphoblastic leukemia (ALL). Chemo-
therapy is initiated and a complete remission is achieved.
Incidence and Epidemiology

Childhood cancer is rare, with a reported incidence in the United States of approximately
1 case per 7,000 children age 15 years and younger. In
contrast to the adult population, in whom solid tumor
malignancies predominate, almost 40% of childhood cancers
Abbreviations: are hematologic malignancies (leukemia and lymphoma).
ALL: acute lymphoblastic leukemia Leukemia is the most frequent malignancy that occurs dur-
ANLL: acute nonlymphocytic leukemia ing childhood and comprises approximately 30% of all child-
CLL: chronic lymphocytic leukemia hood cancers. Historically, leukemia was classified initially
CML: chronic myelogenous leukemia in four groups based on clinical presentation and morpho-
CNS: central nervous system logic appearance of the malignant cells: ALL, acute nonlym-
phocytic leukemia (ANLL), chronic myelogenous leukemia
*Professor Emeritus of Pediatrics, University of Arizona, Tucson, Ariz.

blood/neoplasia childhood leukemia
Frequency of Types of
Table 1. 5 years of age. Newborns who have Down syndrome and
manifest transient myeloproliferative disease have at least
Childhood Leukemia in Historic a 25% chance of developing a particular subtype of ANLL
Classification* called acute megakaryoblastic leukemia, which may
evolve during early childhood in children who have
% of Childhood Down syndrome and neonatal myeloproliferative disor-
Leukemia Classification Leukemia der after apparently complete resolution of the neonatal
Acute lymphocytic (ALL) 80 myeloproliferative disorder. Additional disorders associ-
Acute nonlymphocytic (ANLL) 17 ated with an increased risk of leukemia include ataxia
Chronic myelogenous (CML) 3 telangiectasia and other immunodeficiency syndromes,
Chronic lymphocytic (CLL) Virtually none
Fanconi anemia, Bloom syndrome, Klinefelter syn-
*Based on cellular morphology and clinical features. drome, and neurofibromatosis.
Certain environmental factors have an established role
in human leukemogenesis. Japanese survivors of the
(CML), and chronic lymphocytic leukemia (CLL). Sub- atomic bomb explosions had an increased leukemia oc-
sequent research investigations, which evaluated the currence rate, demonstrating that exposure to large
morphologic, immunologic, growth regulation, cytoge- doses of ionizing radiation contributes to an increased
netic, and molecular abnormalities in leukemia cells, risk of leukemia The incidence of leukemia was higher in
further established that the leukemias represent a much survivors who were closer to the atomic epicenter, sug-
more heterogeneous group of malignancies than initially gesting a dose-dependent relationship between ionizing
suggested by the four-group classification. However, the radiation exposure and leukemia. Of note, the time in-
designations of the initial classification still are used clin- terval from radiation exposure to the peak incidence of
ically, and it remains useful to consider how the classifi- leukemia in the atomic bomb survivors was several years.
cation pertains to childhood leukemia (Table 1). Studies that analyzed the risk of childhood leukemia
In the United States, the incidence of childhood ALL following exposure to doses of radiation administered
is highest in children 2 to 5 years of age. Sex differences during conventional prenatal or postnatal radiographic
have been reported, with the incidence being greater in procedures or from exposures to nonionizing electro-
boys. Race differences in incidence also have been ob- magnetic field irradiation have produced conflicting re-
served. Compared with white children, African American sults. (1)(2)
children have a much lower incidence of childhood ALL, The role of chemical agents in the pathogenesis of
particularly during the peak 2- to 5-year age range. leukemia is established best for the occurrence of ANLL
Leukemia occurs slightly more frequently among His- after benzene exposure in susceptible individuals. The
panic children than among whites, but the extent of this extent to which chemical exposures may contribute to
difference is not as pronounced as the difference ob- the development of childhood ALL is less well estab-
served between whites and African Americans. lished. Exposures to tobacco smoke, organic solvents,
and pesticides, among other agents, have been associated
Pathogenesis and Causes with an increased relative risk of developing childhood
Leukemia results from an expansion of malignant hema- leukemia, but determination of exact causal relationships
topoietic or lymphoid cells, and the leukemic cellular requires additional studies.
proliferation is usually monoclonal. Both genetic and Establishing specific timing and quantifying possible
environmental factors may contribute to the develop- dose relationships of environmental exposures remain
ment of leukemia, but in most children, the causal factors problematic. The potentially long interval of years be-
remain unknown. Children who have certain conditions tween exposure to a possible carcinogen and the clinical
have an increased risk for developing leukemia. The most manifestations of leukemia contributes to this difficulty.
common congenital disorder associated with an in- Theoretically, exposures contributing to childhood leu-
creased risk of leukemia is Down syndrome, in which the kemia also might vary by timing and type of exposure:
overall relative risk of leukemia is greater than 15 times 1) parental exposure, including parental occupational
that of the general population. Children born with exposure; 2) prenatal exposure; and 3) exposures during
Down syndrome have an increased occurrence of both childhood.
ALL and ANLL, and it has been estimated that 1% of A recent study conducted by the Children’s Oncology
children who have Down syndrome develop leukemia by Group observed that higher mutation rates of the ras

proto-oncogene in children who have ALL may be asso- child may exhibit a limp or refusal to walk. Bone radio-
ciated with parental exposure to hydrocarbons and spe- graphs may demonstrate osteopenia and, in some in-
cific medications. (3) Maternal exposure to pesticides stances, lytic lesions. Children also may have abnormali-
and chemical agents has been associated with an in- ties detected on radionuclide bone scan. Because some
creased risk of ALL in children who have Down syn- children can present without malignant leukemia cells
drome. (4) Viral infections have been implicated in the detected on a routine blood count, mistaken diagnoses
pathogenesis of certain rare human leukemias, but no of juvenile idiopathic arthritis or osteomyelitis occasion-
viral agent has been demonstrated to have a definitive ally have been considered in children who have leukemia
role in causing the more frequent subtypes of childhood with bone pain. Pathologic fractures through leukemic
ALL. bone are uncommon presentations of leukemia, but they
The increased incidence of ALL in children who re- should be considered if the pattern is atypical or if there
side in developed countries has prompted studies on the are other signs or symptoms suggestive of leukemia.
possible relationship of ALL to frequency of infections Leukemia proliferation within the bone marrow re-
during infancy and early childhood. Data from these sults in decreased production of normal white blood
reports have been divergent regarding the association of cells, red blood cells, and platelets. Malignant leukemia
the risk of leukemia and early childhood infection, result- blast cells are frequently, but not always, observed circu-
ing in differing speculative hypotheses. The observations lating in the blood. Because conditions such as infectious
of an increased risk of leukemia in children who have mononucleosis occasionally can result in large numbers
greater social isolation with fewer exposures to infectious of atypical white cells in the blood, a bone marrow
agents during early childhood (5)(6) has suggested the examination is essential for a conclusive diagnosis of
possibility of a predisposition to developing leukemia leukemia. Bone marrow studies in children who have
resulting from lack of stimulation of a child’s immune leukemia are important to assist in identifying specific
system by common infectious agents. Another study that subtypes of leukemia. Also, because children who have
observed an increased occurrence of leukemia in children leukemia do not always present with lymphadenopathy
who had documentation of infection in the neonatal or hepatosplenomegaly and may not have detectable
period or early infancy hypothesized that these early leukemia cells in the blood, a bone marrow examination
infections were an indication of possible abnormal im- serves to distinguish leukemia from other conditions
mune responses, which later increased the risk of leuke- involving severe bone marrow failure such as aplastic
mia. (7) anemia or myelofibrosis. Children who have aplastic
anemia and children who have acute leukemia may
Clinical Presentation and Diagnosis present with similar degrees of severe anemia, neutrope-
The clinical manifestations of leukemia result from the nia, or thrombocytopenia and similar clinical signs and
effects of proliferation of malignant cells within the bone symptoms produced by the cytopenias.
marrow and other organs. The extramedullary organs Many initial signs and symptoms of leukemia are
most frequently experiencing leukemia infiltration are related to decreased production of normal blood cells
the liver, spleen, and lymph nodes; many, but not all, (Table 2). The major life-threatening complication in a
affected children initially present with enlargement of child who has acute leukemia remains overwhelming
these organs detectable on physical examination. Al- infection, often sepsis or severe pneumonia. The risk of
though hepatomegaly may be massive in some children sepsis can be correlated directly with the severity of
who have leukemia, it is unusual to have corresponding neutropenia; other alterations of host immunity pro-
marked abnormalities in liver function. Other important duced by leukemia also contribute to infection risk.
sites of potential leukemia infiltration are the central Bleeding manifestations in a child who has leukemia
nervous system (CNS) and the testes. Leukemia has the most frequently are due to severe thrombocytopenia. On
potential to involve any body organ, including skin, occasion, severe coagulation factor deficiencies can aug-
kidney, lung, pleura, pericardium, eye, breast, ovaries, ment the bleeding tendency; coagulation factor abnor-
and gastrointestinal tract. malities are most pronounced in a rare subtype of ANLL
Leukemia expansion within the bone marrow may known as acute promyelocytic leukemia.
produce signs and symptoms of bone involvement. Ap- In addition to possibilities of overwhelming infection
proximately 25% of children who have newly diagnosed and severe bleeding, other leukemia manifestations may
leukemia present with a complaint of severe bone pain. be life-threatening. Severe airway obstruction with respi-
When bones of the lower extremity are involved, the ratory distress may result from massive mediastinal

Relationship of Leukemia Pathophysiology to Clinical

Table 2.
Manifestations
Leukemia Abnormality Clinical Signs, Symptoms, or Complications
Anemia Pallor, fatigue, decreased appetite; congestive heart failure with extremely severe anemia
Neutropenia Fever; risk of overwhelming infection increases with severity of neutropenia
Thrombocytopenia Petechiae, ecchymoses, mucosal and other bleeding
Coagulation factor deficiencies Increased bleeding; disseminated intravascular coagulation with severe factor
deficiencies occurs frequently in the acute promyelocytic subset of acute
nonlymphocytic leukemia
Leukemia in bone Bone pain
lymphadenopathy. The risk of massive mediastinal bleeding or overwhelming infection. Five-year survival
lymphadenopathy is greatest in T-cell ALL, a subset of rates for children receiving new diagnoses of ALL in the
ALL that occurs most often in adolescent boys. Hyper- United States and other developed countries are now in
leukocytosis, defined as a white blood cell leukemia blast excess of 80%. (8) Hematopoietic stem cell transplanta-
count more than 100⫻103/mcL (100⫻109/L), can tion used for certain types of leukemia and for salvage of
result in damage to vital organs in children who have children whose leukemia has relapsed after conventional
ANLL. The elevated numbers of leukemia blast cells may chemotherapy also has contributed to improved survival.
sludge in the vascular supply of the brain, lungs, and liver, Certain sites of leukemia involvement have required
producing infarction within these organs. Children who particular attention in the development of treatments.
have ALL are at much lower risk of developing vascular During the early periods of development of combination
sludging from hyperleukocytosis, in part because the chemotherapy, some children were found to develop
ALL malignant blast cells are more deformable than leukemia recurrences in the CNS or the testes at a time
those of ANLL. when the bone marrow showed disease remission. CNS
Kidney function during leukemia onset may be com- leukemia most frequently involves the meninges, with
promised for several reasons, including leukemia infiltra- associated signs and symptoms of increased intracranial
tion of the renal parenchyma. Breakdown of leukemia pressure of headache, vomiting, or papilledema. Testic-
cells frequently results in elevated serum concentrations ular leukemia usually manifests as painless, firm enlarge-
of uric acid, which may impair renal function further. ment of one or both testes, although microscopic leuke-
Children who have the rare B-cell subtype of ALL also mia testicular involvement can occur without any overt
may present with severe acute renal failure with normal clinical signs or symptoms. Extramedullary leukemia re-
blood uric acid values. Abnormal calcium metabolism currences in the CNS and testes, for the most part, have
with either hypercalcemia or hypocalcemia occurs in been due to inherent barriers to the delivery of effective
some children who have leukemia. Due to the potential chemotherapy to these sites. CNS and testicular recur-
for metabolic abnormalities, initial evaluation of an af- rence rates have been reduced by chemotherapy strate-
fected child should include not only a blood count gies that result in enhanced drug delivery to these organs.
but also measurement of serum sodium, potassium, For treatment of CNS leukemia, delivery of chemother-
chloride, bicarbonate, creatinine, calcium, phosphate, apeutic agents directly into the cerebrospinal fluid often
and uric acid. is required. Accordingly, lumbar punctures usually are
performed for children who have newly diagnosed acute
Treatment and Prognosis leukemia, both to assess for the possibility of leukemia
The past 50 years has seen a marked improvement in involvement of the meninges and to administer chemo-
outcome for children who have leukemia. Steady im- therapeutic agents directly into the cerebrospinal fluid.
provements in continuous complete remission and sur- Children generally are treated at pediatric cancer cen-
vival rates have resulted primarily from the development ters and, when appropriate, offered participation in a
of effective combination chemotherapy regimens. In the clinical trial that evaluates treatment results. Analyses of
era before chemotherapy, the median survival for a child previous clinical trial results have contributed greatly to
who had newly diagnosed acute leukemia was 3 months, subsequent trial designs that resulted in the development
with the cause of death predominantly due to massive of chemotherapy regimens with improved outcomes.

Leukemia chemotherapy regimens are generally divided lar subtype and recognition and management of acute
into three phases: induction, intensification, and mainte- renal failure, which may occur with this subtype.
nance. The goals of induction therapy are to achieve a An emerging therapeutic strategy is the development
complete remission of leukemia and to optimize chances and use of agents that target molecular abnormalities
that a remission will be maintained. Children who have detected in leukemia subtypes. The tyrosine kinase inhib-
ALL and are treated with current chemotherapy regi- itor imatinib mesylate, which actively binds to the abnor-
mens have a greater than 95% probability of achieving a mal bcr abl fusion protein and a limited number of other
complete remission within 4 weeks. normally occurring tyrosine kinases, has been efficacious
In addition to evaluation of overall remission rates, in children and adults who have chronic phase CML.
survival, and complications, analyses of clinical trial data Although imatinib therapy for Ph⫹ ALL or blast crisis
have assisted in identifying affected children who have CML has resulted in responses, the overall results have
more favorable as well as less favorable outcomes with been less dramatic than that observed for CML chronic
prior therapy regimens. This resulted in the evolution of phase. Decreased binding of imatinib to the abnormal
different treatments for children based on whether they bcr abl protein in patients who have Ph⫹ ALL or CML
are considered to have a higher risk of initial treatment blast crisis compared with those who have CML chronic
failure or leukemia recurrence. For children who have phase may account for some of the differences in re-
ALL, major clinical determinants of increased risk of sponse rates. In addition to the abnormal bcr abl tyrosine
leukemia recurrence are the child’s age and concentra- kinase found in Ph⫹ leukemia, mutations of other kinase
tion of circulating blasts in the blood. Those who are proteins may occur in children who have ALL. A recent
younger than 1 year or older than 10 years have worse study of Janus kinase (JAK) in childhood ALL found a
greater frequency of mutated JAK kinase in children who
outcomes, as do those who have higher concentrations of
had high-risk ALL, and they also had worse treatment
leukemia cells in the blood, particularly with white blood
outcomes with current therapy. (9) An additional success
cell counts greater than 50.0⫻103/mcL (50.0⫻109/L).
in leukemia therapy directed at specific molecular targets
Certain immunologic, cytogenetic, and molecular ab-
has been the administration of all-trans retinoic acid to
normalities also were identified as risk factors, most likely
children who have acute promyelocytic leukemia. Treat-
because they serve to define specific subtypes of leuke-
ment of such children with all-trans retinoic acid in
mia. The Philadelphia (Ph) chromosome, a cytogenetic
conjunction with other chemotherapeutic agents has
translocation involving the long arms of chromosomes
resulted in improved remission rates and overall survival.
9 and 22, occurs in 3% to 5% of children who have ALL.
Advances in supportive care and management of leu-
The translocation site involves the abl proto-oncogene,
kemia complications also have contributed to better leu-
with production of an abnormal fusion protein (named kemia remission rates and survival. The availability of
bcr abl) that has tyrosine kinase activity. In rare instances, blood components prepared with minimal risk of
the abnormal bcr abl fusion protein may be detected in transfusion-induced infection has been an important ad-
the absence of a discernible karyotypic change. Children junct in the treatment of a child who has newly diagnosed
who have ALL and manifest the Ph chromosome (Ph⫹) leukemia. Platelet transfusion therapy has reduced the
currently have a worse response rate to conventional risk of mortality in children who have leukemia and
chemotherapy compared with children who do not have severe bleeding manifestations. Recognition of the im-
this abnormality. The Ph chromosome with abnormal portance of the expeditious implementation of effective
bcr abl fusion protein also is present in approximately broad-spectrum antibiotic coverage in the neutropenic
50% of children who have CML and rarely occurs in febrile child also has helped to reduce morbidity and
ANNL. mortality from infections. Adequate nutrition support
Risk determinations in childhood leukemia are also has been essential, particularly when children who
treatment-specific, and children who were considered have leukemia require intense therapy such as that used
high risk from previous treatments eventually may have in hematopoietic stem cell transplant regimens.
markedly better outcomes with the development of Improved survival rates have resulted in an expanding
effective treatments for their leukemia subtype. For ex- population of children who have completed treatment of
ample, children who have the B-cell ALL subtype would their leukemia. Many pediatric cancer centers have estab-
have been considered high risk 25 years ago but now lished specific programs dedicated to the long-term
have markedly improved survival due to both chemo- follow-up of childhood cancer survivors, but childhood
therapy regimens that are more effective for this particu- leukemia survivors also receive care in the pediatrician’s

