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Answer Key appears on page 427.

Vol. 36 No. 9 September 2015

COMMENTARY

378 Fever of Unknown Origin: Where Science Meets Art Mobeen Rathore

ARTICLES

380 Pediatric Fever of Unknown Origin James W. Antoon, Nicholas M. Potisek, Jacob A. Lohr

392 Constipation and Encopresis in Childhood Jennifer M. Colombo, Matthew C. Wassom, John M. Rosen

403 Patient Safety and Quality Improvement: Terminology Lucy Pereira-Argenziano, Fiona H. Levy

INDEX OF SUSPICION

414 Case 1: Intractable Rash in a 7-month-old Boy Priyanka Rao, Jennifer Stojan

417 Case 2: Cardiovascular Shock Following Acute Gastroenteritis in a 17-year-old Boy Lina Merjaneh, Lillian R. Meacham

420 Case 3: A Vascular-appearing Eyelid Mass in a Neonate Tiff any J. Herd, Hillary S. Lawrence, Michelle A. Manalang, Laura S. Plummer, Lei Shao, Kimberly A Horii

422 Correction 423 Case 4: How Much Is Too Much? A Case of

Hypercalcemia in a 6-year-old Boy Monica Liao, Philip Magcalas, Patricia Hopkins-Braddock

IN BRIEF

426 Head Growth Mary Elizabeth Wroblewski, Joyce Bevington, Cathi Badik

ONLINE

e30 Visual Diagnosis: Newborn With a Facial Vascular Birthmark Brian M. Faux, Abraham W. Suhr, David T. Hsieh

Fever of Unknown Origin: WhereScience Meets Art

Fever of unknown origin (FUO) is a relatively uncommon condition in United

States children. Nevertheless, FUO remains a challenging clinical problem

for even the most astute clinician that requires excellent history taking

and physical examination skills. In the more elusive cases, repeated history

and physical examination are the hallmarks of evaluation. Although diag-

nostic testing has been extremely valuable, a Sherlock Holmes-like attention

to clues and details is key (being that Sir Arthur Conan Doyle was also a

physician).

Infections remain the most common cause of fever in general and of

FUO in particular. In the past, infections obviously not only contributed to

confirmed causes of FUO but also perhaps to many cases in the unknown

cause categories. However, more advanced and rapid diagnostic techniques

now allow clinicians to diagnose more infectious causes sooner. Accord-

ingly, compared to the past, infections now constitute the cause of a rela-

tively smaller number of cases of FUO.

Even in today’s high-tech era of medicine, FUO is one of those conditions in

which the art of medicine is critical. Good communication between the

clinician and the family and patient is often the key to success, and repeated

history taking and physical examination by the old-fashioned diagnostician

frequently triumph. Asking patients, even young patients, directed questions

may reveal the “undeclared” pet rat in the attic, the dead rabbit they found in

the back yard, or playing with grandma’s neighborhood kittens that the parents

had specifically instructed them to avoid. Parents may not report a visiting

uncle from India or grandaunt who babysits and has been coughing and was

told she has “emphysema.”

In this issue of Pediatrics in Review, Antoon et al present a succinct review of

outpatient FUO in childhood, which is distinct from evaluation of prolonged fever

in a hospitalized patient. Careful history and physical examination guide the

clinician to further evaluation, although sometimes the cause remains elusive,

and not infrequently laboratory and radiologic evaluations are necessary. Because

most cases of FUO can be diagnosed in an outpatient setting without resorting to

extensive laboratory evaluation, clinicians do well to follow a carefully considered

plan that looks initially formore common and treatable causes of FUO.We should

always be looking for horses, but sometimes these horses disguise themselves as

zebras.

Many experts, including the authors of the article in this issue, recommend

a tiered approach to diagnosing FUO. Clearly, no one algorithm can be provided

for diagnostic testing, but that shown in the Table is one approach. Rather than an

algorithm, it offers a framework for evaluating FUO, identifying the more

common causes, and if necessary, referring the patient to a specialist. Moving

AUTHOR DISCLOSURE Dr Rathore hasdisclosed no financial relationships relevant tothis article. This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.

378 Pediatrics in Review

Commentary

from one tier to the next is not linear and varies with each case,

requiring some changes in the evaluative process, including

sometimes skipping a tier or two. Such a plan offers a more

strategic approach to FUOwhilemaking sure that any redflags

for more serious and especially treatable causes of FUO come

to light early in the course of evaluation.

Happy sleuthing!

Mobeen Rathore, MD, CPE*

*Editorial Board member.

Professor and Director,

University of Florida Center for HIV/AIDS Research, Education and Service,

Jacksonville, FL.

TABLE. Laboratory and Imaging Evaluation in Fever of Unknown Origin

BASIC TESTS

Complete white blood cell count with differential count ona peripheral smear

Urinalysis

Erythrocyte sedimentation rate Urine culture

C-reactive protein Blood culture

Examination of peripheral smear Complete metabolic panel

First-tier Tests

Tuberculin skin test/Interferon gamma release assay Serology*: Epstein-Barr virus, human immunodeficiencyvirus, Bartonella, hepatitisChest radiograph

Blood culture

Second-tier Tests

Blood culture Sinus computed tomography scan

Antinuclear antibody, rheumatoid factor, complement 3,complement 4, 50% haemolytic complement (CH50)

Echocardiography

Stool culture and ova & parasites Abdominal ultrasonographySerology*: Rocky Mountain spotted fever, Histoplasma, Ehrlichia,Anaplasma, Lyme disease, Cytomegalovirus, Toxocara gondii

Third-tier Tests

Upper gastrointestinal series with follow-through Bone scan

Cerebrospinal fluid Bone marrow aspiration

*Additional serologic diagnostic tests should be specific for each individual situation.

Vol. 36 No. 9 SEPTEMBER 2015 379

Pediatric Fever of Unknown OriginJames W. Antoon, MD, PhD,* Nicholas M. Potisek, MD,† Jacob A. Lohr, MD††

*Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, University of Illinois at Chicago, Chicago, IL.†Department of Pediatrics, Division of Pediatric Hospital Medicine, Wake Forest School of Medicine, Winston-Salem, NC.††Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.

Educational Gap

Pediatricians often confuse fever without a source and fever of unknown

origin.

Objective After completing this article, readers should be able to:

1. Adopt a systematic approach to evaluation and management of fever

of unknown origin in patients of various ages.

CLINICAL PROBLEM

Fever is a common complaint in children. In most cases, fevers are due to self-

limited viral infections and require no more than symptomatic treatment. Some-

times fever is due to common bacterial infections that are diagnosed by history and

physical examination and require antibiotic treatment without laboratory evalua-

tion. In a few clinical situations, the cause of fever is not easily identified. Fever

without a source (FWS)mayneed further evaluation that includes laboratory tests or

imaging. Rarely, the fever is more prolonged, requires more intensive evaluation,

and falls in the category of fever of unknown origin (FUO).

There is often confusion about the terms FUO and FWS. Distinguishing

between FUO and FWS is important and is based on duration of fever. FWS can

progress to FUO if no cause is elicited after 1 week of fever.

The current incidence and prevalence of pediatric FUO remain unclear.

Several factors contribute to the difficulty in determining the epidemiology,

including the lack of a standardized definition, clinical criteria, and coding using

the International Classification of Diseases-9 code for the condition. Further-

more, the causes of FUO often have an overlapping collection of symptoms and

insidious disease courses. The general direction of the evaluation varies based on

patient presentation, geographic location, associated symptoms, environmental

exposures, physician experience, and available testing techniques.

FEVER PHYSIOLOGY

Body temperature is primarily controlled by the hypothalamus via regulation of

pulmonary, skin, andmetabolic systems. Abasic understanding of the physiologic

factors regulating temperature can help distinguish between normal variance and

fever. The mean basal temperature varies according to age, gender, body habitus,

AUTHOR DISCLOSURE Drs Antoon, Potisek,and Lohr have disclosed no financialrelationships relevant to this article. Thiscommentary does not contain a discussion ofan unapproved/investigative use ofa commercial product/device.


time of day, activity level, menstrual cycle, and other factors.

(1)(2) Importantly, physiologic temperature exhibits a morn-

ing nadir and an early evening peak, which can vary by as

much as 1ºC. Furthermore, infants and young children

maintain higher temperatures than older children and

adults, primarily because of increased metabolic rate and

body surface-to-weight ratio. (1)(3) Of note, core body tem-

perature is positively related to obesity, which should be

taken into account with the growing number of obese

children in the United States.

Fever generally is defined as a core temperature of at least

38.0ºC (100.4ºF) and is the result of a complex series of

signalling cascades initiated in response to specific biologic

stimuli. (2) Fever is believed to provide an evolutionary

advantage in fighting off infection. Bacteria and viruses are

heat sensitive and exhibit temperature-dependent toxin pro-

duction, growth, and response to antibiotics. (4)(5) The body’s

mechanism of increasing core temperature in response to

infection functions to ward off the offending microbes.

Increased metabolic rate accelerates immune system mobi-

lization, lymphocyte transformation, lysosome andneutrophil

activity, and phagocytosis. Increases in lipolysis and proteol-

ysis diminish the amount of free glucose that can be used by

invading organisms. Similarly, the body transiently removes

iron, zinc, and copper, critical cofactors in viral and bacterial

replication, from the blood in response to the presence of

fever. (6) Taken together, the fever response provides a natural

defense mechanism against invading pathogens.

DEFINITION OF FEVER OF UNKNOWN ORIGIN

One of the challenges in investigating and reviewing FUO is

the lack of a standard definition. The number of fever days

before considering FUO historically ranged from 5 to 21 and

required some degree of medical evaluation. (7)(8) The

original literature included a lengthy time course of up to

3 weeks, but the advent of improved and rapid laboratory

techniques has led to a shortened number of fever days

before considering FUO diagnoses. With the availability of

rapid molecular diagnostic techniques for many infections,

most of the common causes of FUO from the past can now

be diagnosed or excluded rapidly, which has shortened the

time that is required to move from FWS to FUO.

FUO has more recently been defined as a temperature

higher than 38.0°C (100.4°F) that lasts longer than at least

8 days without a clear source. (9) Although most children

meeting the definition of FUO would have had some

laboratory assessment, it is not currently a prerequisite.