office. It is important for the pediatrician to be familiar institution of leukemia therapy often preclude the use of
with issues pertinent for leukemia survivors and to coor- fertility preservation interventions.
dinate care with the pediatric cancer center. (10) Partic- The prevalence of second malignancies occurring
ular areas of concern in children who have completed within the first 25 years after treatment for childhood
treatment for leukemia include risk of relapse, sequelae of leukemia is at least 3%, with the CNS being the most
cancer or its treatment, transient immunosuppression in frequent site of involvement. (11) Because this rate of
patients whose therapy recently was discontinued, and malignancy occurrence exceeds that observed for chil-
administration of immunizations that may have been dren and young adults of similar age in the general
delayed or rendered ineffective due to intensive treat- population, it is recommended that survivors of child-
ment. The timing and schedule of immunizations for hood leukemia be counseled to minimize exposures to
childhood leukemia survivors are provided through the known carcinogens, such as cigarette smoke or excessive
American Academy of Pediatrics Red Book or specific sunlight without sun block protection.
recommendations from the pediatric cancer center. Survivors of childhood leukemia, particularly those
After completion of therapy, children are at varying who received intensive therapy to the CNS at a young
risk for both leukemia recurrence and long-term treat- age, are at increased risk of developing neuropsycholog-
ment complications, depending on the type of leukemia ical abnormalities with cognitive defects that can affect
and treatments employed. Some children who have ALL subsequent school performance. Such children require
may develop leukemia relapse after initial therapy com- monitoring of school performance and achievement,
pletion, including recurrences in the extramedullary with appropriate educational interventions when indi-
CNS or testicular sites when the bone marrow remains in cated.
remission. Avascular necrosis of the femoral head, which Although a greater frequency of late complications
presents as hip pain, can be a complication of therapy, occurs in survivors of childhood leukemia, many children
presumably because of effects of corticosteroids. treated for leukemia do well without any major difficul-
When compared with sibling controls, childhood leu-
kemia survivors exhibit a greater number of potential
problems in the areas of general and mental health, Summary
functional impairment, and activity limitations. (11) The
highest level of education and subsequent employment • Based on strong research evidence, leukemia is a
heterogeneous group of disorders that can be
achieved by survivors tended to be lower than that of
classified according to morphologic, immunologic,
siblings; issues also were observed in the survivor’s ability karyotypic, biochemical, or molecular criteria.
to obtain and maintain health and life insurance. The risk • Based on strong research evidence, children who
of treatment-related sequelae is related to the type and have certain congenital disorders such as Down
intensity of therapies employed, with children who re- syndrome are at increased risk for leukemia.
• Based on strong research evidence, many initial
ceived radiation therapy or intensive therapy for relapsed
clinical manifestations of leukemia (eg, pallor, fever,
leukemia more likely to develop long-term complica- purpura) are a consequence of decreased production
tions. The prevalence of certain late effects in childhood of normal red blood cells, white blood cells, and
leukemia survivors frequently can be related to a specific platelets.
treatment modality: growth abnormalities and preco- • Based on strong research evidence, severe bone pain
occurs in approximately 25% of children at the
cious puberty in children who received CNS irradiation,
onset of leukemia, with some children also
secondary malignancies after treatment with radiation exhibiting abnormalities on bone radiographs or
therapy or large cumulative doses of alkylating agents radionuclide bone scan.
or epipodophyllotoxins, and cardiomyopathy related to • Based on strong evidence and practice guidelines, a
high cumulative doses of anthracyclines. Children who bone marrow test is essential in the diagnosis and
classification of leukemia.
received gonadal irradiation or intensive chemotherapy
• Based on strong research evidence, greater than
are at increased risk for impaired fertility. Treatment- 95% of newly diagnosed children who have ALL
related infertility risks are greater for boys and for ado- achieve a complete remission of leukemia, with
lescents compared with prepubertal children. Whenever subsequent 5-year survival rate in excess of 80%. (8)
feasible, cryopreservation of sperm should be offered to • Based on strong research evidence, long-term
leukemia survivors, when compared with sibling
older adolescent male patients prior to administration of
controls, have a greater incidence of general and
treatment modalities that may impair fertility. (12) The mental health functional impairment. (11)
younger age of many patients and necessity for prompt

ties. Some survivors have selected and completed train- household chemical exposure and risk of acute leukemia in Down’s
ing for careers in health-care-related fields, such as social syndrome: a report from the Children’s Oncology Group. Am J
Epidemiol. 2006;164:212–221
work, nursing, or medicine. Continuing research in the 5. Gilham C, Peto J, Simpson J, et al. Daycare in infancy and risk of
treatment of childhood leukemia with novel regimens childhood acute lymphoblastic leukemia: findings from UK case-
and therapeutic agents hopefully will result not only in control study. BMJ. 2005;330:1294
defining regimens with improved survival success but 6. Urayama K, Ma X, Buffler PA. Exposure to infections through
day-care attendance and risk of childhood leukemia. Radiat Prot
also in developing treatment regimens that eliminate or Dosimetry. 2008;132:259 –266
greatly reduce the severity of complications. 7. Roman E, Simpson J, Ansell P, et al. Childhood acute lympho-
blastic leukemia and infections in the first year of life: a report from
the United Kingdom Childhood Cancer Study. Am J Epidemiol.
References 2007;165:496 –504
8. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia.
1. Schulze-Rath R, Hammer GP, Blettner M. Are pre- or postnatal
N Engl J Med. 2006;354:166 –178
diagnostic x-rays a risk factor for childhood cancer? A systematic
9. Mulligan CG, Zhang J, Harvey RC, et al. JAK mutations in
review. Radiat Environ Biophys. 2008;47:301–312
high-risk childhood acute lymphoblastic leukemia. PNAS. 2009;
2. Kheifets L, Shimkhada R. Childhood leukemia and EMF: review 106:9414 –9418
of the epidemiologic evidence. Bioelectromagnetics. 2005;suppl 10. Hutter JJ Jr. Late effects in children with cancer. Am J Dis
7:S51–S59 Child. 1986;140:17–19
3. Shu XO, Perentesis JP, Wen W, et al. Parental exposure to 11. Mody R, Li S, Sallan S, et al. Twenty-five year follow-up among
medications and hydrocarbons and ras mutations in children with survivors of acute lymphoblastic leukemia: a report from the Child-
acute lymphoblastic leukemia: a report from the Children’s Oncol- hood Cancer Survivor Study. Blood. 2008;111:5515–5523
ogy Group. Cancer Epidemiol Biomarkers Prev. 2004;13: 12. Fallat ME, Hutter JJ. Preservation of fertility in pediatric and
1230 –1235 adolescent patients with cancer. Pediatrics. 2008;121:
4. Alderton LE, Spector LG, Blair CK, et al. Child and maternal e1461– e1469
PIR Quiz
Quiz also available online at http://pedsinreview.aappublications.org
6. The genetic disorder most commonly associated with an increased risk of leukemia is:
A. Ataxia telangiectasia.
B. Down syndrome.
C. Fanconi anemia.
D. Klinefelter syndrome.
E. Neurofibromatosis.
7. A previously well 5-year-old girl presents with pallor and bone pain of 3 weeks’ duration. Physical
examination reveals pallor, increased bruising, and scattered petechiae. She is afebrile and has neither
lymphadenopathy nor hepatosplenomegaly. Her hemoglobin is 3.5 g/dL (35 g/L), white blood cell count is
1.1ⴛ103/mcL (1.1ⴛ109/L), and platelet count is 17ⴛ103/mcL (17ⴛ109/L). No blasts are seen on her
peripheral blood smear. You are most concerned about acute leukemia and aplastic anemia. Pending a
bone marrow examination, which should establish the diagnosis, the clinical feature that is most helpful
in pointing to the correct diagnosis is:
A. Absence of blasts on the peripheral blood smear.
B. Absence of hepatosplenomegaly.
C. Presence of bone pain.
D. Presence of fever.
E. Presence of petechiae and purpura.

8. A patient in your practice was diagnosed with acute lymphoblastic leukemia 2 weeks ago and is
undergoing treatment at the regional pediatric oncology center. His parents are concerned that the
oncologists are being too optimistic in stating his prognosis. The overall 5-year survival rate for newly
diagnosed acute lymphoblastic leukemia in developed countries is best described as being at least:
A. 40%.
B. 50%.
C. 60%.
D. 70%.
E. 80%.
9. The family of a 15-year-old boy who was treated successfully 5 years ago for acute lymphoblastic
leukemia recently read about the long-term consequences of therapy. They want to know the likelihood of
his developing a second malignancy. The prevalence of second malignancies occurring within the first 25
years after treatment of childhood leukemia is closest to:
A. 0.01%.
B. 0.05%.
C. 0.3%.
D. 3%.
E. 7%.
10. An 18-year-old boy comes to your office with complaints of fatigue, pallor, bruising, cough, and difficulty
doing any exercise. His physical examination reveals pallor, mild bruising, occasional petechiae, and
moderate respiratory distress. He is afebrile, but his respiratory rate is 35 breaths/minute. His chest is
clear. He has diffuse cervical adenopathy and moderate hepatosplenomegaly. The results of a complete
blood count are hemoglobin of 8.9 g/dL (89 g/L), white blood cell count of 44.0ⴛ103/mcL (44.0ⴛ109/L),
and platelet count of 19ⴛ103/mcL (19ⴛ109/L). The most likely cause of his respiratory distress is:
A. Congestive heart failure due to anemia.
B. Intrapulmonary hemorrhage.
C. Mediastinal lymphadenopathy.
D. Pneumonia.
E. Pulmonary hyperleukocytosis.

Childhood Leukemia
John J. Hutter
Pediatr. Rev. 2010;31;234-241
DOI: 10.1542/pir.31-6-234


Periorbital and Orbital Cellulitis
Andrea Hauser and Simone Fogarasi
Pediatr. Rev. 2010;31;242-249
DOI: 10.1542/pir.31-6-242

Article eye

Andrea Hauser, MD,*
Simone Fogarasi, MD†
1. Recognize the difference between periorbital and orbital cellulitis on the basis of
history and physical examination findings.
Author Disclosure 2. Describe the cause, pathophysiology, and management of periorbital and orbital
Drs Hauser and cellulitis.
Fogarasi have 3. Understand the importance of sinus disease in both periorbital and orbital cellulitis.
disclosed no financial 4. Know the indications for computed tomography scan and specialist consultation for
relationships relevant eyelid swelling.
to this article. This 5. Recognize the complications of periorbital and orbital cellulitis.
commentary does not
contain a discussion
of an unapproved/
Case Study
A 19-month-old boy presents with a 1-day history of left eyelid swelling. The swelling is greater
investigative use of a
in the lower lid and accompanied by local erythema, tenderness, and temperature up to
commercial product/ 38.4°C. His parents state that he has decreased appetite and activity. For the past week, the boy
device. has been experiencing clear, watery rhinorrhea, sneezing, and a mild cough. Today, he was
given diphenhydramine without any improvement of the eyelid swelling. His parents deny any
history of trauma or recent insect bites to the face. The past medical history is significant for
mild intermittent asthma and allergic rhinitis. He is exposed to tobacco at home.
On physical examination, the child appears ill, but not toxic. His temperature is 36.9°C,
heart rate is 123 beats/min, respiratory rate is 26 breaths/min, and blood pressure is
117/82 mm Hg. Both upper and lower left eyelids appear significantly edematous, with
surrounding erythema and tenderness to light touch. No chemosis or proptosis is apparent.
Extraocular movements and visual acuity can be evaluated only partially due to pain.
Introduction
Infections of the eye occur in the pediatric population and may present with complaints
of eyelid swelling and pain. Expeditious and proper diagnosis is essential because there
is potential for significant morbidity and mortality. Periorbital and orbital infections
have much in common. We illustrate the similarities and differences of these two clinical
entities.
Anatomic Considerations
The orbital septum is a thin membrane separating the superficial eyelid from the deeper
orbital structures. This septum forms a potential barrier, preventing infections of the eyelid
from penetrating deeper into the orbit. Infection of the soft tissues anterior to the orbital
septum is termed periorbital cellulitis and affects the eyelids and
adnexa. Infections posterior to the septum include orbital cel-
lulitis, orbital abscess, and subperiosteal abscess.
Abbreviations Certain anatomic characteristics of the orbital structures
CNS: central nervous system allow extension of infection to adjacent structures. First, the
CT: computed tomography thin orbital septum may be incomplete, thereby risking the
Hib: Haemophilus influenzae type b spread of periorbital infection to underlying orbital structures.
MRSA: methicillin-resistant Staphylococcus aureus Second, infection may spread from the paranasal sinuses (which
RPOC: recurrent periorbital cellulitis surround the orbital cavity on three of the orbit’s four walls)
through the bone into the orbit. Third, the valveless orbital
*Pediatric Hospitalist, New Orleans Children’s Hospital, New Orleans, La.

†
Pediatric Hospitalist, Ochsner Medical Center, New Orleans, La.

eye periorbital & orbital cellulitis
Microbiology
Haemophilus influenzae type b
(Hib) historically was one of the
pathogens associated most com-
monly with orbital cellulitis and
hematogenously spread periorbital
cellulitis. With the advent of the
Hib conjugate vaccine in 1985, the
incidence of Hib infections has de-
clined significantly. However, Hib
still should be considered, particu-
larly in unimmunized or partially
immunized children, because inva-
sive Hib disease in children younger
than 5 years of age has been re-
ported recently. (4) Streptococcus
pneumoniae infections also are on
Figure 1. Simplified anatomy of the eye, paranasal sinuses, and venous drainage. the decline as a result of the routine
use of pneumococcal conjugate
veins can allow passage of hematogenous infection in vaccine. Consequently, the pattern of pathogens respon-
both antegrade and retrograde directions (Fig. 1). sible for eye infections is evolving.
Currently, Staphylococcus aureus, S epidermidis, and
Epidemiology S pyogenes account for approximately 75% of pediatric
Periorbital cellulitis is a bacterial infection of the eyelid periorbital infections from which cultures are obtained.
and surrounding soft tissues. It is primarily a pediatric (5) Staphylococcus and Streptococcus have become the two
disease, occurring mostly in patients younger than 5 most common pathogens responsible for pediatric or-
years of age, and is almost three times more common bital cellulitis. Community-acquired methicillin-resistant
than orbital cellulitis. There is no sex predilection. S aureus (MRSA) has become increasingly prevalent
Orbital bacterial infections can present in all age (Fig. 4). (6) In fact, one retrospective study from Hous-
groups but are seen more often in the pediatric popula- ton, Texas, examining the microbiology of pediatric
tion. In a retrospective analysis of pediatric orbital in- orbital cellulitis, found that MRSA represented 73% of all
fections, the average age of affected patients was 6.8 S aureus isolates. (1)
years, ranging from 1 week to 16 years. (1) A 2:1 male
predominance has been described. Throughout the
world, orbital cellulitis occurs more often in winter
months because it is associated closely with paranasal
sinus and upper respiratory tract infections. Most cases
have a unilateral presentation. (2)(3)
Pathogenesis
Rhinosinusitis, especially ethmoiditis, is by far the most
common predisposing factor for pediatric orbital celluli-
tis. However, periorbital and orbital cellulitis also can
result from extension of external ocular infection such as
a hordeolum (stye) or dacryocystitis/dacryoadenitis
(infection of the lacrimal system); an upper respiratory
tract infection, such as complicated rhinosinusitis
(Fig. 2); a dental abscess (Fig. 3); a superficial break in
the skin, due either to an infected insect bite, impetigo, Figure 2. A 19-month-old boy who has periorbital cellulitis
acne, eczema, periocular surgery, or direct penetrating and presents with left eyelid swelling, erythema, and tender-
injury to the orbit; and hematogenous seeding. ness due to acute rhinosinusitis.

Figure 4. A 15-month-old girl who has periorbital cellulitis

and fever following infection of an insect bite to her lower
right eyelid despite treatment with several days of cephalexin.
She was placed on clindamycin for suspected community-
acquired methicillin-resistant Staphylococcus aureus infec-
tion and improved over the next 48 hours.
Figure 3. A 14-year-old boy who presented with marked left-

may be necessary to retract the eyelids. If complete
sided facial pain. Prior to admission, he developed facial swelling
that progressed to involve the left eyelid. He was diagnosed with examination of the affected eye is not possible, imaging
left periorbital cellulitis and a tooth abscess, prompting intrave- and consultation with an ophthalmologist may be appro-
nous clindamycin therapy and tooth extraction. priate.
Infection must be differentiated from other causes of
eyelid swelling, such as allergic reactions (which usually
Other, less common organisms found in pediatric respond to antihistamine medications), edema due to
orbital abscess fluid and sinus cultures include S milleri, hypoproteinemia (classically presenting with bilateral
Haemophilus, Neisseria, diphtheroids, Bacteroides, Veil- eyelid edema and other associated signs of fluid reten-
lonella, Prevotella, Peptostreptococcus, and Moraxella ca-
tarrhalis. (1) Polymicrobial infections involving aerobic
and anaerobic bacteria also have been described in odon-
togenic disease.
Clinical Aspects
Unilateral erythema, swelling, warmth, and tenderness of
the eyelid can be seen in both periorbital and orbital cellu-
litis. Fever, systemic signs, and a significant degree of toxic-
ity may be present. Blurred vision, ophthalmoplegia, pro-
ptosis, and chemosis help identify orbital cellulitis because
they are signs of increased intraorbital pressure, which
should not be present in periorbital cellulitis (Fig. 5).
Hematogenous spread with periorbital seeding
should be considered in children younger than age 3
years who present with systemic signs of illness and
rapidly progressive eyelid swelling preceded by a viral
upper respiratory tract infection.
When evaluating a child for possible periorbital or
orbital cellulitis, a history of past sinus or dental disease,
previous eye surgery, and trauma should be explored. It Figure 5. An 11-year-old boy who has pan-sinusitis and left
can be challenging to assess the eye. The clinician should orbital cellulitis and presented with fever, severe left eye pain,
begin the examination with the least invasive maneuvers. proptosis, chemosis, and limitation of extraocular movements.
If there is a large amount of swelling around the eye, it Note that he has limited adduction of his left eye.

tion), and rarely, orbital wall infarction and subperiosteal teral antimicrobial coverage of both gram-positive and
hematomas in patients who have sickle cell disease. (7) gram-negative organisms. Transition to oral antibiotics
Several other clinical entities belong in the differential may be considered once significant improvement has
diagnosis of proptosis. One is idiopathic inflammation from been achieved, for a total 10- to 14-day course. A full
orbital pseudotumor, which can present with pain, propto- septic evaluation must be considered if the patient ap-
sis, local swelling, and conjunctival injection. Patients who pears toxic or evidence suggests neurologic involvement.
have orbital pseudotumor also may have diplopia, visual A high white blood cell count, C-reactive protein
loss, ptosis, and limited extraocular movements. Radio- value, or erythrocyte sedimentation rate may suggest the
graphic findings demonstrate inflammatory changes and an diagnosis of orbital cellulitis over the more superficial
abnormal mass density of the intraorbital soft tissues. Com- periorbital cellulitis. However, these studies alone never
puted tomography (CT) scan is essential for differentiating should be used to make a definitive diagnosis.
orbital pseudotumor from orbital cellulitis because pseudo- The clinician should try to obtain cultures for identi-
tumor requires corticosteroid administration for treatment. fication and sensitivity of the pathogens involved. Al-
(8) Other disorders that present with proptosis include though blood cultures are obtained to evaluate for bac-
orbital myositis, Wegener granulomatosis, sarcoidosis, leu- teremia, a retrospective study from Texas Children’s
kemia, Burkitt lymphoma, rhabdomyosarcoma, retinoblas- Hospital had only a 7% yield for a positive blood culture
toma, metastatic carcinoma, and histiocytosis. Dysthyroid in pediatric orbital cellulitis infections associated with
exophthalmos as a result of endocrine dysfunction also can sinus disease. Due to the low yield, routine blood cul-
present with proptosis. tures are not indicated for patients who lack evidence of
Periorbital cellulitis is diagnosed primarily on clinical bacteremia or systemic illness. Culture of other sites was
found to be more successful in identifying an organism.
findings and does not require routine laboratory or ra-
Ocular discharge can be cultured with high yield. Or-
diologic confirmation, unless the diagnosis is unclear or
bital, epidural abscess, and sinus fluid obtained surgically
neurologic involvement is a concern. Wound culture of a
may be positive in more than 90% of cases. (1) Less
purulent drainage site may be helpful if a resistant or un-
invasive culture techniques may be helpful, including
usual pathogen is suspected as well as blood cultures if
swabbing of the maxillary or ethmoid sinus aperture, just
systemic symptoms are present and hematogenous spread is
beneath the turbinates.
suspected.
Patients who have orbital cellulitis presenting with
eyelid swelling, diplopia, reduced visual acuity, abnormal
Management light reflexes, proptosis, or ophthalmoplegia should be
Management of simple periorbital cellulitis usually is admitted for inpatient care. In addition, any patient who
empiric and should offer coverage of Staphylococcus and appears systemically ill or presents with signs of central
Streptococcus (Table). Knowledge of local prevalence and nervous system (CNS) involvement such as lethargy,
characteristics of MRSA should determine the choice of vomiting, headache, seizure, or cranial nerve deficit
first-line therapy for this organism. No evidence suggests should be admitted. Finally, any patient for whom it is
that intravenous antibiotics are better than oral antibiot- not possible to examine the eye fully should be moni-
ics in the management of simple periorbital cellulitis (10) tored as an inpatient.
in terms of quicker recovery time or prevention of sec- Ideally, an interdisciplinary team comprised of a pediat-
ondary complications. Therefore, the choice of route ric ophthalmologist, pediatric otorhinolaryngologist, and
should be based on general appearance of the patient, pediatrician should provide inpatient care to patients re-
ability to take oral medication, compliance, and clinical quiring admission. Medical management with intravenous
progression of the disease. The typical length of therapy antibiotics most often is sufficient treatment. Antibiotic
is 7 to 10 days but ultimately should be guided by therapy should have empiric coverage against staphylo-
symptom resolution. Clinical improvement should be coccal and streptococcal species as well as organisms as-
evident within 24 to 48 hours. If expected improvement sociated with rhinosinusitis. MRSA coverage should be
does not occur, complications or resistant organisms may strongly considered. Clindamycin plus a second- or third-
be present, and consultation with an infectious disease generation cephalosporin is a reasonable initial regimen.
specialist, ophthalmologist, otolaryngologist, and neuro- Orbital cellulitis requires antibiotic therapy for a total of
surgeon should be considered. (11) 10 to 14 days. Transitioning from parenteral to oral antibi-
Periorbital cellulitis as a consequence of hematoge- otics may be considered once significant improvement has
nous seeding requires inpatient management with paren- been achieved.

Table. Management of Periorbital Cellulitis

Predisposing Factor Pathogen Management Other Considerations
Hordeolum (stye) Staphylococcus aureus Oral dicloxacillin, first-generation Warm compresses may
cephalosporin hasten drainage
Oral trimethoprim-sulfamethoxazole
(TMP-SMX) or clindamycin if
methicillin-resistant S aureus (MRSA)
is suspected
Dacryoadenitis, Streptococcus pneumoniae Empiric therapy based on Gram stain of Consider ophthalmologic
dacryocystitis S aureus aspirate consultation
S pyogenes
Haemophilus influenzae
Pseudomonas aeruginosa
Insect bite S aureus Oral dicloxacillin, first-generation
cephalosporin
Impetigo S pyogenes Oral TMP-SMX or clindamycin if MRSA
is suspected
Eczema Vancomycin for severe infections
Complicated S pneumoniae High-dose amoxicillin-clavulanate, oral Consider otolaryngologist
rhinosinusitis H influenzae second- or third-generation consultation
Moraxella catarrhalis cephalosporin (cefuroxime, cefdinir,
or cefpodoxime) for 10 to 14 days
If clinical improvement is not achieved,
consider intravenous cefotaxime or
ceftriaxone
Dental abscess Mixed aerobic and Clindamycin or amoxicillin-clavulanate/ Evaluation by a dentist is
anaerobic bacteria ampicillin-sulbactam suggested
Hematogenous spread S pneumoniae Parenteral third-generation
associated with H influenzae cephalosporin (cefotaxime or
preceding viral S pyogenes ceftriaxone) plus clindamycin or
upper respiratory S aureus vancomycin if MRSA is suspected
tract infection
From Custer et al. (9)
Dose suggestions follow; confirm all doses prior to use.
Amoxicillin/clavulanate: 80 to 90 mg/kg per day PO divided every 8 to 12 hours
Ampicillin/sulbactam: 100 to 200 mg/kg per day IV divided every 6 hours (based on ampicillin component)
Cefotaxime: 100 to 200 mg/kg per day IV divided every 6 to 8 hours
Ceftriaxone: 50 to 100 mg/kg per day IV divided every 12 to 24 hours
Clindamycin: 10 to 30 mg/kg per day PO divided every 6 to 8 hours, 25 to 40 mg/kg per day IV every 6 to 8 hours
Dicloxacillin: Mild/moderate infection, 12.5 to 25 mg/kg per day PO divided by every 6 hours; severe infection, 50 to 100 mg/kg per day PO divided every
6 hours
TMP/SMX: Mild/moderate infection, 8 to 12 mg/kg per day divided every 12 hours; severe infection, 20 mg/kg per day divided every 6 to 8 hours
Vancomycin: 40 mg/kg per day divided every 6 to 8 hours
Adjuvant therapies for rhinosinusitis, such as saline Contrast-enhanced CT scanning with sagittal, coronal,
nasal irrigation, antihistamines, decongestants, muco- and axial slices of the orbit and sinuses is the ideal modality
lytic agents, and intranasal steroids, currently are not for localizing sinus infection and staging the extent of
recommended. (11) One small retrospective study (12) orbital inflammation (Fig. 6). Indications for CT scan in-
reported that intravenous corticosteroids do not appear clude: 1) eyelid edema that makes complete examination
to affect clinical outcomes adversely and may be benefi- impossible; 2) presence of CNS involvement (such as focal
cial in the treatment of pediatric orbital cellulitis with neurologic deficits, seizure, or altered mental status); 3) de-
subperiosteal abscesses. However, corticosteroid therapy teriorating visual acuity or color vision, gross proptosis, or
may depress the patient’s immune response and allow or ophthalmoplegia; and 4) clinical deterioration or no im-
mask the progression of infection. Future prospective, provement after 24 to 48 hours of appropriate treatment.
randomized research is needed to clarify the role of Baseline CT scan should not be performed routinely due to
corticosteroids in treating orbital infections. radiation exposure. (3)

Figure 6. Contrast-enhanced computed tomography scan for

a patient who has orbital cellulitis. The sagittal image shows
marked left proptosis, intraorbital free air (solid arrow),
phlegmon formation, and left paranasal sinus opacification.
The coronal view demonstrates stranding of the intraconal fat
along the orbital floor (dotted arrow).
Figure 7. A 15-month-old girl who has recurrent periorbital

On CT scan, several changes may be evident in orbital cellulitis and was diagnosed with herpes simplex virus-1 via
cellulitis, including diffuse fat infiltration, subperiosteal direct fluorescent assay. She was treated with acyclovir.
abscess, and true orbital abscesses. Foreign bodies may
be detected, depending on the characteristics of the
foreign body. Although the incidence of orbital cellulitis is low,
The primary goals of surgical intervention include serious complications are likely if the infection is not
draining abscesses, releasing pressure on the orbit, and treated. Cavernous sinus thrombosis is one such unto-
obtaining cultures to guide antimicrobial therapy. Surgi- ward complication. This condition may be challenging to
cal consultants should determine whether surgery is in- diagnose because it may present similarly to orbital cel-
dicated. Possible surgical interventions for orbital cellu- lulitis or may occur as a consequence of it. Typically,
litis include sinus surgery, canthotomy, orbital surgery, patients who have cavernous sinus thrombosis have acute
combined sinus and orbital surgery, and neurosurgery. or slowly progressive proptosis, periorbital edema, and
ophthalmoplegia. Loss of vision and meningismus may
Complications and Prognosis be late findings.
Complications of periorbital cellulitis include local ab- Both orbital cellulitis and cavernous sinus venous
scess formation, ensuing orbital cellulitis, and intracranial thrombosis can extend and progress to intracranial infec-
extension of infection. tions, such as subdural empyema, intracerebral abscess,
Recurrent periorbital cellulitis (RPOC) is a clinical extradural abscess, and meningitis. These severe compli-
condition described as three periorbital infections oc- cations are associated with high morbidity and some-
curring within 1 year, spaced by at least 1 month of times with mortality. Septic emboli of the optic nerve as
convalescence. This entity should be distinguished from well as ischemia due to compression may cause visual
treatment failure due to microbial resistance. The most loss. Magnetic resonance imaging may be of value in
common causes of RPOC are comparable to those of determining these circumstances.
acute periorbital infection. Other underlying causes
must be considered, including atopy, nonbacterial or-
ganisms such as herpes simplex (Fig. 7) and atypical Case Study Follow-up
mycobacteria, collagen vascular disorders, systemic dis- Laboratory tests showed a white blood cell count of
eases (such as human immunodeficiency virus infection), 15.86⫻103/mcL (15.86⫻109/L) (59% neutrophils, 1%
intraorbital or paranasal neoplasms, and structural/ bands, 28% lymphocytes, 12% monocytes), a hemoglobin
anatomical abnormalities (osteomeatal obstruction, ab- concentration of 13.3 g/dL (133 g/L), and a platelet count
normal uncinate process). A thorough clinical reassess- of 497⫻103/mcL (497⫻109/L). A CT scan of the orbits
ment and, in some cases, imaging may help elicit the was obtained due to the inability to examine the eye fully.
fundamental cause. (13)(14) Imaging revealed extensive left periorbital soft-tissue swell-

ing, with extension of edema or a phlegmon noted between ACKNOWLEDGMENTS. Special acknowledgments to
the medial rectus muscle and adjacent lamina papyracea. Dr Tere Vives, Dr Pulin Shah, Alonso Sierra, and
Complete opacification of both maxillary and ethmoid si- Ximena San Vicente for their invaluable assistance.
nuses was noted.
The patient was admitted to the hospital with ophthal- References
mology and otorhinolaryngology consultation and placed 1. McKinley SH, Yen MT, Miller AM, et al. Microbiology of
on intravenous ceftriaxone and clindamycin therapy and pediatric orbital cellulitis. Am J Ophthalmol. 2007;144:497–501
2. Liu IT, Kao SC, Wang AG, Tsai CC, Liang CK, Hsu WM.
pain control. After 3 days of hospitalization, he showed Preseptal and orbital cellulitis: a 10-year review of hospitalized
significant improvement, with decreased eyelid swelling patients. J Chin Med Assoc. 2006;69:415– 422
and resolution of pain. He was switched to oral antibiotic 3. Ho CF, Huang YC, Wang CJ, Chiu CH, Lin TY. Clinical
therapy and discharged from the hospital with follow-up analysis of computed tomography-staged orbital cellulitis in chil-
dren. J Microbiol Immunol Infect. 2007;40:518 –524
appointments with his pediatrician, ophthalmologist, and
4. Centers for Disease Control and Prevention. Invasive Hae-
otorhinolaryngologist. mophilus influenzae type B disease in five young children—
Minnesota, 2008. MMWR Morbid Mortal Wkly Rep. 2009;58:1–3
5. Botting AM, McIntosh D, Mahadevan M. Paediatric pre- and
post-septal peri-orbital infections are different diseases. A retrospective
review of 262 cases. Int J Pediatr Otorhinolaryngol. 2008;72:377–383
Summary 6. Blomquist PH. Methicillin-resistant Staphylococcus aureus in-
• Eyelid swelling is a common pediatric complaint and fections of the eye and orbit. Trans Am Ophthalmol Soc. 2006;104:
must be evaluated expeditiously by a pediatrician. 322–345
• Based primarily on consensus and observational 7. Ozkavukcu E, Fitoz S, Yagmurlu B, Ciftci E, Erden I, Ertem M.
studies, differentiation of periorbital and orbital Orbital wall infarction mimicking periorbital cellulitis in a patient
cellulitis must be attempted through thorough with sickle cell disease. Pediatr Radiol. 2007;37:388 –390
history taking, including predisposing factors, and 8. Anderson J, Thomas T. Orbital pseudotumor presenting as
physical examination focused on the eye. (5) orbital cellulitis. Can J Emerg Med. 2006;8:123–125
• CT scan scanning may aid in the diagnosis, according 9. Custer JW, Rau RE, Lee CK, eds. The Harriet Lane Handbook:
to primarily consensus and observational studies. (3) a Manual for Pediatric House Officers/the Harriet Lane Service,
• Based primarily on consensus and observational studies, Children’s Medical and Surgical Center of the Johns Hopkins Hos-
simple periorbital cellulitis may be treated empirically pital. 18th ed. Philadelphia, Pa: Mosby; 2008
with oral antibiotic therapy and close follow-up. (10) 10. Al-Nammari S, Roberton B, Ferguson C. Should a child with
• Consensus and observational studies suggest that early preseptal periorbital cellulitis be treated with intravenous or oral
recognition and treatment of orbital cellulitis is antibiotics? Emerg Med J. 2007;24:128 –129
essential. (2) 11. American Academy of Pediatrics. Clinical practice guideline:
• When a patient presents with ophthalmoplegia and management of sinusitis. Pediatrics. 2001;108:798 – 808
proptosis, consensus and observational studies 12. Yen MT, Yen KG. Effect of corticosteroids in the acute man-
recommend initiation of appropriate empiric antibiotic agement of pediatric orbital cellulitis with subperiosteal abscess.
therapy targeted at MRSA and Streptococcus. (6) Ophthalmic Plast Reconstruct Surg. 2005;21:363–367
• Based primarily on consensus and observational studies, 13. Sorin A, April MM, Ward RF. Recurrent periorbital cellulitis:
the patient’s clinical course must be monitored closely, an unusual clinical entity. Otolaryngol Head Neck Surg. 2006;134:
with clinical deterioration or lack of improvement 153–156
possibly requiring imaging to look for underlying 14. Karkos PD, Karagama Y, Karkanevatos A, Srinivsan V. Recur-
complications and determine the need for surgical rent periorbital cellulitis in a child: a random event or an underlying
intervention. anatomical abnormality? Int J Pediatr Otorhinolaryngol. 2004;68:
1529 –1532