(10) However, any previous evaluation would help to

broaden or narrow the differential diagnosis.

CAUSES

FUO remains a diagnostic dilemma for many pediatricians

because it is frequently difficult to distinguish clinically

between benign and potentially life-threatening causes.

The spectrum of FUO causes is broad and includes in-

fectious, autoimmune, oncologic, neurologic, genetic, fac-

titious, and iatrogenic (Fig 1). Pediatricians face the

significant challenge of not missing the diagnosis of a seri-

ous illness or an easily treatable condition that can result in

increased morbidity. Fortunately, FUO is usually an uncom-

mon presentation of common diseases, most of which are

easily treatable without increased morbidity.

Relatively few studies document the cause of FUO in

developed countries; most of the current knowledge is

derived from three studies performed almost 4 decades

ago. (11)(12)(13) Low patient numbers and narrow patient

populations in more recent studies limit the value of con-

clusions. (14)(15)(16)(17) More recent studies conducted in

adult patients indicate a clear shift to noninfectious causes

of FUO, but few corresponding studies confirm this shift in

children. (10)(18)(19) Although numerous follow-up studies

in developing countries catalogue the underlying causes of

FUO, varying medical resources and endemic pathogens in

these countriesmake it unclear whether such findings apply

to the United States. (20)(21)(22)(23)(24)

The sentinel studies on pediatric FUO in theUnited States

found that approximately 90% of cases had an identifiable

cause: approximately 50% infectious, 10% to 20% collagen-

vascular, and 10% oncologic. (11)(12)(13) Smaller subsequent

studies from the 1990s had highly variable results: 20% to

44% infectious, 0% to 7% collagen-vascular, 2% to 3%

oncologic, and up to 67% undiagnosed. (14)(15) The reason

for this seemingly paradoxic increase in undiagnosed cases of

FUO in the setting of improved diagnostic techniques is

unclear. However, the shift from infectious to unidentifiable

causes of FUO correlates with advances in diagnostic test-

ing, including wider availability and rapid turnaround time.

The advent of polymerase chain reaction, improved culture

techniques, and better understanding of atypical viral and

bacterial pathogenesis and autoimmune processes likely

contribute to earlier diagnosis of the cause of FWS and fewer

children advancing to the category of FUO. This shift to

unidentifiable causes due to laboratory advances is supported

by recent studies from developing countries with significant

laboratory limitations, which show primarily infectious

causes of FUO, similar to those of older studies in developed

countries. (20)(21)(22)(23)(24)

Most cases of “undiagnosed” FUO appear to be benign,

with many resolving spontaneously without a confirmed


cause. These cases possibly consist of prolonged viral syn-

dromes or difficult-to-confirm atypical bacterial infections.

Substantially more evidence in the adult population sup-

ports the dynamic etiology of FUO over time, with multiple

studies over several decades demonstrating an increasing

trend toward undiagnosed cases. Some studies suggest that

as many as 50% of adult FUO cases remain undiagnosed.

(18)(19) These investigations also show decreased infectious

and increased inflammatory diagnoses in the adult popu-

lation over the same period of time. A better understanding

of the current etiologic categories of FUO in children should

improve the ability of medical practitioners to generate

a differential diagnosis.

FEVER OF UNKNOWN ORIGIN IN DEVELOPINGCOUNTRIES

Recent literature from developing countries indicates that

the causes of FUO remain primarily infectious. (20)(21)(22)

(23)(24)(25) Chow et al (20) reviewed FUO causes in several

developing countries from 1990 to 2008. In published

studies with greater than 49 patients, infection (36%–

78%) was by far the most common cause compared to other

causes such as malignancy (2%–12%), collagen-vascular

(2%–21%), miscellaneous noninfectious (2%–50%), and

unknown (12%–29%). Most of these infections were of

bacterial or atypical bacterial origin in contrast to the more

common viral causes in developed countries. A more recent

report of FUO in Turkey revealed a similar composition,

with infection beingmost common, followed bymalignancy

and collagen-vascular diseases. (23) A 2012 study of 95

pediatric patients in Iran demonstrated that collagen-

vascular diseases were more common causes than malig-

nancy, but there was a high rate of undiagnosed cases. (26)

Interestingly, Chantada et al (25) reviewed 113 cases of

FUO in Argentina according to three age categories: 0 to

11 months, 12 to 59 months, and older than 60 months.

Infection was themost common cause across all age groups,

but infectious causes were less common in those ages 12 to

59 months compared to the other two age groups. Children

Figure 1. Causes of pediatric fever of unknown origin.


ages 12 to 59 months had a corresponding increase in

neoplastic and miscellaneous noninfectious causes of

FUO. These results differed from a study of 80 patients

in Turkey, which suggested a decreased likelihood of infec-

tious causes with increasing age. (21) As with recent studies

in developed countries, small sample sizes and variation in

endemic infections limit generalization of these findings.

Several contributing and complicating factors are asso-

ciated with the higher infectious burden of FUO in devel-

oping countries. The prevalence of certain infections known

to cause FUO, such as human immunodeficiency virus

(HIV), tuberculosis, leishmaniasis, and malaria, is higher

in developing countries. Similarly, the rate of vaccine-

preventable diseases is higher in developing compared to

developed countries. Limited public health prevention pro-

grams and diminished access to health-care workers likely

contribute to an increased incidence of infectious diseases as

the cause for FUO, as does a decreased frequency of early

recognition of infectious causes. Furthermore, limited aware-

ness and ability to test for newly recognized causes of FUO,

such as hemophagocytosis syndrome, may limit diagnosis of

certain noninfectious causes.

EVALUATION

Initially distinguishing among infectious, autoimmune,

malignancy, and miscellaneous causes of FUO may be

difficult, but a thorough history and physical examination

can often generate a directed differential diagnosis. We

highly recommend a tiered approach to FUO to decrease

overall costs and the use of invasive testing.

History and Physical ExaminationEvaluation of FUO should be systematic and logically guided

by history and physical examination findings. A detailed

history, a thorough physical examination, and a proper

interpretation of laboratory tests already performed are

critical. The speed with which the evaluation should proceed

and whether it should be outpatient or inpatient depends, in

large part, on how ill the patient appears.

The first step in evaluating FUO is documentation that

fever is actually present. Parental perception of fever often

varies from the medical definition. It is useful to determine

what the parent defines as fever and whether this varies

from the medical definition of 38.0°C (100.4ºF). In our

experience, parents frequently report tactile or subjective

fevers without actually measuring the patient’s temperature

with an instrument. Parents should be asked if the temper-

ature was checked using a thermometer.

Pseudo-FUO has been defined as successive episodes of

benign, self-limited infections with fever that the parents

perceive as one prolonged fever episode. (27) This needs to

be carefully ruled out before undertaking an expensive and

unnecessary evaluation. Usually, pseudo-FUO starts with

a well-defined infection (most often viral) that resolves but is

followed by other febrile viral illnesses that may be less well

defined.Diagnosis of pseudo-FUOusually requires a careful

history, focusing on identifying afebrile periods between

febrile episodes. Differentiating pseudo-FUO from real

FUO can be challenging. If pseudo-FUO is suspected and

the patient does not appear ill, keeping a fever diary can be

helpful. In rare situations, a basic laboratory evaluation may

be necessary.

Any associated symptoms and the timing of antipyretic

administration is particularly important. A detailed descrip-

tion of the patient’s fever pattern as intermittent (eg, tuber-

culosis), recurrent (periodic fever disorders), relapsing (rat

bite fever), remittent (endocarditis, juvenile idiopathic

arthritis [JIA]), or sustained (pyogenic abscess) can some-

times narrow the differential diagnosis. (12)(13) Information

on the frequency and timing of fevers can be helpful in

determining the fever curve and ability to document the

fever in the medical setting. Periodicity of fever and the

presence of other symptoms at the time fever is present can

aid in making certain diagnoses, such as periodic fever,

aphthous stomatitis, pharyngitis, and adenopathy (PFAPA)

or other periodic fever disorders, without further expensive

evaluation. (28)

Fever can be the initial presentation of certain immuno-

deficiency syndromes, but many affected patients have a his-

tory of repeated infections, diarrhea, or abnormal physical

findings, such as a rash. A history of atopy or autoimmune

disease increases the likelihood of an autoimmune or rheu-

matologic cause. Furthermore, neutropenic fever in certain

situations can be a medical emergency, and the presence of

neutropenia may broaden the potential infectious sources of

fever while narrowing the diagnostic possibility (eg, cyclic

neutropenia). Determining the patient’s risk factors for neu-

tropenic fever and any associated signs and symptoms is an

important step in an evaluation of FUO.

Information regarding the ethnicity, race, family history,

and genetic background of the patient can behelpful. Periodic

fever disorders often run in families and are more common

in certain ethnicities. For example, familial dysautonomia is

most common in the Ashkenazi Jewish population whereas

familial Mediterranean fever is seen in those of Arab, Jewish,

Armenian, and Turkish descent. (29)(30)

Geographic location and corresponding endemic patho-

gens known to cause FUO should be taken into consideration.


For example, coccidioidomycosis is more common in the

southwestern United States and 60% of the cases of Rocky

Mountain spotted fever are reported from North Carolina,

Oklahoma, Arkansas, Missouri, and Tennessee. Travel to or

residence in these areas is an important clue formaking these

diagnoses. A thorough travel history is critical in the evalu-

ation of FUO and should include exposure to animals,

unusual foods, insect bites, and sick contacts. Even if there

is no travel history, clinicians should determine the patient’s

overall exposure to any domestic or wild animals (eg, home,

school, woods, playground, friend’s or relative’s house) rather

than simply asking “Do you have any pets?” when evaluating

for zoonoses (Table 1) (For a more extensive list of zoonoses,

see the table of diseases transmitted by animals in the Red

Book.) Similarly, a thorough history of any sick contacts or

high-risk exposures (eg, recent travel to foreign countries,

prisons, the homeless) can help narrow the differential diag-

nosis based on epidemiologic factors.