PIR Quiz
Quiz also available online at http://www.pedsinreview.aappublications.org
11. A 3-year-old unimmunized child presents with a 1-day history of acute left eyelid swelling. She also has had
mild rhinorrhea and nasal congestion for the past 3 days. She never has been hospitalized with any serious
illness. Of note, her father intermittently complains of skin boils, which usually resolve without treatment.
Physical examination of the nontoxic-appearing child reveals swollen, erythematous, indurated eyelids of the
left eye and mild nasal discharge. Of the following, the MOST appropriate management plan is:
A. Anticipatory guidance only.
B. Antihistamine and follow-up visit if symptoms worsen.
C. Hospital admission for intravenous (IV) antibiotics (to cover methicillin-resistant Staphylococcus aureus
[MRSA] and Haemophilus influenzae type b).
D. Initiation of oral antibiotics to cover MRSA and H influenzae type b.
E. Ophthalmology consultation and computed tomography scan of the orbits.
12. You have been caring for a 2-year-old previously healthy boy who has been hospitalized for presumed
orbital cellulitis of his right eye. After receiving IV antibiotics for 36 hours, his right eyelid swelling, eye
pain, and proptosis have improved noticeably, although they have not resolved completely. In discussion
with the family, your plan now includes which of the following?
A. Addition of a third IV antibiotic to hasten recovery.
B. Addition of steroids to hasten recovery while receiving antibiotics.
C. Consultation with a pediatric ophthalmologist for possible surgical intervention.
D. Continuation of both IV antibiotics until all symptoms resolve, then discharge.
E. Switching to comparable oral antibiotics to complete a 10- to 14-day course at home.
13. A 6-year-old child is brought to the emergency department by his parents because of upper respiratory
tract symptoms, a progressively swollen left eye, and altered mental status. He has been otherwise healthy
and is fully immunized. Upon examination, he is difficult to arouse. Local signs include a markedly swollen
left eye with proptosis. Eye movements are difficult to assess because of the boy’s poor neurologic status.
He is febrile, but hemodynamically stable. The most likely pathogenesis is:
A. Acute bacterial meningitis, with secondary infection of the left orbit.
B. Bacteremia causing both ocular and intracranial illness.
C. Head trauma, with ocular and intracranial manifestations.
D. Intracranial mass causing ocular and neurologic manifestations.
E. Orbital cellulitis, with the neurologic complication of bacterial meningitis.
14. A father calls your office to report that his 2-year-old daughter has had nasal congestion and fever for
the past 2 days. She received a nonprescription medication this morning, and today her right eye is
“swollen shut.” When she arrives in your office, she is febrile but nontoxic. Her right eyelids are swollen
and erythematous. It is nearly impossible to determine whether her extraocular movements are normal, but
she exhibits increased tearing of the affected eye. Of the following, the most reasonable diagnosis and
plan of treatment are:
A. Allergic reaction and trial of antihistamine at home.
B. Periorbital cellulitis and IV antibiotics and CT scan of the orbits.
C. Periorbital cellulitis and ophthalmology consultation and IV antibiotics.
D. Periorbital cellulitis and oral antibiotics at home.
E. Reactive periorbital swelling from sinusitis and nasal decongestant at home.

Andrea Hauser and Simone Fogarasi
Pediatr. Rev. 2010;31;242-249
DOI: 10.1542/pir.31-6-242


Research and Statistics: A Question of Time: Cross-sectional Versus
Longitudinal Study Designs
Sarah Lindstrom Johnson
Pediatr. Rev. 2010;31;250-251
DOI: 10.1542/pir.31-6-250

research and statistics
A Question of Time:
Cross-sectional Versus Longitudinal
Study Designs
Sarah Lindstrom Johnson, PhD*
Case Study between variables. They also can es-

You are seeing a 12-year-old boy who tablish the prevalence of a problem.
has attention-deficit/hyperactivity A cross-sectional design allows for
disorder (ADHD). Like so many of his the determination that children who
peers, he loves video games and spends have ADHD are more likely to report
many hours a day playing. You know playing video games. However, it
that gamers spend an average of would not be possible to determine
8 hours each week playing. Besides the that they play more video games be-
lost opportunity to exercise, you begin cause they have ADHD or that their
Author Disclosure to wonder about the effect of video video-game playing led to ADHD.
Dr Johnson has disclosed no financial games on behavior. Are children who These questions imply causality, for
relationships relevant to this article. play video games more likely to have which a longitudinal study design is
ADHD? Embedded in your question needed.
This commentary does not contain a
are two possible lines of inquiry: Causality necessitates a time or-
discussion of an unapproved/
1) Does video game playing cause der. To determine that video game
investigative use of a commercial ADHD? and 2) Are children who playing causes ADHD, it is necessary
product/device. have ADHD more likely to play video to determine that the video game
games? Each question suggests a playing happened before the ADHD.
slightly different study design (Table). Longitudinal study designs with data
collection points occurring over time
Definitions permit this determination. Longitu-
In cross-sectional study designs, data dinal study designs have three differ-
collection occurs at one point in ent variants. A longitudinal design
time. In longitudinal study designs, that has repeated measures on the
subjects are followed over time, with same individuals is called a panel
data collection occurring at predeter- study and typically is used to deter-
mined intervals or at set events (eg, mine causality at the individual level.
graduation from high school). The A specific type of panel study is the
most powerful longitudinal study de- cohort study, in which a group of
signs also are called prospective study individuals determined by a specific
designs because they follow subjects event (eg, a certain birth year) are
forward over time. Longitudinal de- followed over time. Another type of
signs allow for a determination of the longitudinal design, called a repeated
timing of events and, therefore, can cross-sectional study, attempts to
discern something about the order of make causal inferences at the popula-
effects. tion level by surveying a random
sample of the population at different
points in time.
Use of Study Designs
Cross-sectional study designs allow
for the examination of associations Limitations
A difficulty faced by both longitudi-
*General Academic Pediatrics Fellow, Johns Hopkins nal study designs and cross-sectional
School of Medicine, Baltimore, MD. research designs is determining

research and statistics
Table. Summary of Designs

Study Design Definition Strengths Weaknesses
Cross-Sectional Single data collection point ● Quick ● Difficult to determine causality
● Inexpensive ● Possible spurious associations
● Establishes prevalence
● Suggests future research directions
Longitudinal Multiple data collection ● Can determine causality ● Time-consuming
Prospective points occur over time ● Can monitor trends ● Expensive
Retrospective ● Less concerned with spuriousness
whether an association is true (real) dition, longitudinal studies must be Conclusion

or false (spurious). An association concerned with subject fatigue and The research question dictates the
can be spurious if a third variable is attrition. Ensuring that a representa- appropriate study design. If you are
related to both the independent tive sample stays representative in- interested in knowing if children
(video game playing) and dependent volves a major investment of both who have ADHD are more likely
variable (ADHD). The association time and money on the part of the to play video games (ADHD and
then would be a result of confound- researcher. Due to this investment, video game playing are associated), a
ing and would be noncausal. For ex- cross-sectional study designs serve an cross-sectional design would answer
ample, confounding would occur if important role in research because your question most efficiently. How-
television viewing was related to they suggest areas in which longitu- ever, if you are interested in know-
both video game playing and dinal studies could be beneficial. ing if playing video games cause
ADHD. In this case, it would be There are methods to bypass ADHD, a longitudinal study design
impossible to determine whether some of the limitations of each study is necessary. Of note, published
video game playing was causing design. In a cross-sectional study de- cross-sectional studies suggest an as-
ADHD or whether television view- sign, it is possible to ask participants sociation between video games and
ing was causing ADHD and video about their previous behavior. This ADHD but caution that longitudinal
game playing simply was related to questioning is most beneficial when research is needed to establish causal-
television viewing (Figure). the information asked to be recalled ity.
Cross-sectional designs do offer can be remembered accurately. Lon-
some benefits. They usually are quick gitudinal designs also can use infor-
and relatively inexpensive to con- mation about previous behavior.
duct. By definition, longitudinal Suggested Reading
Such studies are called retrospective Chan PA, Rabinowitz T. A cross-sectional
studies take time to conduct. In ad- study designs and many times involve analysis of video games and attention-
the use of data already collected (eg, deficit hyperactivity disorder symptoms
medical records). Another possibility in adolescents. Ann Gen Psych. 2006;5:
16 –26
for longitudinal studies is the use of
Coggan D, Rose G, Barker DJP. Epidemiol-
secondary data sets, meaning that the ogy for the Uninitiated. 4th ed. London,
researchers use longitudinal data that United Kingdom: BMJ Publishing
were collected for another purpose Group; 1997:Chapters 7 and 8. Ac-
to answer their question. A potential cessed March 2010 at: http://
www.bmj.com/epidem/epid.html
drawback to this method is that the
Schuster DP, Powers WJ. Translational and
variables needed to address possible Experimental Research: Clinical Re-
spurious associations may not be search. Philadelphia, Pa: Lippincott, Wil-
Figure. Possible spurious relationships. available. liams & Wilkins; 2005

Research and Statistics: A Question of Time: Cross-sectional Versus
Longitudinal Study Designs
Sarah Lindstrom Johnson
Pediatr. Rev. 2010;31;250-251
DOI: 10.1542/pir.31-6-250


Ethics for the Pediatrician: Autonomy, Beneficence, and Rights
Christy L. Cummings and Mark R. Mercurio
Pediatr. Rev. 2010;31;252-255
DOI: 10.1542/pir.31-6-252

ethics for the pediatrician
Autonomy, Beneficence, and Rights

Christy L. Cummings, MD,* Mark R. Mercurio, MD, MA†
Editor’s Note: In response to the addi- Autonomy

tion of a new section entitled Ethics for The word autonomy derives from the
Primary Pediatricians to the Ameri- Greek words auto, meaning self, and
can Board of Pediatrics’ core content, nomos, meaning governance or rule.
Pediatrics in Review offers a series of The principle of autonomy refers to
articles on many aspects of ethical the individual’s right (in this case, the
decision-making. The writing and re- patient’s right) to make decisions
viewing of articles are contributed pri- and act on them freely and without
marily by members of the American interference. (1) One person’s right
Academy of Pediatrics Section on Bio- often implies another’s obligation,
ethics. and in the case of autonomy, if one
Author Disclosure person has a right to control what is
Drs Cummings and Mercurio have done to his or her body (eg, the right
Introduction to refuse a particular treatment), this
disclosed no financial relationships
Unique to pediatrics is the physician- decision implies an obligation for
relevant to this article. This patient-parent relationship. Medical others to respect that autonomy and
commentary does not contain a decisions are made best with the not forcefully override a patient’s re-
discussion of an unapproved/ rights and obligations of each of fusal. The principle of respect for au-
investigative use of a commercial these individuals kept in mind as well tonomy is considered by many to be
as an understanding of widely ac- at the core of modern medical ethics.
product/device.
cepted principles of medical ethics. At its most basic, it implies the pa-
This article presents a brief overview
tient’s right to refuse and the physi-
of the ethical principles of autonomy
cian’s obligation to respect that re-
and beneficence; the patient’s best
fusal.
interest standard; and the rights of
There are at least two important
parents, children, and adolescents in
qualifications to the right to auton-
medical decision-making. Each is
omy in the medical setting. First, the
discussed in light of relevant policies
decision-maker should possess the
and guidelines of the American
capacity to make the decision at
Academy of Pediatrics (AAP). It
hand. The term “capacity” refers to
should be noted that the principle-
the degree to which an individual has
based analysis described herein is one
reasonable approach to ethical the ability to understand a proposed
decision-making in the practice of therapy or procedure, including its
pediatrics, but there are others. The risks, benefits, and alternatives; to
reader also is encouraged to consider communicate relevant questions;
other approaches, such as care-based and to arrive at a decision consistent
ethics or feminist ethics, to gain a with his or her values. (1) In most
fuller appreciation of the issues. (1) situations, the presence or absence of
(2)(3) capacity seems clear; most adults are
believed to possess capacity unless
there is compelling evidence to the
*Department of Pediatrics, Division of Neonatology,
contrary (eg, significant cognitive
Yale University School of Medicine, New Haven, impairment). If capacity is in ques-
Conn. tion, psychiatric consultation occa-
†
Associate Professor, Department of Pediatrics, Yale
University School of Medicine; Director, Yale sionally is sought. Second, the right
Pediatric Ethics Program, New Haven, Conn. of a decision-maker who possesses

the capacity to refuse any therapy case of children, this role generally ment, surgical or medical, by an adult
does not necessarily imply a right to falls to the parents. (10) who has the capacity. The situation is
demand any therapy. (4) In some more complex, however, when the
settings, the physician may have the Beneficence and Patient’s patient possesses the capacity regard-
right, and perhaps even the obliga- Best Interest ing some decisions, but not others,
tion, to refuse a patient’s demand for The principle of beneficence under- particularly in the case of children, or
what clearly seems an inappropriate scores the moral obligation to act for when capacity waxes and wanes with
treatment. the benefit of others, including pro- time.
Because a truly autonomous deci- tecting the rights of others, prevent-
sion requires a decision-maker who ing harm to others, and helping
possesses capacity, the principle of those in danger. In medicine, the Parental Authority
patient autonomy usually does not principle of beneficence can be seen As previously noted, when a patient
apply in pediatrics. Children gener- as requiring the physician to act in is not competent to make medical
ally are not believed to possess the the patient’s best interest. When de- decisions for him- or herself, a surro-
capacity to make important medical ciding between two therapeutic op- gate decision-maker is designated.
decisions. Capacity, however, should tions, the physician should choose For adults, this surrogate most often
be seen not as an absolute, but as the one that maximizes the benefits is a spouse or an adult son or daugh-
dependent on the question at hand. compared with burdens to the pa- ter. In the case of children, this role
For example, young children gener- tient. nearly always falls to parents, based
ally do not possess the capacity to At times, beneficence can conflict on an understanding of their funda-
decide whether to receive medication with the principle of autonomy. For mental right to speak for and deter-
or surgery, but they may possess the example, if a physician feels strongly mine what is done to their child.
capacity to make lesser decisions, that a certain treatment would bene- Some refer to this role as a right to
such as which arm the injection goes fit a patient who possesses capacity, parental autonomy, but this designa-
in or what flavor of acetaminophen but the patient refuses the treatment, tion may be a misnomer because one
to be given. Depending on the age the two principles seem to require cannot have “self-rule” over some-
and on the particular situation, chil- very different actions. Currently, if one else. A more appropriate term is
dren generally should be included in the patient possesses capacity, auton- parental authority, and it is a right
the decision-making process, recog- omy generally is seen to trump benef- dating to antiquity. In ancient Rome,
nizing and respecting the child’s de- icence in the United States and many children were viewed as property, not
veloping ability to participate and, other countries, although possibly unlike livestock, giving the owner
where appropriate, to assent. (5)(6) not universally. The physician may (the father) wide discretion as to
This principle becomes less clear try to convince the patient that he or what was done with them. (1)
in the specific case of adolescents she (the physician) should not per- Although children no longer are
who, although not generally ac- form the treatment in question with- viewed in this light, the long-
corded all the same rights as adults, out the patient’s permission, even if standing historical tradition of paren-
may have the capacity to make med- the patient could die as a result of the tal authority remains a central aspect
ical decisions. Autonomy becomes refusal. This idea was expressed elo- of American and many other cultures
increasingly relevant as the adoles- quently and succinctly by the Amer- and is not disputed here. Contempo-
cent develops the necessary cognitive ican jurist Benjamin Cardozo in a rary justifications for parental author-
skills and experience. Engaging the famous case in the early 20th cen- ity have included: 1) Parents are re-
adolescent in decision-making re- tury: “Every human being of adult sponsible for bringing up their
garding his or her own health care years and sound mind has the right to children, and that responsibility nec-
recognizes that developing auton- determine what shall be done with essarily requires having rights for de-
omy. (7)(8)(9) Nevertheless, for ma- his body; and a surgeon who per- cision-making; 2) Apart from the
jor decisions, the principle of respect forms an operation without his pa- children, parents will be the ones
for autonomy usually does not apply tient’s consent commits an assault, most likely to have to live with the
in the setting of pediatrics. When a for which he is liable in damages.” consequences of any decisions made;
patient does not possess capacity to (11) This fundamental tenet of 3) Parents know the child best; and
decide, a surrogate decision-maker American medical ethics still stands 4) Affection and close family ties
speaks on the patient’s behalf. In the and applies to refusal of any treat- make parents most likely to reach

decisions based on the child’s best ing disagreement regarding a child’s

interest. (12) Summary best interest and treatment, it should
Some justifications are based on be remembered that the best ap-
the assumption that parents are best • The unique physician-patient- proach to medical decision-making
poised to decide and advocate for the parent triad that exists in in pediatrics is for the parents, pedia-
pediatrics requires careful
child, but some justifications clearly consideration of the ethical trician, and, when appropriate, the
are based on a perceived right of the principles involved when child to discuss the relevant informa-
parents themselves. It is widely be- making health-care decisions in tion and the risks and benefits of the
lieved that parents have a basic right pediatrics, including patient various options to arrive at a decision
to raise their children as they (the autonomy, parental authority, together. (5)(6) The parents’ right
beneficence, and the patient’s
parents) see fit. In this way, parental best interests standard. to make medical decisions for their
authority can be seen as consistent • The rights and obligations of all children should not be seen as abso-
not only with long-standing tradi- involved, as well as the lute, but neither should it be forgot-
tion but also with a rights-based ap- importance of the family unit, ten.
proach to surrogate decision- must be taken into account.
• Recognizing the difficulty
making. The choice of parents as sometimes inherent in
decision-makers also can be seen as balancing the best interests of
consistent with care-based or femi- the patient with parental rights,
References
we fully endorse the use of 1. Beauchamp TL, Childress JF. Principles
nist ethics, which places great em- of Biomedical Ethics. 6th ed. Oxford, United
phasis on the importance of relation- calling on institutional ethics
committees, as outlined by the Kingdom: Oxford University Press; 2009:
ships, family, and interdependence. AAP, for the resolution of 99, 114, 138, 207, 371
Parental authority, although ethically challenging cases. (16) 2. Cavalier R. Ethics of care. In: Online
Guide to Ethics and Moral Philosophy. 2002.
widely accepted, is more limited than
Accessed March 2010 at: http://
patient autonomy. For example, al- caae.phil.cmu.edu/cavalier/80130/part2/
though competent adults have the ent’s decision about an important II_7.html
right to refuse even lifesaving medi- medical question (eg, life-sustaining 3. Tong R, Williams N. Feminist ethics. In:
cal treatment for themselves, they medical treatment) seems to the phy- Zalta EN, ed. The Stanford Encyclopedia of
Philosophy. Fall 2009. Accessed March 2010
generally are not accorded the right sician to be “clearly opposed” to the
at: http://plato.stanford.edu/archives/
to do so for their children, as ex- child’s best interest, the physician fall2009/entries/feminism-ethics/
pressed by the United States Su- should seek to override that parental 4. President’s Commission for the Study of
preme Court: “Parents are free to decision. (14) The threshold of clar- Ethical Problems in Medicine and Biomed-
become martyrs themselves. How- ity may vary among physicians; phy- ical and Behavioral Research. Deciding to
Forego Life-Sustaining Treatment. 1983;
ever, it does not follow that they are sicians likely differ in their degree of
199 –229
free, in identical circumstances, to deference to parents in difficult ethi- 5. American Academy of Pediatrics Com-
make martyrs of their children before cal judgments. A useful guideline for mittee on Bioethics. Informed consent, pa-
they have reached the age of full and all pediatricians, however, has been rental permission, and assent in pediatric
legal discretion when they can make provided by the AAP Committee on practice. Pediatrics. 1995;95:314 –317
that choice for themselves.” (13) Bioethics: “All children are entitled 6. Mercurio MR, Adam MB, Forman EN,
Ekman Ladd R, Friedman Ross L, Silber
Thus, parental authority is not abso- to medical treatment that is likely to TJ. American Academy of Pediatrics Policy
lute and can be limited based on a prevent serious harm, or suffering, or statements on bioethics: summaries and
consideration of the child’s best in- death.” (15) In the rare case in which commentaries: part 1. Pediatr Rev. 2008;
terests. a pediatrician is concerned that a 29:e1– e8
It is expected that parents will de- child is being denied this basic right 7. American Academy of Pediatrics Com-
mittee on Bioethics. Communicating with
cide for a child based on their assess- due to parental choice, help from children and families: from everyday inter-
ment of the child’s best interest. others, such as the hospital ethics action to skill in conveying distressing infor-
Such judgments, however, are often committee and, in rare circum- mation. Pediatrics. 2008;121:e1441–
difficult and subjective, and when the stances, the courts, should be sought e1460
balance of benefits and burdens to as time allows. 8. Berlan ED, Bravendar T. Confidential-
ity, consent and caring for the adolescent
the child is not clear, the pediatrician Although the previously cited population. Curr Opin Pediatr. 2009;21:
generally should defer to the parents’ guidelines are important for the rela- 450 – 456
preference. However, when a par- tively rare situations involving ongo- 9. American Academy of Pediatrics Com-

mittee on Adolescence. The adolescent’s Calif: Wadsworth Publishing Co; 1996: committees. Pediatrics. 2001;101:205–
right to confidential care when considering 175–183 209 (Reaffirmed Oct 2008)
abortion. Pediatrics. 1996;97:746 –751 13. Prince v. Massachusetts, 321 US 158
10. Buchanan AE, Brock DW. Deciding for (1944). Accessed March 2010 at: http://
Others: The Ethics of Surrogate Decision supreme.justia.com/us/321/158/case.html# Online Resources
Making. Cambridge, United Kindgom: 170 AMA Code of Medical Ethics. Accessed
Cambridge University Press; 1989 14. American Academy of Pediatrics Com- March 2010 at: http://www.ama-
11. Schloendorff v. The Society of the New mittee on Bioethics. Guidelines on forgoing assn.org/ama/pub/physician-resources/
York Hospital (105 N.E. 92) 1914. Ac- life-sustaining medical treatment. Pediat- medical-ethics/code-medical-ethics.shtml
cessed March 2010 at: http://www. rics. 2000;106:1151–1153 National Institutes of Health. Belmont Re-
lawandbioethics.com/demo/Main/Legal 15. American Academy of Pediatrics Com- port: Ethical Principles and Guidelines
Resources/C5/Schloendorff.htm mittee on Bioethics. Religious objections to for the Protection of Human Subjects and
12. Forman EN, Ladd RE. Making deci- medical care. Pediatrics. 1997;99:279 –281 Research. 1979. Accessed March 2010
sions – whose choice? In: Ladd RE, ed. 16. American Academy of Pediatrics Com- at: http://ohsr.od.nih.gov/guidelines/
Children’s Rights Re-Visioned. Belmont mittee on Bioethics. Institutional ethics belmont.html#goc1

Ethics for the Pediatrician: Autonomy, Beneficence, and Rights
Christy L. Cummings and Mark R. Mercurio
Pediatr. Rev. 2010;31;252-255
DOI: 10.1542/pir.31-6-252


Index of Suspicion
Jenny H. Lin, Bhawana Arora, Usha Sethuraman and Carolyn Roy-Bornstein
Pediatr. Rev. 2010;31;257-261
DOI: 10.1542/pir.31-6-257

index of suspicion
Case 1 Presentation ders, is negative. She is not taking any

An 8-month-old previously healthy medications.
boy presents to the ED with fever On examination, her temperature
and nystagmus. He has been having is 37.0°C, heart rate is 132 beats/
cough, congestion, and rhinorrhea min, respiratory rate is 26 breaths/
for about 1 week. Over the past min, and blood pressure is 113/
2 days, he has been persistently fe- 52 mm Hg. She appears pale and
brile despite antipyretics. Today in anxious. A swelling is apparent on
his pediatrician’s office, he was diag- her left lower gum, with active bleed-
nosed with bilateral acute otitis me- ing near the second molar tooth and
The reader is encouraged to write dia (AOM). However, the physician mild swelling of her left cheek. There
possible diagnoses for each case before noted horizontal nystagmus in the is associated painless left submandib-
turning to the discussion. We invite child and sent him to the ED for ular lymphadenopathy. The rest of
readers to contribute case presentations further evaluation. the physical examination findings are
and discussions. Please inquire first by
contacting Dr. Deepak Kamat at Physical examination reveals a normal.
dkamat@med.wayne.edu. well-appearing, interactive, fair- Laboratory investigations reveal
skinned boy who has light, cream- Hgb of 4.2 g/dL (42 g/L), WBC
colored hair. He has bilateral otitis count of 14.2⫻103/mcL (14.2⫻
Author Disclosure media with profuse otorrhea. Com- 109/L), platelet count of 249⫻103/
Drs Lin, Arora, Sethuraman, and Roy- plete neurologic evaluation yields mcL (249⫻109/L), mean corpuscu-
Bornstein have disclosed no financial normal results with the exception lar volume of 62 fL, red cell distribu-
relationships relevant to these cases.
of intermittent, right-sided, jerky tion width of 18%, and reticulocyte
nystagmus. count of 2%. Serum iron concentra-
This commentary does not contain a
Initial laboratory results show a tion is 13 mcg/dL (2.3 mcmol/L),
discussion of an unapproved/ normal CBC and serum electrolyte ferritin is less than 2 ng/mL
investigative use of a commercial concentrations. A CSF examination (4.5 pmol/L), and total iron binding
product/device. does not show any evidence of infec- capacity is 571 mcg/dL (102.2
tion, and a head CT scan demon- mcmol/L). She receives a packed red
strates bilateral middle ear and mas-
toid effusions but no acute intra-
cranial process. An EEG is read as
Frequently Used Abbreviations normal. The patient is seen by an
ALT: alanine aminotransferase ophthalmologist for further investi-
AST: aspartate aminotransferase gation of the cause of his nystagmus,
BUN: blood urea nitrogen and the findings on the funduscopic
CBC: complete blood count examination lead to a clinical diagno-
CNS: central nervous system sis.
CSF: cerebrospinal fluid
CT: computed tomography
ECG: electrocardiography Case 2 Presentation
ED: emergency department A 3-year-old girl presents to the ED
EEG: electroencephalography with a history of intermittent swell-
ESR: erythrocyte sedimentation ing and bleeding from her gums for
rate the past 2 months. She has no history
GI: gastrointestinal of bleeding from any other site.
GU: genitourinary Yesterday she had one episode of
Hct: hematocrit hematemesis and appeared pale.
Hgb: hemoglobin There is no fever, cough, runny nose, Figure 1. CT scan showing a lucent,
MRI: magnetic resonance imaging dental caries, or trauma to the face. lytic lesion on the left side of mandible
WBC: white blood cell Past medical history and family his- (arrow), with displacement of tooth and
tory, including for bleeding disor- soft-tissue extension.

index of suspicion
blood cell transfusion because of se- cross-table lateral view, the preverte- Subsequent DNA sequence analysis
vere anemia. CT scan of the mandi- bral space, at the level of the second showed an alanine-to-valine amino
ble reveals a lucent, lytic lesion in the cervical vertebra, is increased acid mutation in the OCA2 gene that
left mandible with adjacent soft- (17 mm). An additional imaging confirmed the diagnosis.
tissue involvement (Fig. 1). study reveals the cause of his head
tilt. The Condition
OCA is a heterogeneous group of
Case 3 Presentation congenital disorders that affect mel-
A 13-month-old boy presents to the Case 1 Discussion anin synthesis and are transmitted in
office for follow-up of an ED visit the Many conditions can cause nystag- an autosomal recessive pattern. Each
day before. He had fallen from a mus. An infectious cause, such as of the four types of OCA (Table 1)
couch onto the top of his head and meningitis, encephalitis, or intracra- has varying degrees of hypopigmen-
was “holding his head funny.” He nial abscess, was considered in this tation of the skin, hair, and eyes.
has been having mild cold symptoms patient but was unlikely, given the Regardless of the type, all forms of
and a low-grade fever. He was dis- normal CBC, CSF analysis, and head OCA share common clinical features:
charged from the ED with a diagno- CT scan results. Nystagmus with cutaneous hypopigmentation, nys-
sis of torticollis; no diagnostic studies concurrent AOM always should raise tagmus, and the characteristic fundu-
were performed. the suspicion of labyrinthitis, but scopic findings of ocular albinism.
In the office, his rectal tempera- head imaging would confirm the di- Nystagmus, which is due to sensory
ture is 37.6°C, heart rate is agnosis. Intracranial neoplasms as deprivation resulting from retinal hy-
140 beats/min, respiratory rate is 38 well as seizures were unlikely in the popigmentation and foveal hypopla-
breaths/min, and oxygen saturation presence of normal findings on head sia, can be present at birth. More
is 100% on room air. He is fussy. His CT scan and EEG. Intrinsic ocular often, however, the nystagmus man-
head is normocephalic and atrau- disease resulting in sensory depriva- ifests later in life and usually is evi-
matic, but he has a definite head tilt tion and subsequent development of dent by 3 to 4 months of age.
to the left. His tympanic membranes abnormal eye movements should be OCA 2, caused by mutations in
are clear and have normal landmarks. investigated when there is no other the OCA2 gene leading to abnormal-
There is no oropharyngeal erythema obvious cause for the nystagmus. ities in P protein, has a prevalence of
or edema. His neck resists flexion. 1 in 38,000 to 1 in 40,000 in the
There is mild cervical lymphadenop- Diagnosis general population and 1 in 1,500 to
athy. His lungs are clear to ausculta- Funduscopic examination revealed a 1 in 8,000 in the African/African
tion. pale fundus, with hypopigmentation American population. More than 50
A swab of his throat is sent for of the retina, foveal hypoplasia, and genetic mutations have been identi-
culture. His WBC count is prominent choroidal vasculature fied on chromosome 15q11.2-q12,
24.6⫻103/mcL (24.6⫻109/L), consistent with ocular albinism. with a 2.7-kb deletion being the
with 86% neutrophils, 4% bands, 5% These characteristic ocular findings, most common mutation in the sub-
lymphocytes, and 5% monocytes. Ra- along with his skin and hair hypopig- Saharan African population.
diographs of the cervical spine dem- mentation, were suggestive of oculo- When an individual presents with
onstrate the left-sided head tilt. On cutaneous albinism type 2 (OCA2). OCA, isolated OCA must be dis-
Table 1. Types of Oculocutaneous Albinism