Many causes of FUO are accompanied by associated

symptoms. A detailed review of systems and their timing

in relation to fever can lead to a diagnosis. Because many

patients with FUOwill have received a variety of treatments,

it is important to determine whether therapeutic interven-

tions may have influenced the disease or fever course. This

is particularly important because drug fever is one of the

causes of FUO and simply discontinuing a chronically

administered agent may lead to fever resolution.

The most important aspect of evaluation for FUO is

repeated history taking and encouraging the patient and

family to report any new, different, or unusual signs or

symptoms regardless of how trivial they may seem. Most

cases of FUO are diagnosed because important historical

information guides the direction of further evaluation.

A thorough physical examination should be performed

that documents vital signs and any reported weight loss.

Physical signs commonly provide evidence of the underly-

ing diagnosis (Table 2). Serial physical examinations should

be performed, and observation in a controlled inpatient

setting may be beneficial because up to 25% of significant

physical findings may be absent at the time of presentation.

TABLE 1. Zoonoses and Fever of Unknown Origin

EXPOSURE ZOONOSES

Birds Psittacosis, cryptosporidiosis, histoplasmosis, West Nile virus

Cats Bartonella henselae, tularemia, Pasteurella multocida, rabies, Capnocytophaga, Salmonella,Campylobacter, Cryptosporidium, Giardia lamblia, Toxoplasma gondii, Toxocara cati,Echinococcus, Ancylostoma braziliense, Dipylidium caninum, leptospirosis, Sporothrix schenckii,Microsporum canis

Cows, Sheep, Goats Escherichia coli, Campylobacter, Salmonella, Cryptosporidium, Coxiella, tularemia, Brucella

Dogs Rabies, Brucella, Pasteurella multocida, Capnocytophaga, Salmonella, Campylobacter, Giardialamblia, Toxocara canis, Ancylostoma caninum, Echinococcus, Dipylidium caninum

Ferrets Salmonella, Campylobacter, cryptosporidiosis, toxocariasis, tuberculosis, leptospirosis, listeriosis,influenza, Giardia, Mycobacterium microti, rabies

Water (Fish, Water Mammals, Oysters Clams) Mycobacterium marinum, schistosomiasis, Vibrio parahaemolyticus, V vulnificus, BrucellaLegionella, Pseudomonas, Parachlamydia, Giardia, Mycobacterium leprae, M avium, Mmarinum, M ulcerans, M simiae, Burkholderiaceae, Coxiella burnetii, Francisella tularensis,Enterobacteriaceae, Vibrionaceae, Listeria monocytogenes, Helicobacter pylori, Cryptococcusneoformans

Squirrels Toxoplasma gondii, Rickettsia prowazekii

Horses Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium difficile, Brucella,Rhodococcus equi, Coxiella burnetii

Insect Bites (Mosquitoes, Ticks, Fleas) Malaria, Trypanosoma cruzi, equine encephalitis, West Nile virus, Lyme disease, ehrlichiosis,babesiosis, Yersinia pestis, tularemia, Dirofilaria immitis, leishmania, coltiviruses (Colorado tickfever), Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, babesiosis, Toscana virus

Rabbits Salmonella, tularemia, Yersinia, Cryptosporidium, Trichophyton, Pasteurella multocida, rabies,babesiosis

Reptiles Salmonella, Edwardsiella tarda, Plesiomonas, pentastomiasis

Rodents Tularemia, leptospirosis, rat bite fever (Streptobacillus moniliformis and Spirillum minus), rabies,Salmonella, lymphocytic choriomeningitis virus, Trichophyton, hantavirus, Pasteurella


(11) On the other hand, completely normal physical exam-

ination findings at the time of the initial FUO evaluation are

highly indicative of a benign underlying cause. (13)

During the evaluation, as the clinician expands the extent

of laboratory and imaging assessment, repeated history

taking and physical examinations are essential. They may

reveal new information that could aid in determining

appropriate laboratory and imaging studies.

Laboratory Studies and ImagingA number of basic laboratory studies may be used to deter-

mine the source of FUO. A complete blood cell count (CBC)

with differential count and smear can suggest an infectious or

oncologic cause. Blood and urine cultures are recommended,

with the understanding that repeat culturesmay be needed. If

the patient has neurologic symptoms, cerebrospinal fluid

(CSF) studies are also indicated. Whenever possible, cultures

should be obtained before initiating antibiotics to avoid

ambiguity and contamination of results. Abnormalities in

serum electrolytes or liver enzymes may indicate viral, atyp-

ical bacterial, or hematologic causes. Specific molecular

testing for HIV, tuberculosis, or atypical bacterial pathogens

and viral serologies is expensive and final results can be

delayed days toweeks. These tests should be performed based

on specific risk factors or suggestive physical findings.

Testing for acute-phase reactants, such as C-reactive

protein (CRP), erythrocyte sedimentation rate (ESR), and

ferritin, is common in the evaluation of FUO. These tests

results are nonspecific and not diagnostic of any particular

disorder. On the other hand, elevated acute-phase reactants

should encourage the physician to proceed with further

appropriate evaluation. Of note, normal acute-phase reac-

tant results do not exclude serious causes of FUO.

The CRP is a ring-shaped protein, consisting of five

subunits, that is synthesized by the liver in response to

inflammation. Detectable elevation of serum CRP occurs

within 6 hours of the trigger, heightens to a peak, and

resolves quickly following resolution of the stimulus. (32)

Physiologic levels of CRP vary based on age, gender, obesity,

exercise tolerance, sleep deprivation, and stress levels.

Therefore, clinicians should note the relative elevation of

CRP from baseline in the patient rather than rely on a single

initial value. CRP can be pathologically elevated in a wide

variety of disease processes, including inflammatory, infec-

tious, and autoimmune. There has been much interest in

CRP as a predictor of serious bacterial infection, and current

evidence suggests that a markedly elevated CRP is required

for specificity for bacterial infection. (33)(34)(35)(36) When

evaluating FUO, particularly in the hospital setting, mildly

elevated CRP values should not be used to rule in or out

a particular disease process. TrendingCRP values are amore

valuable diagnostic tool and can be used to evaluate treat-

ment response and direct treatment modalities. (37)

ESR responds to stimuli similar to those influencing CRP

synthesis but is slower to elevate andhas a longer half-life. ESR is

an indirect measurement of serum acute-phase protein concen-

trations, and physiologic values vary based on age, gender, and

other factors. Serum ESR may be altered in cases of abnormal

serum protein concentrations, including fibrinogen, albumin,

and immunoglobulin. In addition, ESR is subject to hemoglobin

concentration and size, shape, and number of red blood cells.

ESR is useful in determining chronic inflammation or infection,

but for the previously stated reasons, it should be used with

caution as a diagnostic tool, particularly in the setting of possible

alterations in serum protein concentrations.

Ferritin is another acute-phase reactant. Elevated ferritin

(in the absence of increased iron)may indicate an infectious,

autoimmune, oncologic, or inflammatory process. (38) Some

investigators have suggested that serum ferritin may

be helpful in evaluation of FUO to distinguish between

infectious and noninfectious causes. (39)(40) We have

found that serum ferritin can be particularly helpful in

diagnosing hemophagocytic lymphohistiocytosis (HLH), an

increasingly recognized cause of pediatric FUO. (41) Recent

guidelines have aided in the diagnosis of disease, and a serum

ferritin value greater than 10,000 mg/mL is 90% sensitive

and 96% specific for HLH. (42)(43)

Radiographs and imaging may play a role in the evalu-

ation of FUO, but research suggests that empiric imaging

has limited utility. (15) Chest radiographs should be per-

formed if pulmonary symptoms are present or if there is

concern for atypical bacterial infection, HIV, tuberculosis, or

oncologic processes. Additional imaging techniques, partic-

ularly computed tomography (CT) scan and magnetic res-

onance imaging (MRI), are associated with various risks and

should be performed discriminately. CTscans are known to

increase the risk of leukemia and brain tumors, particularly

in the pediatric population, andMRI is time-consuming and

often requires sedation in young children. (44) Therefore,

we recommend judicious imaging with specific diagnoses

in mind. For example, in a patient with gastrointestinal

symptoms, weight loss, and elevated CRP/ESR, an abdom-

inal CTscanmay aid in the diagnosis of inflammatory bowel

disease, abscess, or cancer. Of note, all patients with a poten-

tialmalignancy should receive a chest radiograph to evaluate

for a mediastinal mass before CT scan or MRI to avoid

airway complications while lying supine for imaging.

Other imagingmodalities, such aswhite blood cell (gallium-

or indium-111-labeled) scans, positron emission tomography,

and immunoscintigraphy scanning, have not been well


TABLE 2. Physical Findings and Associated Fever of Unknown OriginDiagnoses (31)

SYSTEM FINDING ASSOCIATED ILLNESS

Abdomen

Hepatomegaly Lymphoma, metastatic carcinoma, relapsing fever, granulomatous hepatitis,hemophagocytic lymphohistiocytosis, Q fever, typhoid fever, viral infections,salmonellosis, brucellosis, bartonellosis, endocarditis, malaria, leukemia

Liver edge tenderness Bartonellosis, liver abscess

Splenic abscess Infective endocarditis, brucellosis, enteric fever

Splenomegaly Leukemia, lymphoma, tuberculosis, brucellosis, infective endocarditis,cytomegalovirus, hemophagocytic lymphohistiocytosis, Epstein-Barr virus,psittacosis, relapsing fever, typhoid fever, Rocky Mountain spotted fever,Kikuchi-Fuijmoto disease

Chest

Murmur Infective endocarditis, atrial myxoma

Relative bradycardia Typhoid fever, malaria, leptospirosis, psittacosis, central fever, drug fever

Eyes

Abnormal funduscopicexamination findings

Miliary tuberculosis, toxoplasmosis, vasculitis

Conjunctival suffusion Leptospirosis, relapsing fever, Rocky Mountain spotted fever

Conjunctivitis Epstein-Barr virus, Newcastle disease, leptospirosis, Kawasaki disease (limbicsparing), tuberculosis, systemic lupus erythematosus, bartonellosis,chlamydial infection, histoplasmosis, tumor necrosis factor receptor-associated periodic syndrome, familial cold autoinflammatory syndrome

Decreased pupillary constriction Hypothalamic or autonomic dysfunction

Dry eyes Familial dysautonomia, systemic lupus erythematosus, polyarteritis nodosa,Sjögren syndrome

Ischemic retinopathy Polyarteritis nodosa

Periorbital edema Tumor necrosis factor receptor-associated periodic syndrome

Subconjunctival hemorrhage Endocarditis, trichinosis

Uveal tract involvement Tuberculosis, juvenile idiopathic arthritis, toxoplasmosis, sarcoidosis, systemiclupus erythematosus

Lymph Nodes

Lymphadenopathy Lymphoma, bartonellosis, tuberculosis, lymphogranuloma venereum,cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus,toxoplasmosis, juvenile idiopathic arthritis, brucellosis, Kikuchi-Fuijmotodisease, tularemia, viral infections, mycobacterial infection, leukemia,hyperimmunoglobulin D syndrome, familial cold autoinflammatorysyndrome

Genitourinary

Epididymo-orchitis Tuberculosis, lymphoma, brucellosis, leptospirosis, Epstein-Barr virus,blastomycosis, carcinoma

Musculoskeletal

Bone tenderness Osteomyelitis, malignancy, infantile cortical hyperostosis

Costovertebral tenderness Chronic pyelonephritis, perinephric abscess

Hyperactive reflexes Hyperthyroidism

Continued


studied in the diagnosis of pediatric FUO. Limited evidence

in children and additional studies in adults suggest that these

techniques have low sensitivity and specificity in the evalu-

ation of FUO and should be used only if traditional imaging

fails to reveal a diagnosis. (45)(46)(47)(48)

If fever persists and laboratory studies and imaging fail to

reveal the underlying cause, invasive procedures may be

necessary. Bonemarrow biopsy can be performed to evaluate

for oncologic or hematologic etiologies. Lumbar puncture,

thoracentesis, joint aspiration, or biopsies may also be indi-

cated to obtain fluid or tissue for analysis. These should be

performed as a last resort in the non-acute patient.

Initial Diagnostic ApproachWe recommend that the initial laboratory evaluation of

pediatric FUO consist of a CBC, basic metabolic panel,

TABLE 2. (Continued)

SYSTEM FINDING ASSOCIATED ILLNESS

Hypoactive reflexes Familial dysautonomia

Joint tenderness Familial Mediterranean fever, rat-bite fever, systemic lupus erythematosus, Lymedisease, lymphogranuloma venereum, brucellosis,hyperimmunoglobulinemia D syndrome, tumor necrosis factor receptor-associated periodic syndrome

Muscle tenderness Brucellosis, trichinellosis, arboviral infection, dermatomyositis, polyarteritis,subdiaphragmatic abscess (trapezius tenderness)

Spinal tenderness Subacute vertebral osteomyelitis, infective endocarditis, brucellosis,typhoid fever

Oropharynx

Anomalous dentition Anhidrotic ectodermal dysplasia

Dental or fascial abscess Sinusitis, brain abscess, mediastinal abscess

Epistaxis Relapsing fever, leukemia, psittacosis, rheumatic fever

Gingival hypertrophy Leukemia, Langerhans cell histiocytosis

Pharyngeal hyperemia Cytomegalovirus, Epstein-Barr virus, toxoplasmosis, tularemia, leptospirosis

Smooth tongue Familial dysautonomia

Ulcerations Behçet disease; periodic fever, aphthous stomatitis, pharyngitis, and adenitis(PFAPA); hyperimmunoglobulin D syndrome

Skin (limited review)

Blotchy skin Familial dysautonomia

Decreased body hair, hypohidrosis Anhidrotic ectodermal dysplasia

Dehydration Diabetes insipidus, ectodermal dysplasia, familial dysautonomia

Erythema nodosum Infection, juvenile idiopathic arthritis, systemic lupus erythematosus,malignancy, inflammatory bowel disease

Erythema migrans Lyme disease, southern tick-associated rash illness (STARI)

Eschar Tularemia

Macular salmon-pink rash Juvenile idiopathic arthritis

Malar erythema Systemic lupus erythematosus

Palpable purpuric lesions Polyarteritis nodosa

Petechiae Endocarditis, bacteremia, viral infection, rickettsia

Seborrheic rash Histiocytosis

Urticarial macular rash Serum sickness, familial cold autoinflammatory syndrome, Muckle-Wellssyndrome, neonatal-onset multisystem inflammatory disease


Figure 2. Focused approach to fever of unknown origin based on suspected disease category.


liver function tests, urinalyses, and blood and urine cul-

tures. If the patient has neurologic symptoms, CSF studies

may be considered. These tests should be performed

before initiating treatment to prevent contamination of

results.

The evaluation of FUO should be targeted if any find-

ings on history, physical examination, or laboratory and

imaging evaluation direct suspicion toward an organ

system or diagnosis. A patient with known tick exposure,

rash, and hyponatremia should receive serologic evalua-

tion for Rocky Mountain spotted fever, Lyme disease,

ehrlichiosis, anaplasmosis, or babesiosis, depending on

the endemic region or travel history. (49) When deciding

which laboratory tests to order, it is important to note that

uncommon presentations of common diseases are more

likely to cause FUO than uncommon or rare diseases.

A well-appearing child with fever, rash, lymphadenopathy,

and transaminitis is more likely to have Epstein-Barr virus or

cytomegalovirus infection rather thanHLHor systemic lupus

erythematosus. In a nonacute patient, ruling out common

causes of FUO before testing for uncommon causes or

performing invasive testing can minimize the likelihood of

dealing with false-positive, false-negative, or equivocal results

for rare diseases.

We have established an initial diagnostic algorithm based

on the broad etiologic categories of FUO that may be per-

formed if a practitioner is suspicious for a particular disease

process (Fig 2). The recommended evaluation provides diag-

nostic “first steps” in the evaluation of these categories that

may be performed before referral for specialized or invasive

testing. This tiered approach to FUO can decrease overall

costs and the use of invasive testing.

MANAGEMENT AND EMPIRIC TREATMENT

The initial management of FUO remains an area of debate.

Pediatric FUO is often overtreated because most cases are

caused by benign or nonacute disease. Physician concern

for serious illness or parental pressure can lead to empiric

treatment before sufficient evaluation. Physicians may be

inclined to start antipyretics, corticosteroids, or antibiotics

for an unknown disease process, which can affect future

laboratory data, imaging, or treatment. Many cases of FUO

resolve without a diagnosis and empiric treatmentmay mask

the diagnosis of life-threatening oncologic, infectious, and

autoimmune diseases. Empiric treatment should be initiated

with caution and in conjunction with judicious testing.

The first step in the management of FUO is to discon-

tinue all nonessential pharmacologic agents, including anti-

pyretic medications. Drug fever can manifest at any time

after starting amedication, with an overall incidence of up to

5%. (50) Drug fever is a common source of FUO and can be

caused by any agent, including antibiotics, ibuprofen, and

acetaminophen (Table 3). Once the drug is discontinued,

fever usually abates within 24 hours or two half-lives of the

drug, typically resolving within 72 to 96 hours. (51) If drug

fever is suspected and the patient is taking multiple med-

ications, eliminating one drug at a time may be helpful in

identifying the offending agent. However, other causes of

fever should be explored, based on history and physical

TABLE 3. Common Causes of Drug Fever

CLASS DRUGS

Antimicrobial agents Acyclovir, carbapenems, cephalosporins, tetracyclines, mebendazole, nitrofurantoin, penicillins,rifampin, sulfonamides, vancomycin

Anticonvulsants Barbiturates, carbamazepine, phenytoin

Antidepressants Doxepin, nomifensine

Antineoplastic agents 6-mercaptupurine, bleomycin, chlorambucil, cisplatin, cytosine arabinoside, daunorubicin,hydroxyurea, interferon, L-asparaginase, procarbazine, streptozocin, vincristine

Cardiovascular drugs Clofibrate, diltiazem, dobutamine, furosemide, heparin, hydralazine, hydrochlorothiazide,methyldopa, oxprenolol, procainamide, quinidine, triamterene

Histamine-2 blockers Cimetidine, ranitidine

Immunosuppressants Azathioprine, everolimus, mycophenolate mofetil, sirolimus

Nonsteroidal anti-inflammatory drugs Ibuprofen, sulindac, phenothiazines, salicylates

Other Allopurinol, antihistamines, folate, herbal remedies, iodide, metoclopramide, piperazine,propylthiouracil, prostaglandin E2, ritodrine, sulfasalazine, sympathomimetics, theophylline,thyroxine


examination findings, when discontinuing the medication

to ensure that fever resolution is due to drug fever rather

than resolution of another cause.

In an otherwise healthy, well-appearing child with FUO,

we do not recommend routine use of empiric antibiotics or

anti-inflammatory agents. Empiric antibiotics can delay the

diagnosis of common infectious causes of FUO, such as

endocarditis, osteomyelitis, central nervous system infec-

tion, or abscesses. Pediatricians commonly prescribe tetra-

cyclines (namely, doxycycline) or macrolides for presumed

atypical bacterial infections in the absence of risk factors

or clinical criteria for these diseases. These agents have

activity against some typical bacteria and have limited anti-

inflammatory effects, which can delay the manifestation

or natural disease process of alternative causes of FUO.

(52)(53)(54) We recommend the use of these agents when

there is high clinical suspicion and only after the diag-

nostic tests for the pathogen are obtained.

The decision to use empiric anti-inflammatory agents is

challenging. Corticosteroids can play a significant role in

treating certain causes of FUO, such as autoimmune dis-

ease. There is no urgency for empiric treatment in most

autoimmune diseases, and treatment should be started after

the diagnosis is confirmed. On one hand, corticosteroids

affect a broad range of physiologic processes, including the

immune system; can potentially increase the risk of acquir-

ing an infection or worsen an underlying infection; and can

impair the diagnostic usefulness of blood and tissue sam-

ples in oncologic testing and staging. On the other hand,

immune suppression should not be a contraindication for

specifically indicated short-term corticosteroids. Clinical

immune suppression associated with corticosteroid use

manifests after 14 to 21 days of daily administration. (55)

(56)(57)(58) We recommend the use of corticosteroids if

there is high suspicion for serious autoimmune and inflam-

matory conditions, such as systemic lupus erythematosus or

JIA, but not until oncologic etiologies have been excluded.