Genetic Testing Clinical Manifestations
1 TYR (tyrosinase) gene
1a No melanin synthesis ● Snow white scalp, skin, and hair at birth; translucent, blue irises; does not change
throughout life
1b Variable melanin synthesis ● Yellow/light/dark blond/brown hair, variable eye color; slight skin pigmentation
2 OCA2 (P) gene ● Pigmented hair at birth (light yellow, blond, brown) that varies little throughout life;
variable eye color
3 TYRP1 gene ● Light brown hair/skin that tans with exposure
● “Brown” OCA in African/African American populations

index of suspicion
tinguished from OCA that occurs Lessons for the Clinician The girl was discharged from the
as a part of another syndrome. hospital receiving iron supplementa-
● Nystagmus has many different
Hermansky-Pudlak syndrome (HPS) tion and with instructions for follow
causes, and a careful and thorough
has the exact same ocular and cuta- up with oromaxillofacial and inter-
history and physical examination,
neous findings as OCA, but individ- ventional radiology.
with attention to all organ systems,
uals who have HPS also present with
can help narrow the differential di-
bleeding diatheses and develop pul- The Condition
agnosis.
monary fibrosis later in life. Chediak- Vascular malformations (VMs) are
● In the absence of other obvious
Higashi syndrome (CHS) also mani- caused by disturbances in angiogen-
causes for the nystagmus, a formal
fests with OCA and bleeding esis and result in the persistence of
ophthalmologic evaluation should
diatheses, but individuals who have arteriovenous anastomoses, which
be obtained.
CHS have a history of frequent are formed during embryonic life.
● Ocular and oculocutaneous albi-
sinopulmonary infections, and exam- They may be arterial, venous, capil-
nism present with nystagmus and
ination of the peripheral blood lary, lymphatic, or mixed. VMs of
always should be part of the differ-
smear reveals large, eosinophilic, arterial or arteriovenous origin are
ential diagnosis in the appropriate
peroxidase-positive inclusion bodies termed “high-flow vascular malfor-
clinical setting.
in granulocytes. mations” and are the causes of mas-
● OCA is a benign group of hetero-
sive hemorrhages. They can occur in
geneous disorders whose primary
Management and Prognosis any organ in the body, in order of
clinical manifestations, decreased
OCA2 is a relatively benign disorder frequency: head and face, limbs,
visual acuity and skin cancer risk,
whose primary clinical manifestations trunk, and internal organs. Half of all
may be minimized with proper ed-
are limited to the skin and eyes. Be- intraosseous AVMs occur in the max-
ucation and close monitoring.
cause of the decreased melanin syn- illofacial region and seldom in the
thesis leading to hypopigmentation, (Jenny H. Lin, MD, Johns Hopkins mandible. Such lesions can go unrec-
patients are at increased risk for the Children’s Center, Baltimore, Md.) ognized for years. AVMs usually are
development of skin cancers, both present as developmental anomalies
squamous and basal cell carcinomas. from birth and grow in size with
This risk can be minimized through Case 2 Discussion physical growth. The peak incidence
meticulous sun protection. Individu- MRI revealed an expansive bony le- of presentation of intraosseous vas-
als who have OCA are counseled to sion in the left mandible with patchy cular lesions is at puberty, with equal
wear large, wide-brimmed hats; sun- enhancement and cortical break- frequency in males and females.
glasses; long-sleeved shirts; and sun- through. Magnetic resonance an- Spontaneous involution has not been
screen. giography did not show any feeding described.
Nystagmus may slow and become vessels. The child was taken to the
less prominent with age, but it does operating room (OR) for evaluation Clinical Symptoms
not disappear and can be exacerbated and biopsy. In the OR, a pulsating Patients usually present with soft-
by stress and fatigue. Hypoplasia of mass was felt at the base of the tooth, tissue swelling, local pain, teeth mo-
the fovea, where the cones’ photo- and aspiration yielded frank blood. bility, discoloration of overlying skin
receptors are located, results in de- The biopsy was aborted and the child and oral mucosal surfaces, paraesthe-
creased visual acuity that ranges from underwent arteriography, which re- sia and facial asymmetry, local pulsa-
20/30 to 20/400. The decrease in vealed a left posterior mandibular tion, periodontal bleeding, or spon-
visual acuity is nonprogressive, and arteriovenous malformation (AVM) taneous bleeding from the tooth.
vision remains stable after early child- with the nidus supplied by the distal Intraosseous AVMs near the alveolar
hood. Photophobia and photosensi- facial artery branches and by hyper- bone often present with pericoronal
tivity due to ocular hypopigmenta- trophied inferior alveolar artery bleeding, mobile teeth, and occlusal
tion can be minimized through the branches. Transcatheter emboliza- anomalies. Gingival bleeding seems
use of sunglasses. tion of the facial artery branches was to be a symptom common in most
Our patient was counseled and performed, and the parents were ad- documented cases. The recurrent
educated about appropriate protec- vised of the need for a second embo- bleeding can lead to severe anemia, as
tive measures and was followed in lization of the hypertrophied inferior seen in our patient. Instances of mas-
primary and subspecialty clinics. alveolar artery a few months later. sive hemorrhage, even exsanguina-

index of suspicion
tions, have been documented follow- requires a multidisciplinary team ap- Case 3 Discussion
ing the extraction of teeth associated proach. In the case of intraosseous Torticollis or wry neck is defined as a
with such AVMs. AVMs of the mandible, a combina- lateral head tilt with chin rotation
tion of embolization and surgery is toward the opposite side. Torticollis
Diagnosis recommended. Endovascular embo- is a symptom or sign, and a search for
Plain radiography does not reveal any lization therapy alone can cure its cause is essential. The differential
pathognomonic features for these le- mandibular and maxillary vascular diagnosis of torticollis is extensive. In
sions. AVMs may appear as honey- malformations that have limited soft- infants, congenital torticollis may be
comb radiolucencies or have a soap tissue involvement without the func- caused by skin webs, cervical spine
bubble appearance, and the differen- tional limitation and cosmetic abnormalities, or injury to the ster-
tial diagnosis includes the conditions deformities incurred with surgical re- nocleidomastoid muscle. Common
mentioned in Table 2. Root resorp- sections. For larger AVMs that have causes in older children include
tion may be seen on a plain radio- soft-tissue involvement, an emboli- trauma, cervical adenitis, and viral
graph, creating an appearance of a zation procedure controls the acute myositis. Ocular disorders such as
tooth floating in the adjacent alveolar hemorrhage but does not eliminate eye muscle weakness can cause head
osseous erosion. An incision biopsy the risk of a recurrence due to the tilt as the child adjusts his or her head
can help in making a definitive diag- presence of a collateral circulation. position to maintain binocularity.
nosis of the lesions, which mimic Torticollis associated with head-
Resection of the mandibular frag-
AVM on radiography. A CT scan and aches, vomiting, or neurologic find-
ment containing the lesion is needed
MRI can show the shape, extent, and ings suggests a brain tumor, particu-
for complete healing. In some cases,
boundaries of lytic lesion and the in- larly in the posterior fossa.
curettage of the resected fragment
volvement of major vessels in in- Torticollis in the setting of fever,
with immediate reimplantation has
traosseous AVM. Superselective fussiness, and upper respiratory tract
been tried, which reduces the mor-
angiography can provide crucial in- symptoms, as in this child, suggests
bidity associated with the procedure
formation on the feeder arteries, an infection of the deep neck spaces.
and the difficulty of reconstruction.
draining veins, flow rate, and collat- A CT scan of this boy’s neck revealed
Lesional curettage without resection
eral flows of the AVM. Such exami- a left retropharyngeal abscess (RPA)
preserves bone support, but the exci-
nations can be of great help for de- (Fig. 2).
finitive diagnosis. sion often is inadequate. Rarely, in
extensive vascular malformations, to- The Condition
Management tal eradication of the vascular malfor- An RPA develops in the potential
Management of AVMs in the maxil- mation may become difficult. space that extends from the base of
lofacial area typically is complex and the skull down to the mediastinum at
Lessons for the Clinician

Differential
Table 2.
Diagnosis of ● AVMs of the mandible may lead to

fatal hemorrhages, especially dur-
Lesions Appearing ing routine dental procedures.
as Honeycomb ● Any child presenting with gingival
bleeding or swelling should be sus-
Radiolucencies or pected of having this condition.
Soap Bubble ● Aggressive management with em-
bolization to stop the bleeding and
● Follicular cyst
● Aneurysmal cyst a close follow-up evaluation and
● Ameloblastomas possible surgical management
● Ameloblastic fibromas should be considered.
● Odontogenic keratocysts
● Giant cell granulomas
(Bhawana Arora, MD, Usha
● Malignant primary or metastatic
tumors Sethuraman, MD, Children’s Hospi- Figure 2. CT scan of the neck shows a
tal of Michigan, Detroit, Mich.) left retropharyngeal abscess.

index of suspicion
the level of the first or second tho- space at the level of C2 and more cervical spine; spread of infection to
racic vertebra. This space is limited than 14 mm at the level of C6 sug- adjacent structures, including the ca-
anteriorly by the posterior pharyn- gest RPA. Because expiration, swal- rotid sheath; and necrotizing fasciitis
geal wall, laterally by the carotid lowing, crying, and neck flexion can all have been reported. Most compli-
sheath, and posteriorly by the prever- change these radiographic dimen- cations occur with delayed diagnosis
tebral fascia. RPA usually follows an sions, CT scan is used commonly to or inadequate treatment.
upper respiratory tract infection that diagnose deep neck infections. This This patient was treated initially
involves the lymph nodes of Rou- imaging technique has a sensitivity of with intravenous ampicillin-
viere, which inhabit the retropharyn- 43% to 100% and specificity of 57% to sulbactam. His throat culture grew
geal space. Because these nodes usu- 88%. Nonetheless, differentiation be- GABHS. When he remained febrile
ally disappear by 3 to 5 years of age, tween cellulitis and true abscess may despite appropriate antibiotic ther-
RPA generally is an infection of not be possible. Routine laboratory apy, surgical incision and drainage
young children. Fifty percent of cases studies are not always helpful in es- was undertaken. His operative cul-
occur in children between 6 and 12 tablishing the diagnosis of RPA. An ture grew few GABHS, rare S aureus
months of age, and 96% of all cases elevated white blood cell count is susceptible to ampicillin-sulbactam,
occur in children younger than 6 common. A throat culture often and normal upper respiratory flora.
years of age. grows group A streptococci, the He was discharged from the hospital
Children who have RPA generally leading cause of pediatric RPA. on hospital day 4 receiving oral
present with cervical adenopathy, fe- ampicillin-sulbactam and has done
ver, difficulty swallowing, and neck Treatment and Prognosis well.
stiffness. If undetected, compression When diagnosed early, most cases of
of the trachea or pharynx by the en- RPA can be managed medically with
larging fluctuant mass causes drool- close monitoring, intravenous antibi- Lessons for the Clinician
ing, stridor, and respiratory distress. otics, and consultation with an oto-
Croup, epiglottitis, bacterial trache- laryngologist. Success rates vary from ● Retropharyngeal abscess is a dis-
itis, and peritonsillar abscess share 30% to 75%. Individual culture re- ease of infants and young children
many of these clinical findings. sults and local bacterial susceptibility whose diagnosis can be challeng-
RPA often is a polymicrobial in- patterns should guide antibiotic se- ing.
fection. Group A beta-hemolytic lection when available. Intravenous ● Early recognition and treatment is
Streptococcus (GABHS) is the most clindamycin, ampicillin-sulbactam, crucial to avoid serious complica-
common pathogen cultured in RPA. and cefazolin are reasonable choices, tions. Careful history and physical
Other isolates include viridans strep- although consideration of potential examination and a high index of
tococci, Staphylococcus, Bacteroides, methicillin-resistant S aureus in- suspicion are critical to making the
Peptostreptococcus, Fusobacterium, volvement may require the addition diagnosis.
and rarely Haemophilus and Kleb- of vancomycin or linezolid. Surgical
siella. drainage should be considered for (Carolyn Roy-Bornstein, MD,
children who do not respond Merrimack Valley Child & Adoles-
Diagnosis promptly or worsen with conserva- cent Health, Haverhill, Mass.)
Imaging studies establish the definitive therapy or who present with se-
tive diagnosis of RPA. Lateral neck vere respiratory compromise. To view Suggested Reading lists for
films are readily available and can Complications are rare but may be these cases, visit http://pedsinreview.
provide valuable clues to the diagno- grave. Airway compromise; aspira- aappublications.org and click on In-
sis. More than 7 mm of prevertebral tion pneumonia; osteomyelitis of the dex of Suspicion.

Index of Suspicion
Jenny H. Lin, Bhawana Arora, Usha Sethuraman and Carolyn Roy-Bornstein
Pediatr. Rev. 2010;31;257-261
DOI: 10.1542/pir.31-6-257

Supplementary Material Supplementary material can be found at:

/DC1

Toilet Training
Diane M. Howell, Karen Wysocki and Michael J. Steiner
Pediatr. Rev. 2010;31;262-263
DOI: 10.1542/pir.31-6-262

in brief
In Brief
Toilet Training
Diane M. Howell, MD Racial and Socioeconomic Differ- In contrast to other less developed
Karen Wysocki, MA, MEd ences? Horn IB, Brenner R, Rao M, countries, the average age to complete
Michael J. Steiner, MD Cheng TL. J Pediatr. 2006;149: toilet training in the US has been in-
Department of Pediatrics 165–168 creasing steadily over recent decades,
North Carolina Children’s Hospital at from younger than 18 months of age in
the University of North Carolina Toilet training provides a universal chal- the late 1940s to 27 months in 1980 to
Chapel Hill, NC lenge to children, parents, and physi- 37 months in 2003. Studies within the
cians. Despite families and physicians US have suggested differences in toilet
having addressed this issue for genera- training among America subcultures:
Author Disclosure tions, there still is no consensus regard- both African American caregivers and
Drs Howell, Steiner, and Serwint and ing the best method or even a standard caregivers from lower socioeconomic
Ms Wysocki have disclosed no definition of toilet training. This uncer- statuses have expectations for earlier
financial relationships relevant to tainty occurs, in part, because of the training. In addition, sex differences
wide variety of parental preferences have been noted, with girls tending to
this In Brief. This commentary does
and expectations for toilet training. In achieve toilet training milestones ap-
not contain a discussion of an addition, few studies compare the effi- proximately 2 to 3 months ahead of
unapproved/investigative use of a cacy of different strategies, which lim- boys. On average, girls achieve urine
commercial product/device. its the ability of physicians to make control at approximately 32.5 months
evidence-based recommendations. For of age versus 35 months for boys; the
these reasons, toilet training continues corresponding values for stool control
The Effectiveness of Different Methods to be a complex behavioral and devel- are 31.5 months and 34.7 months of
of Toilet Training for Bowel and opmental stage that has a variety of age. Barriers to effective toilet training
Bladder Control. Klassen TP, acceptable approaches and methods. include the coexistence of family stres-
Kiddoo D, Lang ME, et al. Bethesda, One of the questions posed most fre- sors such as divorce, death in the fam-
Md: Agency for Healthcare Research quently to physicians is when to initiate ily, the expectation of a new baby, or
and Quality; 2006:No. 07-E003 toilet training. There is no definitive the planning of a move.
Toilet Training Guidelines: Clinicians— answer to this query, and many factors A variety of factors influence the
The Role of the Clinician in Toilet
influence when a child is ready to begin readiness of an individual child to begin
Training. Stadtler AC, Gorski PA,
the process, such as sex, individual neuro- the process. To be successful in inde-
Brazelton TB. Pediatrics. 1999;
103(suppl):1364 –1366 physiologic and developmental status, pendent toilet training, children must
Sequential Acquisition of Toilet- parental expectations, cultural beliefs, be “neurophysiologically ready,” which
training Skills: A Descriptive Study and presence of familial stressors. Al- includes the ability to follow direc-
of Gender and Age Differences in though physicians in the United States tions, be aware of their urges, have dry
Normal Children. Schum TR, (US) usually broach the topic at the 18- periods (of approximately 2 hours or
Kolb TM, McAuliffe TL, Simms MD, or 24-month health supervision visit, more), have the desire to remain dry
Underhill RL, Lewis M. Pediatrics. literature from around the world docu- and emulate older family members, and
2002;109:E48 ments successful toilet training of in- have the necessary motor skills to sit
Toilet Training of Healthy Young Tod- fants 4 to 6 months of age. This stark still on the toilet and pull clothes and
dlers: A Randomized Trial Between a
difference likely is due, in part, to cultural underwear up and down.
Daytime Wetting Alarm and Timed
differences and differences in definition, Numerous strategies and methods
Potty Training. Vermandel A,
Weyler J, De Wachter S, Wyndaele although it is unclear if physiologic dif- may be used for toilet training. Among
JJ. J Dev Behav Pediatr. 2008;29: ferences are also present or if lifestyle the most commonly implemented are
191–196 and varied parental expectations miti- the passive/child-oriented approach (as
Beliefs About the Appropriate Age for gate the need for full neurophysiologic supported by the American Academy of
Initiating Toilet Training: Are There readiness. Pediatrics) and the “toilet-train-in-a-

in brief
day” method proposed by Azrin and care Research and Quality evidence- training. Finally, physicians should con-
Foxx. More recently, data have been based publication on toilet training tinue to be a source of support to
published supporting the use of enure- found that both of these strategies parents throughout the process to help
sis alarms as an initial method of train- resulted in successful toilet training for reduce unnecessary stress and frustra-
ing rather than a tool to eliminate healthy children. tion for the entire family.
persistent nocturnal enuresis. Regardless of the method employed
The passive/child-oriented method to toilet train, some children have de-
is a relaxed approach that emphasizes layed mastery of these skills, and in the Comment: I am reminded of a pa-
the importance of the child’s interest case of severe physical or development tient in my practice who had emigrated
in toilet training and attempts to min- disabilities, never may achieve mastery. from China. His mother proudly told
imize the stress and demands sur- If successful toilet training is delayed, me that she had toilet trained him by
rounding the process. Children are in- physicians should perform a history 6 months of age. She was intensely
troduced to a potty-chair and gradually and physical examination to screen for observant of his facial grimacing and
progress from simply sitting on it to using signs of developmental delay, genito- would hold him over the toilet when
it appropriately with the encourage- urinary abnormalities, or constipation. she perceived his need to defecate or
ment of positive reinforcement. “Ac- If the evaluation does not reveal any urinate. Her motivation was that they
cidents” are acknowledged but never abnormalities, parents should be reas- had neither washing machine nor dis-
should result in reprimands or punish- sured and encouraged to de-emphasize posable diapers, so this process mini-
ment. This method typically takes weeks the process in an effort to transfer more mized the amount of soiled cloth dia-
to months for the child to achieve responsibility to the child. Toddlers also pers. This strategy is termed “assisted
continence. are in the process of developing in- infant toilet training” and is used by
In contrast, the “train-in-a-day” creased independence, and this issue parents in many developing countries
method involves an intense period of can produce an unwanted power strug- throughout the world. This example
instruction designed to achieve conti- gle. Parents should be reminded to demonstrates the important cultural
nence in 24 to 48 hours. The training is provide incentives for desired toileting differences and parental expectations
conducted in one room and generally behaviors and to avoid criticism. All regarding toilet training. To allow pedi-
begins with a doll that can wet in the caregivers for the child should follow a atricians to provide evidence-based
potty to demonstrate toileting actions. consistent toilet training plan. anticipatory guidance, future research
Then the child is taken through the Toilet training is a normal develop- needs to determine standardized defi-
same motions and subsequently pro- mental task, but it continues to stimu- nitions, paying attention to cultural
vided with large amounts of liquids to late frequent questions and concerns differences. Randomized trials should
induce frequent urination. The child from parents. Physicians should edu- be conducted that compare the effec-
also is given frequent reminders and cate parents about neurophysiologic tiveness of different approaches, in-
checked for dryness every 3 to 5 min- readiness and provide realistic expec- cluding the assisted infant toilet train-
utes with positive reinforcement (eg, tations based on age and sex popula- ing and any resultant adverse outcomes
praise, toys, or food) for all successful tion averages for achieving continence. associated with these strategies.
toileting behaviors. “Accidents” result Physicians also must demonstrate
in the child being verbally reprimanded awareness and understanding that cul-
or taking the responsibility to change tural differences and personal desires Janet Serwint, MD
into dry pants. The Agency for Health- may affect the type and timing of Consulting Editor, In Brief