PROGNOSIS AND OUTCOME

A major difference between adult and pediatric FUO is

outcome. The prognosis of pediatric FUO is likely favorable

compared to FUO in the adult population due to differences

in causes. (59)(60) The original studies on pediatric FUO

from the 1970s demonstrated a mortality rate of 6% to 9%.

(12)(13) However, with the shifting causes of pediatric FUO,

further study is needed to define outcomes in both adult and

pediatric cases.

The increasing percentage of “undiagnosed” causes of

FUO has influenced the previously documented pediatric

mortality rates. Recent evidence suggests reassuring out-

comes for undiagnosed pediatric FUO. Talano and Katz (17)

followed 19 children with undiagnosed FUO for amedian of

3.5 years. Sixteen of 19 (82%) children with initially undi-

agnosed FUO were afebrile and clinically healthy at long-

term follow-up. Of the three children who remained febrile

or were not clinically well, two were subsequently diagnosed

with JIA and the other with intussusception. Similarly, Miller

et al (16) studied 40 children referred to a rheumatology

clinic for evaluation of FUO. Of the 40 children, 37 were

available at long-term follow-up (median 60.5 months); 34

had complete resolution of fevers and 2 (5%) developed

evidence of inflammatory bowel disease during follow-up.

Of note, neither of these studies was powered for morbidity

or mortality analysis. Whether the mortality rate of 6% to

9% found in previous studies applies to current cases of

FUO is currently unknown, particularly given the evolving

changes in underlying etiology over time. Further study is

needed to determine the mortality and overall outcomes

associated with pediatric FUO.

References for this article are at http://pedsinreview.aappubli-

cations.org/content/36/7/380.full.

Summary• On the basis of strong clinical evidence, the causes of FUO are broadand include both benign and life-threateningmedical conditions. (12)

• On the basis of observational studies, most cases of FUO have shiftedto noninfectious etiologies over the past several decades. (10)

• On the basis of observational studies, completely normal physicalexamination findings at the time of the initial FUO evaluationsuggest a benign underlying cause. (13)

• On the basis of consensus and expert opinion, a stepwise, tieredapproach to FUO should be implemented to decrease cost andtime to diagnosis. (13)

Parent Resources from the AAP at HealthyChildren.org• https://www.healthychildren.org/English/health-issues/conditions/fever/Pages/When-to-Call-the-Pediatrician.aspx

• Spanish: https://www.healthychildren.org/spanish/health-issues/conditions/fever/Paginas/When-to-Call-the-Pediatrician.aspx


http://pedsinreview.aappublications.org/content/36/7/380.full.


http://HealthyChildren.org

https://www.healthychildren.org/English/health-issues/conditions/fever/Pages/When-to-Call-the-Pediatrician.aspx

https://www.healthychildren.org/spanish/health-issues/conditions/fever/Paginas/When-to-Call-the-Pediatrician.aspx

PIR Quiz

REQUIREMENTS: Learnerscan take Pediatrics inReview quizzes and claimcredit online only at:http://pedsinreview.org.

To successfully complete2015 Pediatrics in Reviewarticles for AMA PRACategory 1 CreditTM,learners mustdemonstrate a minimumperformance level of 60%or higher on thisassessment, whichmeasures achievement ofthe educational purposeand/or objectives of thisactivity. If you score lessthan 60% on theassessment, you will begiven additionalopportunities to answerquestions until an overall60% or greater score isachieved.

This journal-based CMEactivity is availablethrough Dec. 31, 2017,however, credit will berecorded in the year inwhich the learnercompletes the quiz.

1. A 5-year-old female has had a fever to 39.7°C (103.6°F) once or twice daily for 8 days. Herpediatrician notes on history complaints of body aches and fatigue. Other than fever, thereare no abnormal findings on physical exam. Which of the following is the most likelydiagnosis at this time?

A. Bacteremia.B. Fever of unknown origin (FUO).C. Fever without a source.D. Influenza.E. Rheumatoid arthritis.

2. Which of the following best describes usual etiologies of FUO?

A. A common presentation of an uncommon disease.B. An uncommon presentation of a common disease.C. An untreatable disease with increased morbidity.D. A relatively serious disease that is usually treatable.E. A relatively uncommon disease requiring minor or no treatment.

3. Based on sentinel studies, which of the following are the most common identifiableetiologies of FUO in the United States?

A. Allergic diseases.B. Autoimmune diseases.C. Collagen vascular diseases.D. Infectious diseases.E. Oncologic diseases.

4. A 10-year-old male presents with a 14-day history of FUO. His elevated temperature to40.1°C (104.2°F) has been relatively sustained throughout this time period. Which of thefollowing etiologies based on this fever pattern most likely underlies this child’s problem?

A. Endocarditis.B. Juvenile idiopathic arthritis.C. Pyogenic abscess.D. Rat bite fever.E. Tuberculosis.

5. Periodic fever disorders often run in families and are more common in certain ethnicities.Among which of the following ethnic groups is familial dysautonomia most common?

A. Arab population.B. Armenian population.C. Ashkenazi Jewish population.D. Sephardic Jewish population.E. Turkish population.


http://pedsinreview.org

Constipation and Encopresis in ChildhoodJennifer M. Colombo, MD,* Matthew C. Wassom, PhD,† John M. Rosen, MD*

*Division of Gastroenterology, Children’s Mercy Kansas City, University of Missouri at Kansas City School of Medicine, Kansas City, MO.†Division of Developmental & Behavioral Sciences, Children’s Mercy Kansas City, University of Missouri at Kansas City School of Medicine, Kansas City, MO.

Educational Gap

A recent study in Pediatrics concluded that 25% of childrenwith functional

constipation continued to experience symptoms at adult age, suggesting

that referral to specialized clinics at an early stage for children who are

unresponsive to first-line treatment may help improve outcomes. (1)

Objectives After completing the article, the reader should be

able to:

1. Know that constipation is a common problem in childhood with

a diverse clinical presentation.

2. Understand that functional constipation is a symptom-based diagnosis

that does not require extensive testing.

3. Recognize that most children who present with fecal incontinence or

encopresis have associated constipation.

4. Describe the treatment of constipation and encopresis, which should

include a medical-behavioral approach that focuses on maintaining

soft and regular bowel movements and improving toileting behavior.

INTRODUCTION

What do the following children have in common?• A 12-month-old girl with hard pellet-like stools.

• A 3-year-old girl with frequent complaints of dysuria and hard stools.

• An 8-year-old boy with a weekly stool that is large enough to clog a toilet.• A 12-year-old boy with daily loose stools in his underpants.

Answer: They share a familiar diagnosis: functional constipation.

Constipation is a common pediatric problem and parental concern. In general,

a complaint of constipation accounts for 5% of general pediatric office visits and

25% of all referrals to pediatric gastroenterologists. The estimated worldwide

prevalence is 0.7% to 29.6%. (2) Constipation rarely signifies a serious disease,

but it has an unfavorable impact on patient quality of life, parental satisfaction,

and health-care costs. Children with constipation often complain of abdominal

pain, decreased appetite, and painful stooling, which can be distressing to both

the child and the parents. Common transient problems with defecation, if un-

recognized and untreated, can develop into disruption of toilet training and

AUTHOR DISCLOSURE Drs Colombo,Wassom, and Rosen have disclosed nofinancial relationships relevant to this article.This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.


interference with achieving and maintaining bowel conti-

nence. The chronic nature of constipation and common

misconceptions about the symptoms and pathophysiology

of constipation can lead to frustrating experiences for pa-

tients and families. Multiple office visits, emergency depart-

ment visits, and unnecessary diagnostic testing contribute

to the rising cost of health-care.

DEFINITION

Defining constipation remains a challenge because stooling

patterns are highly variable in childhood. Generally, infants

have an average of three to four stools per day and a toddler

may have two to three stools per day. (3) By the age of 4 years,

children have a pattern and frequency of bowel movements

that are similar to those of adults. (4) A consistent, reliable

method for diagnosis allows for better understanding of and

communication about the disorder. Constipation can be

roughly defined as infrequent passage of hard, uncomfort-

able stools that are distressing to the child.

Encopresis is the repeated passage of feces into inappro-

priate places (usually the underpants). Some have suggested

replacing the term fecal incontinence with the term enco-

presis in the literature to clarify that most children treated

for this problem have either current or intermittent con-

stipation. However, we continue to reference the term

encopresis along with fecal incontinence due to the preva-

lence of this term in the literature. Fecal incontinence/

encopresis is often the result of liquid/soft stool leaking

around a large mass of stool in the rectum, which clinicians

should describe as constipation with overflow.

Encopresis differs from delayed bowel training in that

children with encopresis pass liquid/soft stool in their under-

pants unknowingly because of constipationwith overflow and

difficulty feeling the indication to stool. Children with encop-

resis also generally do not have accidents of formed stool

whereas children with delayed bowel training simply refuse

to use the toilet and have regular bowel movements in their

diapers or underpants. Children with encopresis often also

use the toilet to pass formed or semiformed stool.

Children with delayed bowel training may refuse to use

the toilet because of fear, anxiety, oppositional behavior, skill

deficits, or lack of interest or motivation. Bowel continence

is expected to occur by the age of 4 years. Encopresis is not

a developmental variation after the age of 4 to 5 years.

PATHOGENESIS

Causes for the development of constipation include inade-

quate hydration, low-fiber diet, slow intestinal transit,minimal

activity level or inactivity, and behavioral factors. Because some

or all components may play a role in the development of

constipation and encopresis, these conditions should be

conceptualized in the biopsychosocial framework. Constipa-

tion can manifest at any age and most commonly presents

during a period of transition in the child’s life. In infancy,

constipation may present when the breastfed infant is

transitioned to formula or whole milk or when transitioning

from pureed to solid foods. In toddlers, constipation may

arise when toilet training begins. In childhood, constipation

ismore likely when a child enters school and is using a toilet

away from home.

Normal Anatomy and PhysiologyThe internal anal sphincter, external anal sphincter,

puborectalis muscle, and rectum must work together for a

productive bowel movement. The internal anal sphincter and

the rectum are composed of circular smooth muscle. The

external anal sphincter and puborectalis muscle are made up

of skeletal muscle. When the rectum is empty and collapsed,

the internal and external anal sphincters are tonically con-

tracted, maintaining continence. The puborectalis muscle

forms a sling around the rectum, pulling the rectum forward

when it is contracted and increasing the angle acuity between

the rectum and the anus.

When a bolus of stool reaches the rectum, distension of

the rectal wall signals the urge to defecate. The internal anal

sphincter reflexively relaxes and the external anal sphincter

contracts. There are two options at this time: 1) squatting

or sitting on the toilet, relaxing the puborectalis muscle,

straightening the anorectal angle, relaxing the external anal

sphincter, and increasing intra-abdominal pressure to evac-

uate stool or 2) maintaining and increasing contraction of

the external anal sphincter and gluteal muscles to force stool

back into the rectum.When the stool is pushed back into the

rectum, the sensation or urge to have a bowel movement

disappears.

Constipation and WithholdingWhen children do not recognize or respond to the urge to

defecate, stool is retained in the rectum, the urge to defecate

subsides, and the rectal wall stretches to accommodate the

fecal load. Repeated withholding or avoidance of defecation

leads to larger stool load in the rectum, causing further

stretching and potential thinning of the rectal wall. The

retained stool becomes larger, harder, drier, andmore difficult

to pass the next time the urge arises.

Prolonged and repetitive stool withholding and avoid-

ance of defecation leads to large amounts of retained stool in

the rectum. The large fecal mass becomes impacted and


extremely difficult to evacuate. Peristaltic movement of the

colon pushes semiformed and liquid stool lower in the

colon, resulting in leakage around the large mass of stool

into the child’s underpants. This is especially true if the

impacted fecal mass is putting downward pressure on the

anosphincteric complex, distending a normally tonically

contracted outflow barrier and making voluntary closure

of the external anal sphincter more difficult. Therefore,

a common complication of unrecognized and untreated or

undertreated chronic constipation is encopresis or fecal

incontinence.

If chronic constipation and encopresis are untreated,

they can lead to other significant clinical issues, such as

enuresis, frequent urinary tract infections, rectal prolapse, or

pelvic dyssynergia. The hard fecal mass in the rectum puts

pressure on the urethra and bladder, causing incomplete

evacuation of the bladder. Incomplete bladder evacuation can

predispose children to urinary stasis and sensations of ur-

gency followed by hesitancy. Chronic fecal soiling exposes the

urethra to bacterial pathogens that can ascend into the

bladder, causing infection. In addition, the enlarged dilated

rectum may result in decreased tone and contractility. Thus,

increasing intra-abdominal pressure (necessary for defeca-

tion) may ultimately result in rectal prolapse during a defe-

cation attempt. Finally, chronic constipation and encopresis

can contribute to the development of pelvic dyssynergia, or

pelvic floor dysfunction, in which pelvic floor muscles con-

tract instead of relax with attempted defecation, continuing

the cycle of incomplete rectal evacuation.

There are many reasons why a child may start to withhold

stool or avoid defecation. Stool withholding may be an inten-

tional behavior to avoid unpleasant sensations or associations

with defecation. It may be a response to a painful bowel

movement that is caused by a stool that was larger or harder

than normal, an analfissure, or a perianal infection. The child

may not want to use the toilet at school due to limited time,

lack of privacy, or concern about restroom cleanliness, choos-

ing instead to withhold stool until arriving home. A child may

not want to interrupt an enjoyable activity to have a bowel

movement. Finally, stool withholding may be a learned avoid-

ance behavior that is less intentional or even unconscious due

to repeated painful bowel movements.

Early recognition of stool withholding can prevent chronic

constipation and long-term defecation problems. Certain

behaviors, such as extending and crossing legs, clenching

gluteal muscles and the external anal sphincter, and avoid-

ing the squatting position, are compatible with active stool

withholding. These behaviors can be confusing for parents

whomay interpret them as strenuous efforts to have a bowel

movement.

DIFFERENTIAL DIAGNOSIS

Some of the multiple causes for constipation (Table 1) are

reviewed in this article. Most of the diagnoses discussed are

exceedingly rare. Functional constipation is most common

in childhood.

FunctionalInfant dyschezia describes healthy infants younger than

6 months of age who strain excessively with bowel move-

ments. They appear to be in significant discomfort, often

crying or screaming, turning red in the face, and bringing

their knees up to their abdomens, before eventually passing

soft stools. Symptoms abate following the stool passage.

Infants of this age have not yet coordinated increasing intra-

abdominal pressure with relaxation of pelvic floor muscles

to have a bowel movement. Infant dyschezia often sponta-

neously resolves around 6 months of age.

Functional constipation and functional fecal retention

are synonymous and the terms are often used interchange-

ably. Functional constipation refers to hard or infrequent

TABLE 1. Differential Diagnosis of Constipationand Defecation Disorders

FUNCTIONAL NEUROLOGIC

• Infant dyschezia • Hirschsprung disease

• Functional constipation • Neuronal dysplasia

• Nonretentive fecal soiling • Anal achalasia

• Disorders of the spinal cord

Obstructive Endocrine/Metabolic

• Anal stenosis • Hypothyroidism

• Anterior displacementof the anus

• Celiac disease

• Small left colon syndrome • Diabetes

• Meconium ileus • Cystic fibrosis

• Colonic stricture

Medications Dietary/Allergy

• Opioid narcotics • Cow milk protein allergy

• Anticholinergic agents • Low-fiber diet

• Tricyclic antidepressants • Decreased fluid intake forage

Other

• Sexual abuse

• Chronic intestinal pseudo-obstruction


stools in the absence of any other disorders, including neuro-

logic, obstructive, endocrine, or metabolic, and is discussed in

more detail throughout this review.

NeurologicHirschsprung disease (HD) is a congenital form of con-

stipation in which the infant or child cannot evacuate stool

due to a lack of ganglion cells in the myenteric and sub-

mucosal plexus of the intestinal wall. Without ganglion cells

and nerve fibers to innervate the intestinal musculature, the

affected colonic segment remains in a chronic contracted

state.

HD should be considered in any newborn who has de-

layed passage ofmeconium (ie, beyond 48 hours after birth).

Age at presentationmay depend on the length of the affected

intestine. Infants with long-segment HD develop signs of

distal intestinal obstruction, which may include abdominal

distention, vomiting, irritability, lethargy, and failure to pass

meconium or stool. Enterocolitis with or without bowel

perforation must be considered if the infants develop fever,

bloody diarrhea, and continued abdominal distention. One

of the most serious and possibly fatal complications of

Hirschsprung enterocolitis is progression to toxic mega-

colon and overwhelming sepsis.

Infants with shorter segments of HD may not be diag-

nosed until childhood. They may experience intermittent

abdominal distention and severe constipation that is refrac-

tory to standard treatment. They may also have poor growth

or failure to thrive due to decreased caloric intake. Only

rarely do children who have HD experience encopresis or

inadvertent leakage of stool.

Anal achalasia is the failure of the internal anal sphincter

to relax despite the presence of ganglion cells on biopsy. It is

unclear if anal achalasia is a variant or mild form of HD.

Neuronal dysplasia and hypoganglionosis are rare dis-

orders involving inadequate or inappropriate numbers of

ganglion cells. These conditions are infrequent and incom-

pletely understood. They can be associated with neurofibro-

matosis, multiple endocrine neoplasia type IIb, or Chagas

disease.

ObstructiveAnal stenosis presents with painful and difficult defecation

in infancy. This is due to the presence of a tight anal opening

or ring.

Anterior displacement of the anus is a congenital vari-

ation in the placement of the anus. External anal inspection

can reassure the clinician that anterior displacement is not

present. Theoretically, the anogenital index can be calculated

after careful examination and measurement of the perineum

by dividing the distance (in centimeters) from the vagina or

scrotum to the anus by the distance (in centimeters) from the

vagina or scrotum to the coccyx. The normal anogenital index

in females is 0.30 – 0.09 and inmales is 0.56 – 0.2. Affected

children have difficulty with defecation because they are not

able to straighten the anorectal canal completely due to mal-

position of the anal sphincter complex in relation to the

anus.

Meconium ileus causes delayed passage of meconium in

children with cystic fibrosis. It is one of the earliest signs of

cystic fibrosis and is almost always associated with pancre-

atic insufficiency. The meconium in infants with cystic

fibrosis is much thicker than the meconium in unaffected

children, which is attributed to an altered ratio of albumin

and water concentrations. The viscous meconium and in-

creased mucus production can lead to partial or total bowel

obstruction. This is often recognized at birth or within the

first few days of birth.

Strictures can occur anywhere in the intestinal tract. If

they occur more distally, children often have symptoms of

distal obstruction, including lower abdominal pain, abdom-

inal distention, and infrequent or total lack of bowel move-

ments. Strictures can be congenital or acquired due to

necrotizing enterocolitis in infants or inflammatory bowel

disease in children and adolescents.

Small left colon syndrome is a rare diagnosis that is most

closely associated with infants born to women who have

diabetes. Infants with signs of distal intestinal obstruction

and a small left colon noted on barium enema should be

screened for HD and cystic fibrosis because a small-caliber

left colon is a common finding on barium enema due to the

aganglionic segment inHD or as a result ofmeconium ileus

in cystic fibrosis.

OtherHypothyroidism may slow the motility of the gastrointesti-

nal tract, leading to constipation. Other symptoms of hypo-

thyroidism include fatigue; weight gain; shortness of breath;

and changes in the skin, hair, or nails. This constellation of

findings can help direct appropriate testing.

Celiac disease is an autoimmune sensitivity to gluten and

gluten-containing products in genetically susceptible indi-

viduals. The clinical presentation of this disease is so vari-

able that the “atypical” or nonclassic presentation of celiac

disease is becoming more commonplace. Children may

present with diarrhea, constipation, bloating, abdominal

pain, poor weight gain, short stature, skin rash, or iron

deficiency anemia. Evaluation for celiac disease should be

considered in children who have constipation that does not

respond to laxative therapy.


Chronic intestinal pseudo-obstruction manifests as se-

vere alteredmotility of the intestinal tract. This rare disorder

can be congenital or acquired. Children with this disorder

experience recurrent signs and symptoms of bowel obstruc-

tion, such as vomiting, abdominal pain and distention, and

constipation or diarrhea without an anatomic obstruction.