Toilet Training
Diane M. Howell, Karen Wysocki and Michael J. Steiner
Pediatr. Rev. 2010;31;262-263
DOI: 10.1542/pir.31-6-262


North American Dimorphic Fungal Infections in Children
Brian L. Montenegro and John C. Arnold
Pediatr. Rev. 2010;31;e40-e48
DOI: 10.1542/pir.31-6-e40
http://pedsinreview.aappublications.org/cgi/content/full/31/6/e40

Article infectious diseases
North American Dimorphic Fungal Infections

in Children
Brian L. Montenegro,
MD,* John C. Arnold,
MD*† 1. Understand the term “dimorphic fungi.”
2. Identify the geographic regions in which coccidioidomycosis, histoplasmosis, and blasto-
mycosis occur.
Author Disclosure 3. Describe the clinical manifestations of infections with the dimorphic fungi endemic to
Drs Montenegro and North America.
Arnold have disclosed 4. List the diagnostic tests of choice for the different dimorphic fungi.
no financial 5. Discuss the general treatments for infections caused by dimorphic fungi.
relationships relevant
to this article. This
commentary does not
Introduction
contain a discussion The term “dimorphic fungus” refers to a fungus that assumes one of two different physical
of an unapproved/ forms, as dictated by environmental influences such as temperature and humidity. In the
investigative use of a environment, and when grown in culture at ambient temperatures, these mold forms (also
commercial product/ known as “saprobic,” “saprophytic,” and “mycelial” forms) consist of long hyphae, which
are difficult to distinguish macroscopically from other molds. The saprophytic forms have
device.
microscopic aerosolizable elements, which not only lead to wide environmental distribu-
tion but also are infectious on inhalation. Following infection in humans, or when grown
in culture at 37.0°C, the organisms appear as individual round “yeast” forms. These fungal
elements are not contagious but will grow into either the yeast or mold form, depending
on the incubation temperature.
Histoplasmosis, coccidioidomycosis, blastomycosis, sporotrichosis, penicilliosis, and
paracoccidioidomycosis all are infections caused by dimorphic fungi (Table). Histoplas-
mosis and coccidioidomycosis are relatively well known in North America; blastomycosis
and sporotrichosis cause sporadic infections in North America and throughout the rest of
the world. Prior to the human immunodeficiency virus (HIV) epidemic, only 29 cases of
infection due to Penicillium marneffei were reported in the medical literature. Penicilliosis
is now a relatively common acquired immune deficiency syndrome (AIDS)-related oppor-
tunistic infection in Southeast Asia. Paracoccidioides immitis
causes cutaneous and osteoarticular infections, primarily in
South America. Most pediatric clinicians in North America
Abbreviations are unlikely to encounter penicilliosis or paracoccidioidomy-
AB-D: amphotericin B-deoxycholate cosis, although a familiarity with histoplasmosis, coccidioid-
AB-LC: amphotericin B lipid complex omycosis, blastomycosis, and sporotrichosis is important
AIDS: acquired immune deficiency syndrome because of the geographic distribution of the pathogens and
CF: complement fixation the outdoor activities of many pediatric patients.
CNS: central nervous system Although the epidemiologic and clinical features of each
CSF: cerebrospinal fluid species are unique, some characteristics are shared among the
HIV: human immunodeficiency virus dimorphic fungi. Because the mold forms contain infectious
IDSA: Infectious Diseases Society of America particles, the laboratory must be notified if such infections
Ig: immunoglobulin are suspected. The gold standard for diagnosis is culture, but
PDH: progressive disseminated histoplasmosis serologic or antigen detection methods may be available.
SSKI: saturated solution of potassium iodide Selective fungal media can be incubated for many weeks
without significant bacterial overgrowth. A dimorphic fun-
*Department of Pediatrics.
†
Division of Infectious Diseases, Naval Medical Center, San Diego, Calif.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department
of the Navy, Department of Defense, or the United States Government.
e40 Pediatrics in Review Vol.31 No.6 June 2010

infectious diseases dimorphic fungal infections
Comparative Features of the Dimorphic Fungi Present in North

Table.
America
Geographic
Location
(Within the Common Other Common Method
Dimorphic Fungus Americas) Presentation Clinical Manifestations of Diagnosis Treatment
Coccidioidomycosis Southwestern Lower respiratory Cutaneous lesions, Serology ● Amphotericin
United States, tract infection adenopathy, ● Itraconazole
Central/South (valley fever) osteoarticular and (osteoarticular)
America CNS disease ● Fluconazole
(CNS)
Histoplasmosis Ohio/Mississippi Lower respiratory Cutaneous lesions, Serology ● Amphotericin
River valleys, tract infection adenopathy, PDH, Urine or ● Itraconazole
Central intestinal (mimicking serum antigen
America Crohn disease) and
CNS disease
Sporotrichosis Common in Subacute or Pulmonary, Culture ● Amphotericin
South chronic skin osteoarticular, and ● Itraconazole
America, ulcer CNS disease ● Terbinafine
scattered ● SSKI
throughout
North
America
Blastomycosis Ohio/Mississippi Lower respiratory Cutaneous lesions; Culture or ● Amphotericin
River valleys tract infection osteoarticular, histopathologic ● Itraconazole
genitourinary, and examination
CNS disease
CNS⫽central nervous system, PDH⫽progressive disseminated histoplasmosis, SSKI⫽saturated solution of potassium iodide
gus may be suspected based on the microscopic appear- allels. Amphotericin-based compounds remain the treat-
ance of the saprophytic phase and is confirmed by the ment of choice for severe infections and for pregnant
microscopic appearance of the typical yeast forms when women, in whom azole therapy is contraindicated due to
grown at higher temperatures. Because the sensitivity of teratogenicity. Several formulations of amphotericin are
fungal culture varies, a presumptive diagnosis often can available for children. Amphotericin B-deoxycholate
be made based on cytopathologic examination of af- (AB-D) has been used for decades and is associated with
fected tissue. The presence of noncaseating granulomas higher rates of renal toxicity and adverse infusion-related
suggests, among other disorders, the presence of a fungal events than the newer formulations. AB-D, however, is
infection. Although yeast forms may be seen with stan- the drug of choice for fungal infections of the urinary
dard staining, fungal stains, such as Gomori- tract. Amphotericin B lipid complex (AB-LC), ampho-
methenamine silver, can highlight the organisms in tissue tericin B liposomal, and amphotericin B colloidal disper-
dramatically. sion are used widely in place of AB-D, primarily due to
Cell-mediated immunity is vital to control fungal intolerance of AB-D or the risk of renal toxicity. Few
infections, as demonstrated by the increased risk of dis- pharmacokinetic data exist to suggest the superiority of
semination in people living with HIV/AIDS, patients one lipid formulation over another, although AB-LC
receiving chemotherapy for malignancies, or recipients of most often is used for central nervous system (CNS)
tumor necrosis factor-neutralizing monoclonal antibod- infection due to a small body of literature supporting
ies. Pregnancy is associated with depressed cell-mediated superior CNS penetration. AB-D generally is adminis-
immunity and, therefore, presents a higher risk of severe tered intravenously at a dose of 0.6 to 1.0 mg/kg per day
infection. The duration of treatment often is dictated by daily, and the lipid formulation doses are 3 to 5 mg/kg
the status of the patient’s immunity. per day or higher.
The treatment of the dimorphic fungi has many par- Generally, the dimorphic fungi are susceptible to itra-
Pediatrics in Review Vol.31 No.6 June 2010 e41

conazole and variably susceptible to fluconazole. Recent

data suggest that voriconazole, as well as the most recent
addition to the azole family, posaconazole, are highly
active against dimorphic fungi. Oral route of administra-
tion, tolerability, and excellent tissue penetration are
favorable aspects of azole therapy, particularly for mild-
to-moderate infections. Combination antifungal therapy
occasionally is used for severe fungal infections, although
no definitive data exist to confirm the superiority of such
regimens.
Coccidioidomycosis
Microbiology and Epidemiology
First described in Argentina in 1892 by Dr Alejandro
Posadas, coccidioidomycosis now is recognized as a sig-
Figure 1. Coccidioides spherule from lung biopsy. Note the
nificant health problem for those who live in or travel to
multiple endospores within the round spherule. Photo cour-
endemic regions. The Coccidioides genus is subdivided
tesy of Dr Michael Quigley, Naval Medical Center, San Diego.
into two distinct strains, referred to as C immitis and C
posadassi, although a distinction between the two is
clinically irrelevant.
The saprophytic phase of Coccidioides is found in the threatening disseminated infection. Risk factors for se-
soil of regions that have hot and dry summers, few winter vere disease include young and old age, immuno-
freezes, and low annual rainfall. Single-cell spores known suppression, pregnancy, and Filipino or African descent.
as arthroconidia are aerosolized by wind or soil disrup- Clinically apparent infections typically present as a
tion. Once inhaled, or rarely percutaneously implanted, process known as “valley fever.” Cough, fever, and chest
arthroconidia enter the parasitic phase, where they en- pain occur 1 to 3 weeks after inhalation of arthroconidia.
large to a spherule and produce hundreds of endospores Systemic symptoms commonly include headache, sore
(Fig. 1). The spherule ruptures, releasing endospores throat, arthralgias, and fatigue. In most cases, valley fever
into nearby tissue. Each endospore is capable of produc- is a self-limited illness lasting 2 to 3 weeks, although
ing another spherule. fatigue can last for several months. Radiographic abnor-
Coccidioides are endemic to the southwestern United
States, particularly southern Arizona, and central Califor-
nia (Fig. 2) as well as parts of Mexico and Central and
South America. The risk of exposure is increased by
severe wind and dust storms, earthquakes, construction,
and wildfires. The incidence of coccidioidomycosis varies
by geographic location. In highly endemic areas, the
incidence of infection may be as high as 91 cases per
100,000 population, although this figure probably is an
underestimation of total infections, given the high rate of
asymptomatic or mildly symptomatic illnesses.
Person-to-person transmission of coccidioidomycosis
does not occur, and infected individuals do not require
isolation. Coccidioides, however, may grow on fomites,
such as bandages or under plaster casts. Perinatal trans-
mission of coccidioidomycosis occurs rarely.
Clinical Manifestations Figure 2. Geographic distribution of skin reactivity to “coc-

Sixty percent of infected individuals are asymptomatic. cidioidin” antigen, estimating exposure to Coccidioides. Cour-
The remaining 40% of individuals present with symp- tesy of the Centers for Disease Control and Prevention (Kirk-
toms ranging from a self-limited flulike illness to a life- land et al. 1996).

malities include a unilateral infiltrate, hilar adenopathy, the success of therapy. CF is a complex test and should be
or pleural effusion. Approximately 5% of individuals who ordered from laboratories experienced in the procedure.
contract valley fever have pulmonary sequelae, including Although some laboratory variation may occur, dissem-
pulmonary nodules, cavities, or chronic fibrocavitary inated disease generally is considered to be present with
pneumonia, although these complications are uncom- titers in the range of 1:16 or greater. The “coccidioidin”
mon in children. A diffuse reticulonodular pneumonia skin testing is not useful clinically. Although growth of
may develop in immunocompromised individuals or in Coccidioides from any site is diagnostic, the sensitivity of
otherwise healthy individuals exposed to a large inocu- culture is low.
lum.
Night sweats, fever, and cough are present in most of Treatment
the 1% of infected individuals who develop disseminated The decision to treat coccidioidomycosis is based on risk
disease. Involvement of the skin, lymph nodes, osteoar- factors for severe disease, the severity of pulmonary in-
ticular structures, or meninges is evidence of dissemina- fection, and the presence or absence of dissemination.
tion. Although papules, plaques, and pustules imply dis- Guidelines are available at the Infectious Diseases Society
semination, erythema nodosum or erythema multiforme of America (IDSA) web site (http://www.idsociety.
represent the host response to infection. Radionuclide org). For mild pulmonary illnesses that generally self-
bone scans generally are performed in cases of dissemi- resolve, no strong data support treatment. Some experts
nated coccidioidomycosis (particularly in young chil- recommend treating all cases of pulmonary coccidioid-
dren) to identify occult osteoarticular foci, which often omycosis, particularly those patients at high risk of dis-
require surgical drainage. semination.
CNS infection is the most serious manifestation of Azoles have replaced amphotericin-based compounds
disseminated coccidioidomycosis and is almost univer- as the first line of treatment of coccidioidomycosis. In
sally fatal, if untreated. The classic history of coccidioidal most cases of meningitis, fluconazole is the treatment
meningitis is a gradual onset of headache, vomiting, of choice due to its excellent CNS penetration.
lethargy, fever, and altered mental status occurring weeks Amphotericin-based regimens are preferred for immuno-
to months after a febrile respiratory illness. Lumbar compromised and critically ill hosts as well as for those
puncture should be performed on all individuals showing who have diffuse pulmonary disease and rapidly progres-
signs of meningeal irritation and should be considered sive infections.
for all those who have disseminated disease. Lympho- The duration of therapy for pulmonary coccidioid-
cytic pleocytosis, elevated protein concentrations, and omycosis ranges from 3 to 6 months. In disseminated
low glucose values are classic cerebrospinal fluid (CSF) infections, a minimum of 1 year of therapy is recom-
findings. Hydrocephalus occurs in 30% to 50% of cases of mended. Lifetime suppressive therapy may be required
coccidioidal meningitis and generally requires CSF to prevent relapses in immunocompromised patients and
shunting. Abscess, hemorrhage, and infarction are other is standard for patients who have meningitis. Rising or
complications of CNS involvement. Intracranial involve- unchanging CF titers while the patient is receiving ther-
ment has been described in infants as young as 4 months apy indicate treatment failure, most often due to non-
of age. compliance, or an occult focus that might require surgi-
cal drainage.
Diagnosis
Serology is the method used most commonly to diag- Histoplasmosis
nose coccidioidomycosis. Although false-positive results Microbiology and Epidemiology
occur rarely, antibodies disappear within months of a Histoplasmosis, first described in Panama in 1905, is
resolved infection, making any positive test result signif- caused by Histoplasma capsulatum variety capsulatum
icant. A negative test result must be interpreted with and Histoplasma capsulatum variety duboisii. The most
caution because serologic results are insensitive during common cause of endemic mycosis in the United States
the initial weeks of infection and can remain negative and throughout the world is H capsulatum var capsula-
indefinitely in immunocompromised hosts. Immuno- tum. H capsulatum var duboisii exists only in Africa. As
globulin M (IgM) antibodies generally are present within the name “capsulatum” implies, the saprophytic form of
3 weeks of the onset of symptoms. The complement the organism has round macroconidia that appear to be
fixation (CF) IgG is considered the most reliable method encapsulated, although this is not a true capsule. The
for serologic detection and can be “trended” to measure infectious particles are aerosolizable elements called mi-