CLINICAL ASPECTS

Diagnosis of constipation relies foremost on an appropriate

definition, including the symptom-based Rome III criteria

for functional constipation. (5) Rome III defines functional

constipation as two ormore of the following (fulfilled at least

weekly for 2 months) in a child older than 4 years who does

not have irritable bowel syndrome:

1. Two or fewer defecations in the toilet per week.

2. At least one episode of fecal incontinence per week.

3. History of retentive posturing or excessive volitional

stool retention.

4. History of painful or hard bowel movements.

5. Presence of a large fecal mass in the rectum.

6. History of large-diameter stools that may obstruct the

toilet.

Similar age-appropriate criteria are also available for chil-

dren younger than 4 years. A variety of supplemental tests

should be applied only in the presence of warning signs

or symptoms or with failure of constipation to respond to

typical therapy. Test results should be interpreted in the

context of the patient’s history and physical examination

findings, which are sufficient for diagnosis in most

cases.

The clinical history should include a description of stool

frequency and quality, associated symptoms such as ab-

dominal pain and rectal bleeding, growth pattern, continence

and toilet training, presence or absence of withholding

behavior, and symptom onset and duration. Delayed pas-

sage of meconium should raise suspicion for HD. Thin,

ribbonlike stools also may suggest HD compared to the

large bulky stools that often are found with functional con-

stipation. Fecal incontinence should be directly assessed in

terms of frequency and quality because it may be concurrent

with constipation due to leakage of liquid stool around a firm

rectal stool mass. Symptoms of overflow incontinence typ-

ically are small-volume liquid stools, often passed in the

afternoon or during activities and sometimes unrecognized

or ignored by the child. Specific questions, including family

history, should be directed toward exclusion of diagnoses

other than functional constipation.

Standardizedmeasures such as themodified Bristol stool

form scale (6) or Amsterdam infant stool scale (7) allow for

a common language and description of stools. These mea-

sures can be used in combination with age-appropriate

questions that engage the patient and caregiver in an effort

to overcome barriers of symptom anxiety, embarrassment,

or denial (eg, Does it take you a long time to push poop out of

your body? Does the poop hurt your bottom when it comes

out?). Physically exemplifying withholding behavior during

the interview sometimes provides a moment of clarity for

caregivers who thought such behavior indicated an attempt

at defecation.

Physical examination should explore both the severity of

constipation and potential causes. Ideally, a growth curve

contains data spanning the onset of constipation to deter-

mine current parameters as well as past growth velocity.

Observation of the patient should not be underestimated in

its ability to elicit information; interaction between the

patient and caregiver, willingness of the patient to engage

in toileting discussion, and ability to sit and climb on or off

the examination table can provide important diagnostic

clues and sometimes direct treatment strategies. Abdominal

distension, tenderness to palpation, and presence of fecal

mass as well as perianal examination for skin tags, fissures,

and anal appearance and location are important for all new

patients in whom constipation is suspected. External anal

inspection can assess for anal atresia and displacement and

may identify anal fissures, skin tags, or external hemor-

rhoids. It may also be useful to assess sphincter tone visually

or identify fecal material around the anus or in the under-

wear. In addition, examining the back for sacral dimples or

spinal deformities and assessing lower extremity motor

tone, strength, and deep-tendon reflexes can indicate

whether additional assessment for neurologic pathology is

indicated.

Digital rectal examination (DRE) is important in specific

circumstances but is not always necessary to diagnose func-

tional constipation. Palpation of a firm or large rectal stool

mass on rectal examination often confirms clinical suspi-

cions, abnormalities in sphincteric tone may indicate anal

stenosis, and an empty rectal vault with expulsion of stool on

finger withdrawal is a classic but infrequently seen finding

in HD. Performing a DRE should be left to the discretion of

the clinician. DRE may provoke anxiety or fear in children

who have had past experiences with painful stool passage. It

is important to avoid reinforcing this negative association

when possible and limiting frightening or painful interven-

tions, which can aid in building a therapeutic alliance

between the patient and caregiver.

Laboratory evaluation is not warranted for constipation

unless warning signs are present (Table 2) or other aspects

of the history or physical examination suggest systemic


disease. Constipation rarely is the sole presenting symptom

of hypothyroidism, electrolyte abnormalities, lead toxicity,

or celiac disease, and routine screening for these diseases is

not recommended. Routine allergy testing is also not rec-

ommended in evaluation of constipation, and cow milk

protein restriction in young children for a limited time to

assess the clinical response remains controversial.

History and physical examination generally precludes the

need for radiography to diagnose functional constipation.

Although the presence or absence of a fecal mass and

determination of stool burden are important to direct ther-

apy, abdominal radiography is usually not necessary. An

abdominal radiograph may help parents visualize the

amount of retained stool, allowing for a better understand-

ing of constipation (with or without overflow) and the pro-

posed treatment plan. A single abdominal radiograph is an

inexpensive, low-risk test, but even when using standard-

ized scales to determine stool burden, it is not clearly

reliable, sensitive, or specific.

The indications for barium enema are extremely limited.

Barium or other contrast enema is suggested but not re-

quired when constipation is accompanied by “red flag”

symptoms (Table 2). It provides information about the

caliber of the rectum and colon and may be useful if ob-

struction in the colon is suspected. It does not require any

specific preparation and does not subject the patient to risk

aside from radiation exposure. Gastrografin enemas in the

setting of suspected meconium ileus may be diagnostic as

well as therapeutic.

Further diagnostic tests when the clinician suspects HD

depend on patient characteristics (age, health status) and

test availability. Full-thickness rectal biopsy remains the gold

standard for diagnosis and is performed under anesthesia,

but rectal suction biopsy can be performed at the bedside

without adjunct medication and is recommended in lieu of

surgical biopsy as initial evaluation. Although rectal suction

biopsy traditionally is performed in infants, it may also be

sufficient in older children and teenagers. Aganglionosis or

hypertrophied nerves on rectal biopsy hematoxylin and

eosin staining can indicate HD. Although the presence or

absence of these findings is typically sufficient for deter-

mining or ruling out the diagnosis of HD, supplementary

analysis may demonstrate aganglionic intestine with altered

acetylcholinesterase morphology or absent calretinin ex-

pression. Anorectal manometry uses a small rectal balloon

and anorectal pressure sensors to determine the presence or

absence of the rectoanal inhibitory reflex (relaxation of the

internal anal sphincter in response to rectal distension).

Although not used as an isolated test to diagnose HD, clear

demonstration of the rectoanal inhibitory reflex is sufficient

to remove HD from diagnostic consideration.

Anorectal manometry may also have a role in determin-

ing rectal sensation threshold and the presence of anorectal

dyssynergia, potentially directing therapy, including the ad-

dition of physiotherapy or biofeedback. High-resolution

anorectal manometry with increased number of pressure

sensors and enhanced computer analysis may better delin-

eate anorectal sensory and motor function, but this test is

not widely available in pediatrics.

Spinal imaging, including magnetic resonance imaging,

should be considered in the child with constipation and

other neurologic signs or symptoms, including lower motor

dysfunction, lower urinary tract symptoms, and lumbosa-

cral spinal abnormalities. The neurologic examination may

yield normal results in constipated children with spinal cord

abnormalities, but routine spinal imaging of constipated

children is not recommended.

MANAGEMENT

Constipation and fecal incontinence are clinical issues that

require a thorough understanding of physiology, biology,

behavior, and psychology for effective management. There-

fore, a combined treatment approach is recommended. Al-

though no objective clinical trials and data support a single

treatment approach to constipation and fecal incontinence,

we discuss a general management protocol. The manage-

ment protocol can be divided into four major treatment

components: 1) education about constipation and encopresis,

2) disimpaction or cleanout of stool, 3) maintenance lax-

ative therapy and establishing regular bowel movements,

and 4) behavior modifications to improve daily toileting

behaviors.

EducationEducation and reassurance comprise the first component in

the management of functional constipation and encopresis

TABLE 2. “Red Flag” Symptoms

n Delayed passage of meconium

n Failure to thrive

n Bloody stools

n Severe abdominal distention

n Perianal fistula

n Absent anal wink

n Sacral dimple


or fecal incontinence and should continue throughout all

stages of management. Education includes talking with the

parents and the child about constipation and its influence on

lower gastrointestinal tract functioning and overflow and

fecal incontinence. Developmentally appropriate discussion

of the anatomy and physiology of the lower gastrointestinal

tract and defecation is important and visual diagrams can

aid in this education. Many parents of children presenting

with encopresis incorrectly assume that the child is soiling

on purpose. Parents need to be educated that fecal incon-

tinence is often involuntary and the result of overflow from

constipation, deconditioning, or altered function of the rec-

tum and pelvic floor as well as learned withholding behav-

iors in some children. Counseling can be provided to

parents to help them establish a positive and supportive

attitude toward their child during treatment. Counseling

can help remove blame from the child and encourage the

parents and child to join the clinician in addressing the

symptoms. Clinicians should recognize and empathize with

families about the stress and frustration surrounding con-

stipation and fecal incontinence.

Disimpaction or CleanoutThe second component in the management of functional

constipation is removal of the fecal impaction. Such removal

decompresses the rectum, allows for the normal passage of

stool, and prevents liquid stool from leaking around the

fecal mass. If the fecal impaction is not removed, a child

with functional constipation cannot achieve a normal stool-

ing pattern, and fecal soiling may be exacerbated, which is

highly frustrating to parents and children.

Among the approaches to disimpaction are high-dose

oral laxatives, enemas, manual disimpaction, or admission

to the hospital for nasogastric administration of a bowel

cleansing agent. High-dose oral laxatives and enemas are

equally efficacious, but the preferred method for evacuation

of fecal impaction is via the oral route. Minimizing attention

to the anus and rectum via oral laxatives can be important

because these children have a history of unpleasant and

painful experiences associated with defecation. Current re-

commendations (Table 3) suggest the use of polyethylene

glycol solution (PEG 3350) at doses of 1 to 1.5 g/kg per day for

3 consecutive days (up to 6 consecutive days if necessary) to

achieve disimpaction. If PEG 3350 is unavailable, once-daily

sodium phosphate, saline, or mineral oil enemas for 3

consecutive days are acceptable. Suppositories may be used

in combination with high-dose oral laxatives to help pro-

mote evacuation of the fecal impaction. Manual disimpac-

tion is rarely necessary and generally not advised except

in cases of severe impaction and obstipation. If manual

disimpaction is required, general anesthesia should be used

to decrease the trauma associated with this procedure.