High-risk exposures, clusters of acute lower respiratory

tract infections, or prolonged respiratory symptoms also
can lead clinicians to test for acute histoplasmosis. Other
pulmonary or parapneumonic manifestations of H cap-
sulatum include chronic cavitary disease, mediastinal
lymphadenopathy or granulomas, pleural effusions, and
broncholithiasis.
Bloodborne dissemination is common during acute
histoplasmosis, but host immunity generally controls the
infection. Dissemination can lead to infection of virtually
any organ, which is highlighted by reports of cutaneous
lesions, osteoarticular infections, endocarditis, interstitial
nephritis, parotitis, and Histoplasma meningitis or cere-
britis. Gastrointestinal involvement mimicking Crohn
Figure 3. Microscopic appearance of mycelial phase of His- disease has been described. Immune dysfunction causing
toplasma, demonstrating macroconidia and microconidia. an inability to control the organism during dissemination
leads to a syndrome termed “progressive disseminated
croconidia (Fig. 3). Histoplasma grow well in warm, histoplasmosis” (PDH). PDH generally manifests with
moist environments. Certain soil compositions, includ- undifferentiated fever, weight loss, organomegaly, and
ing high nitrogen content, high carbon content, and hematologic abnormalities. Although children most of-
lower pH, have been shown to enhance growth of the ten are diagnosed with uncomplicated acute pulmonary
organism. Caves and buildings containing bird and bat histoplasmosis, PDH is well described in infants and
guano classically have been associated with the presence immunocompromised children. A single case of congen-
of H capsulatum. Although birds are not infected by the ital infection with H capsulatum var capsulatum has been
fungus, bats and other mammals can be infected. As with reported.
coccidioidomycosis, infection occurs following inhala- Infections with H capsulatum can be associated with
tion of microconidia. A specific exposure usually cannot postinfectious sequelae, such as pericarditis, mediastinal
be identified, but certain activities, such as spelunking, fibrosis, and articular inflammation, which are presumed
increase the risk of inhalation of microconidia. Construc- to be immune-mediated. Pericarditis may be present in as
tion that causes soil agitation has been associated with many as 10% of children who have histoplasmosis and can
large outbreaks. Human-to-human transmission does be severe enough to cause pericardial tamponade.
not occur.
In North America, H capsulatum var capsulatum is
distributed throughout the central United States, partic-
ularly in the Mississippi and Ohio river valleys. Exposure
studies that tested for cutaneous sensitivity to H capsu-
latum antigen (akin to a purified protein derivative test
for tuberculosis) demonstrated low endemicity in the
southern and southwestern United States (Fig. 4).
Clinical Manifestations
Ninety-five percent of infected individuals are asymp-
tomatic. Approximately 60% to 90% of those who are
symptomatic manifest acute pulmonary symptoms,
which are nearly impossible to distinguish from bacterial
and viral lower respiratory tract infections. Although
symptoms often last only a few days, the prolonged
duration and greater severity of fever, malaise, and fa- Figure 4. Geographic distribution of skin reactivity to “his-
tigue that can accompany and follow the pulmonary toplasmin” antigen, estimating exposure to Histoplasma. Re-
symptoms may lead to a suspicion of histoplasmosis. printed with permission from Oxford University Press.

versus previous infection. Skin testing, used for research

and epidemiologic studies, is neither available nor clini-
cally useful because positive reactions may represent prior
infection, and negative results in acute and disseminated
disease are common.
Treatment
The IDSA has published guidelines for the treatment of
histoplasmosis (www.idsociety.org). Acute pulmonary
histoplasmosis in immunocompetent individuals gener-
ally does not require treatment, although treatment may
be considered for severe or prolonged disease. The route
of medication delivery and the drug of choice vary by
severity of infection. In general, itraconazole is the pre-
Figure 5. Postmortem splenic tissue stained with Gomori- ferred oral antifungal; amphotericin-based regimens are
Methenamine silver stain demonstrating numerous round recommended for more serious infections such as dis-
darkly stained Histoplasma yeast forms. Courtesy of Dr Henry seminated histoplasmosis and for infections during preg-
Krous, Rady Children’s Hospital, San Diego. nancy, in which itraconazole is contraindicated. Long-
term treatment or even lifelong suppression may be
Diagnosis considered for persons who have immunocompromising
The organism may take up to 6 weeks to identify, but conditions.
isolation of H capsulatum from sputum or any normally Nonsteroidal anti-inflammatory and, occasionally,
sterile site is considered definitive proof of infection. The corticosteroid medications are administered for post-
sensitivity of culture varies based on the site of infection infectious complications such as mediastinal fibrosis and
and host risk factors. Although sputum culture may be pericarditis. Itraconazole may be considered for treating
positive in only 10% of cases of acute pulmonary his- postinfectious complications, although the benefit of
toplasmosis, the sensitivity rises to 60% among those who antifungal therapy in such circumstances has been ques-
have cavitary histoplasmosis and 90% in bronchoalveolar tioned.
lavage specimens from AIDS patients who have pulmo-
nary histoplasmosis. Histopathology is a valuable diag- Sporotrichosis
nostic tool for histoplasmosis, often demonstrating non- Microbiology and Epidemiology
caseating granulomas. The parasitic yeast form can be In 1904, B.R. Schenck first described the dimorphic
found wherever invasion occurs (Fig. 5). In disseminated fungus, which later became his namesake. Sporothrix
disease, it occasionally is visible on routine blood smears,
such as those performed for a complete blood count (Fig.
6).
One of the methods used most commonly to diag-
nose histoplasmosis is the Histoplasma urine antigen test.
With a sensitivity of 95% in disseminated infections,
detection of antigenuria can be a valuable diagnostic
tool, although the urine antigen test is positive in only
10% to 40% of patients who have acute pulmonary dis-
ease. Serologic tests to detect antibodies directed against
H capsulatum are available commercially, but cross-
reactivity with other dimorphic fungi, false-positive and
-negative results, and testing in areas of high endemicity
all must be considered when interpreting the results.
Although 10% of people living in an endemic area have
positive CF test results, high titers are associated with
more severe disease and, in combination with immuno- Figure 6. Complete blood count smear demonstrating intra-
diffusion, can be a valuable tool in discerning active cellular and erupting Histoplasma parasitic yeast forms.

schenckii has a worldwide distribution, although most

cases have been reported from South America and, to a
lesser extent, North America. Many clinicians recall this
organism as the causative agent of “rose-gardener dis-
ease,” an apt description because of its association with
infection at sites of trauma contaminated with soil. S
schenckii has been described as a cause of occupational
outbreaks, including outbreaks due to contaminated
timber and sphagnum moss. Several recent reports high-
light the high prevalence in South America, particularly
in children. In one series of 238 cases of cutaneous
sporotrichosis in Peru, 60% of the patients were younger
than 15 years of age. Contact with cats that have cutane-
ous disease caused by sporotrichosis is a well-described
risk factor for infection in humans. Scratches from other
digging animals, such as armadillos, also have been asso-
ciated with disease in humans. Inhalation of conidia
leading to primary pulmonary disease rarely occurs.
Clinical Manifestations
The most common manifestation of sporotrichosis is a
subacute or chronic skin ulcer, particularly on the face or
extremities. Cutaneous lesions often are associated with
lymphangitis and regional lymphadenopathy (Fig. 7).
Disseminated disease, osteoarticular infections, pulmo-
nary infections, and meningeal infections have been re-
ported. As with the other dimorphic fungi, more severe
disease is associated with deficits of cell-mediated immu-
nity. Although pathogens such as Staphylococcus aureus
and Streptococcus pyogenes tend to cause more rapidly
progressive skin and soft-tissue infections, it is difficult to
differentiate S schenckii from other indolent infections,
such as those caused by Nocardia, Leishmania, and
nontuberculous mycobacteria.
Diagnosis
No serologic tests are available clinically to aid in the
diagnosis of sporotrichosis. Material from cutaneous le-
sions may be aspirated or scraped and sent for fungal
culture. Growth of the mold occurs between 1 and
4 weeks. Pathologic examination of biopsy specimens
can reveal granulomatous inflammation in the presence
of the cigar-shaped yeast. The diagnosis of visceral and Figure 7. Infections due to Sporothrix schenckii. A. Multiple
CNS infections often is delayed due to the reliance on slowly progressive facial lesions. B. Primary ulcerated lesion
culture or histopathology. and lymphatic streaking. Courtesy of Dr Peter Pappas, Univer-
sity of Alabama, Birmingham.
Treatment
All cutaneous lesions should be treated because sponta- conazole generally is not recommended due to an overall
neous resolution is rare. The mainstay of therapy for poor efficacy compared with other antifungal agents.
adults and children is oral itraconazole. Terbinafine can Saturated solution of potassium iodide (SSKI) has been
be used as an alternative to itraconazole, although flu- used for more than a century and is effective, although

adverse effects such as gustatory changes, gastrointestinal tially may be diagnosed with community-acquired pneu-
intolerance, and rashes may lead to cessation of therapy. monia. The frequency of spontaneous resolution of acute
Treatment of cutaneous disease is continued for 2 to pulmonary blastomycosis is unknown, and many patients
4 weeks after resolution of the lesion. Although uncom- eventually seek care for a combination of chronic pulmo-
plicated pulmonary or osteoarticular infections can be nary and systemic symptoms, which may mimic tubercu-
treated initially with itraconazole, serious invasive infec- losis. In addition, radiographs reveal a mass in up to one
tions such as meningeal, disseminated, or extensive third of patients, often leading to a presumptive diagno-
osteoarticular disease are treated initially with ampho- sis of malignancy. Occasionally, diffuse pulmonary infil-
tericin B, followed by oral itraconazole for maintenance trates with acute respiratory distress syndrome occur and
therapy. Lifelong suppression may be required if the are associated with a poor prognosis.
patient is immunocompromised. Extrapulmonary disease occurs in at least 50% of
Treatment of pregnant women presents a unique patients who seek care, often seen concomitantly with
challenge because the azole class is teratogenic and SSKI pulmonary symptoms. As the name B dermatitidis im-
is toxic to the fetal thyroid. If treatment during preg- plies, the skin commonly is affected. Lesions are verru-
nancy is deemed necessary, amphotericin B generally is cous or ulcerative and originate from disseminated dis-
used. Local hyperthermia (daily exposure of the lesion to ease, although accidental inoculation in the laboratory
temperatures from 42.0° to 43.0°C for many weeks) has has been reported to cause primary cutaneous blastomy-
been reported to be effective for treating cutaneous cosis. Osteoarticular disease (especially vertebral), geni-
lesions and may be an option for pregnant women or tourinary disease (especially prostate), and CNS disease
other patients in whom oral treatment is contraindicated all have been described. Children infrequently are diag-
or not tolerated. nosed with blastomycosis, but it is unknown if this situ-
Children who have cutaneous lesions may be given ation signifies fewer infections or a higher rate of undi-
itraconazole. One drop of SSK1 three times daily with an agnosed infections than adult counterparts. Congenital
escalation up to 1 drop/kg (maximum 40 to 50 drops) blastomycosis in infants of acutely infected women is
three times daily is an alternative, but gastrointestinal exceedingly rare.
adverse effects limit the usefulness of this regimen in
children. Diagnosis
Serologic diagnosis of blastomycosis is problematic be-
Blastomycosis cause of antigenic cross-reactivity with other fungi as well
Microbiology and Epidemiology as the lack of sensitivity of current assays. Sputum may be
Blastomycosis, occasionally referred to as “Gilchrist dis- submitted for microscopy in patients who have pulmo-
ease” after its discovery by Dr Thomas Casper Gilchrist in nary symptoms. Identification of the organism in culture
1894, is an unusual infection in children. Like H capsu- or by microscopic examination of tissue specimens is the
latum, B dermatitidis generally is transmitted via inhala- most common method for diagnosis. Although the my-
tion of conidia and is endemic to the Ohio and Missis- celial form is nonspecific, the single broad-based bud and
sippi river valleys, with cases occurring from Canada to highly refractile cell wall of the yeast make microscopic
the southern United States. Sporadic cases also have been diagnosis of B dermatitidis relatively easy.
reported from India, Africa, and the Middle East. The
mycelial phase of B dermatitidis grows in warm moist soil Treatment
with high organic content, although such growth is Acute pulmonary infections may resolve without treat-
short-lived because the organism rarely is identified in ment, but the high rates of extrapulmonary disease fol-
the environment in conjunction with an outbreak. Blas- lowing a primary pulmonary infection lead many experts
tomycosis in nonhuman mammals has been described. to recommend treatment for all cases of blastomycosis.
Blastomycosis in a pet, particularly a dog, raises the All patients who have persistent or progressive pulmo-
possibility of a common exposure in the owner. nary disease, all who have extrapulmonary disease, and all
immunocompromised patients should be treated.
Clinical Manifestations Amphotericin-based therapy is preferred for severe and
Pulmonary infection is the most common manifestation life-threatening infections as well as for infections occur-
of blastomycosis, with as many as 50% of infections being ring during pregnancy. Treatments for children are not
asymptomatic. With nonspecific findings such as fever, well established, although children whose disease is se-
cough, malaise, and pulmonary infiltrates, patients ini- vere should be treated with an amphotericin-based com-

pound. Oral itraconazole may be considered for treating Suggested Reading

mild infections in children and adults. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis
Clin North Am. 2003;17:21– 40
Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice
Summary guidelines for the management of blastomycosis: 2008 update
by the Infectious Diseases Society of America. Clin Infect Dis.
2008;46:1801–1812
• The dimorphic fungi, as a group, should be
Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin
considered in the differential diagnosis of a number
Infect Dis. 2005;41:1217–1223
of acute and chronic complaints in children.
• Although these fungal infections are uncommon, the Kauffman CA. Histoplasmosis: a clinical and laboratory update.
consideration of such infections can be lifesaving, Clin Microbiol Rev. 2007;20:115–132
particularly for very young infants and patients who Pappas PG, Tellez I, Deep AE, Nolasco D, Holgado W, Busta-
have deficiencies in cell-mediated immunity. mante B. Sporotrichosis in Peru: description of an area of
• Serologic testing is available for coccidioidomycosis hyperendemicity. Clin Infect Dis. 2000;30:65–70
and histoplasmosis. Disseminated and severe Schutze GE, Hickerson SL, Fortin EM, et al. Blastomycosis in
histoplasmosis also can be diagnosed by using children. Clin Infect Dis. 1996;22:496 –502
antigen detection methods. Stevens DA. Coccidioidomycosis. N Engl J Med. 1995;332:
• Invasive fungal infections often are diagnosed only 1077–1082
by culture or histopathology. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guide-
• Treatments generally are prolonged and vary by the lines for the management of patients with histoplasmosis: 2007
organism, location, and host immunity. update by the Infectious Diseases Society of America. Clin
Infect Dis. 2007;45:807– 825

North American Dimorphic Fungal Infections in Children
Brian L. Montenegro and John C. Arnold
Pediatr. Rev. 2010;31;e40-e48
DOI: 10.1542/pir.31-6-e40

& Services http://pedsinreview.aappublications.org/cgi/content/full/31/6/e40

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Egyptian_Pediatric yahoo group Egyptian_Pediatric yahoo group

242 Periorbital and Orbital Cellulitis

250 Research and Statistics: A Question of Time:

252 Ethics for the Pediatrician:

e40 North American Dimorphic Fungal

Cover: The artwork on the cover of this month’s issue is

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Movement Disorders I: Tics and Stereotypies

Pediatrics in Review Vol.31 No.6 June 2010 223

Table 1. Phenomenologic Classification of Movement Disorders

224 Pediatrics in Review Vol.31 No.6 June 2010

Table 2. Tic Classifications With Examples

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226 Pediatrics in Review Vol.31 No.6 June 2010

Learning disabilities (LDs) are another common co-

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228 Pediatrics in Review Vol.31 No.6 June 2010

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230 Pediatrics in Review Vol.31 No.6 June 2010

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DVD Educational Programming

232 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 233

Updated Information including high-resolution figures, can be found at:

Supplementary Material Supplementary material can be found at:

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1. Discuss the potential roles of genetic and environmental influences in causing

Incidence and Epidemiology

*Professor Emeritus of Pediatrics, University of Arizona, Tucson, Ariz.

234 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 235

236 Pediatrics in Review Vol.31 No.6 June 2010

Relationship of Leukemia Pathophysiology to Clinical

Pediatrics in Review Vol.31 No.6 June 2010 237

238 Pediatrics in Review Vol.31 No.6 June 2010

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240 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 241

Updated Information including high-resolution figures, can be found at:

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Periorbital and Orbital Cellulitis

*Pediatric Hospitalist, New Orleans Children’s Hospital, New Orleans, La.

242 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 243

Figure 4. A 15-month-old girl who has periorbital cellulitis

Figure 3. A 14-year-old boy who presented with marked left-

244 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 245

Table. Management of Periorbital Cellulitis

246 Pediatrics in Review Vol.31 No.6 June 2010

Figure 6. Contrast-enhanced computed tomography scan for

Figure 7. A 15-month-old girl who has recurrent periorbital

Pediatrics in Review Vol.31 No.6 June 2010 247

248 Pediatrics in Review Vol.31 No.6 June 2010

Pediatrics in Review Vol.31 No.6 June 2010 249

Updated Information including high-resolution figures, can be found at:

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Case Study between variables. They also can es-

250 Pediatrics in Review Vol.31 No.6 June 2010

Table. Summary of Designs

whether an association is true (real) dition, longitudinal studies must be Conclusion