Maintenance TherapyThe third component in the management of functional

constipation is maintenance laxative therapy to ensure reg-

ular passage of soft, appropriate-sized stools. Such main-

tenance can eliminate painful defecation and prevent the

recurrence of fecal impaction. This component of treatment

may last many months to years and requires ongoing close

follow-up evaluation. Having families use a bowel symptom

tracking form or calendar to monitor the child’s response to

treatment may be helpful. Clinicians should emphasize the

need for close monitoring and long-term treatment with

parents because nonadherence to prescribedmedications or

discontinuing medications too early can result in the devel-

opment of hard stools and relapses of withholding, leading

to fecal impaction. The most common medication used for

maintenance therapy is PEG 3350 due to its ease of use,

titratability, low adverse effect profile, and efficacy.

When full evacuation of the rectum consistently occurs

with stooling for 1 to 2 months without any development of

hard stools or withholding behaviors, the laxative medica-

tion may gradually be reduced. Early recognition of relapse

by both parents and clinicians is vital to long-term treatment

of functional constipation. Increasing therapy and aggres-

sively treating a relapse can avoid prolongation of the main-

tenance phase.

TABLE 3. Medical Therapy for Disimpaction

∘ Oral (preferred)

n Polyethylene glycol solution 1–1.5 g/kg/day x 3–6 consecutivedays

n Magnesium citrate 4 mL/kg/day x 2 consecutive days

∘ Rectal

n Normal saline enema 10 mL/kg x 3 consecutive days

n Sodium phosphate enema x 3 consecutive days

· 2–4 years: one-half contents of a 2.25-oz pediatric enema

· 5–11 years: 2.25-oz pediatric enema

· >12 years: 4.5-oz enema

n Mineral oil enema x 3 consecutive days

· 2–11 years: one-half contents of a 4.5-oz bottle

· >12 years: 4.5-oz bottle

∘ Nasogastric (requires hospital admission)

n Polyethylene glycol solution 25–40 mL/kg/hr until rectaleffluent is clear (24–48 hr)


Laxatives used for maintenance therapy should be indi-

vidualized for each patient. Dosing guidelines and recom-

mendations are suggestions for starting therapy (Table 4). In

practice, laxative doses should be titrated to achieve at least

one soft bowel movement every day. Understanding the

mechanism of action of each laxative can aid clinicians in

customizing maintenance therapy because combination

therapy can be useful and necessary.

Osmotic laxatives increase the osmotic load within the

lumen of the intestine, allowing for fluid retention. The

retained fluid is incorporated into the stool and distends the

colon, promoting peristalsis. Childrenmay experience bloating,

but these laxatives are generally safe; the most common

adverse effect is diarrhea. Examples of osmotic laxatives

include PEG 3350, lactulose, and magnesium products such

as magnesium hydroxide and magnesium citrate.

Stimulant laxatives such as bisacodyl or senna irritate

smooth muscle of the colon and stimulate the myenteric

plexus to produce peristaltic activity within the colon. Chil-

dren may experience abdominal cramping with the peri-

staltic activity. The abdominal cramping is self-limited and

can be reduced by decreasing the dose. Although stimulant

laxatives are safe, no studies have assessed dependency

with chronic daily use. Stimulant laxatives can generally be

reserved for intermittent use and rescue therapy.

Stool softeners decrease the surface tension of the stool,

which allows integration ofmore water into the stool, thereby

softening it. Docusate has amodest stool softening effect. It is

generally safe, with minimal adverse effects.

Mineral oil may ease the passage of stool by lubricating

the intestine and decreasing water absorption. A common

complaint with use of mineral oil is leaking of the oil from

the rectum, which can be unpleasant. Palatability of mineral

oil is also a challenge for many children. Oral mineral oil is

contraindicated in children younger than age 1 year or with

known or suspected aspiration.

Dietary modification is frequently considered for treat-

ment, but increasing fluid or fiber intake has unclear

efficacy in constipated children. Maintaining adequate

hydration is important for a variety of physiologic functions

and, in most cases, is a safe recommendation. However,

solely increasing fluid intake should not be expected to alter

stooling frequency or consistency. Fiber is often chosen as

first-line therapy in constipated adults, but recent reviews of

evidence cast some doubt on its effectiveness. Dietary fiber

intake may be reduced in constipated children compared to

those without constipation, but increasing fiber does not

clearly improve symptoms and is not recommended as

therapy based on current evidence. Fiber also may be tole-

rated less well than other therapies for constipation in

children. Although complications related to fiber therapy

are unusual, use of fiber as monotherapy may delay im-

plementation of effective treatment and prolong patient

symptoms. Growing evidence supports probiotic and pre-

biotic use as treatment in adult constipation. These agents

may reduce whole-gut transit time, increase stool frequency,

and reduce constipation-associated symptoms. However,

evidence in pediatrics demonstratesmixed efficacy and their

use is associated with additional patient expense, possibly to

the exclusion of other effective therapies.

Behavior ModificationThe fourth treatment component is behavior modification

to improve daily toileting habits and routines. This compo-

nent should be started at the time of bowel disimpaction or

cleanout and continue throughout maintenance treatment.

TABLE 4. Maintenance Therapy for ChronicConstipation

∘ Osmotic laxatives

n Polyethylene glycol 1 g/kg/day

n Lactulose 1–3 mL/kg/day divided into 2 doses

n Magnesium hydroxide

· <2 years: 0.5 mL/kg/dose

· 2–5 years: 5–15 mL/day once before bedtime or in divideddoses

· 6–11 years: 15–30 mL/day once before bedtime or in divideddoses

· ‡12 years: 30–60 mL/day once before bedtime or in divideddoses

∘ Stool Softeners/Lubricants

n Docusate 5 mg/kg/day (up to 400 mg/day)

n Mineral oil 1–3 mL/kg/day divided into 2 doses

∘ Stimulant Laxatives (can be used for rescue therapy)

n Senna

· 1 month-2 years: 2.2–4.4 mg/day at bedtime or in 2 divideddoses

· 2–6 years: 4.4–6.6 mg/day at bedtime or in 2 divided doses

· 6–12 years: 8.8–13.2 mg/day at bedtime or in 2 divided doses

·>12 years: 17.6–26.4 mg/day at bedtime or in 2 divided doses

n Bisacodyl

· 3–12 years: 5–10 mg/day

· >12 years: 5–15 mg/day


Research regarding specific behavioral treatments for en-

copresis is disjointed and difficult to synthesize based on

recent reviews. However, the use of operant procedures

(incentive/reward programs and positive reinforcement)

for goals related to toileting and cleanliness have empiric

support. Incentive/reward systems can be used to target

various goals related to successful toileting. The targets of

intervention may vary with individual children. Reward-

ing the patient for cooperation with the components of

the treatment regimen and NOT just for proper elimina-

tion in the toilet is important. Children must achieve

important goals or behavioral skills on the way to success-

ful toileting, such as gaining confidence and compliance

with toilet sitting, responding appropriately and honestly

to soiling accidents, and learning effective pushing

techniques to produce complete and emptying bowel

movements.

An important part of the standard medical-behavioral

treatment of encopresis is improving toilet sitting behavior.

However, stool withholding and toileting refusal behaviors

may interfere with progress toward toilet sitting goals and

sometimes must be addressed before implementing a toilet

sitting plan. Stool withholding and toileting refusal are

believed to be related to the history of difficult-to-pass or

even painful bowel movements and are often conceptual-

ized as an anxiety or phobia about passing bowel move-

ments, especially into the toilet. The initial focus of stool

withholdingmanagement should be to ensure soft and easy-

to-pass bowel movements so that the child can gain comfort

in passing a bowelmovement on a daily basis. In early stages

of treatment, bowel movements in a pull-up or diaper may

need to be reinforced for the child to gain confidence and

voluntarily relax the pelvic floor to achieve a bowel move-

ment. Toilet refusal behavior should also be treated with

interventions that gradually desensitize children toward

toileting. Desensitization to the toilet may include rewarded

trips to the bathroom to look at the toilet, stand by the toilet,

sit on a closed lid fully clothed, and eventually sit on the toilet

with open lid and pants down. Once the child is having

bowelmovements comfortably in the diaper or a pull-up and

able to sit on the toilet without significant anxiety, parents

can use a shaping procedure to encourage bowel move-

ments closer to the toilet and eventually into the toilet.

Reward systems or incentives are used to encourage

children to take a next step toward successful toileting

behavior.

Once the child is comfortable and compliant with sitting

on the toilet, the overall goal is to improve daily toileting

habits and routines. Empiric evidence suggests that operant

procedures or reward systems should be an active part of

a toilet sitting schedule. Scheduled toilet sits can occur 20 to

30 minutes after meals to take advantage of the gastrocolic

reflex. In addition, pairing toilet sitting with meals is easier

to build into the family routine and can create a behavioral

stimulus condition for bowel movement success. The time

on the toilet should be unrushed and positive. It may include

special activities that are only available while on the toilet

(special books, toys, or handheld electronics). Parents can

also be counseled to provide modeling and coaching during

toilet sitting, which includes the parents showing the child

when they sit on the toilet and that they are pushing to help

get bowel movements out in the toilet. Toilet sits should

generally last 5 minutes, but some children need to grad-

ually work their way up to longer sits if there is initial

resistance. Scheduled, rewarded toilet sits should include

small stepstools to assist the children in getting on the

toilet and to use as leverage for their feet. We recommend

a wider stepstool or potty stool to allow the child to spread

out the feet and knees for better posture to allow successful

defecation and for them to feel more comfortable and

balanced on the toilet. Once children are having more

productive bowel movements in the toilet and soiling

has stopped for a 1 month, the number of daily toilet sits

can be reduced. Often parents can observe which toilet sits

during the day are most productive and begin focusing on

those sits. As treatment progresses, children can start to

earn incentives/rewards for independently going to the

toilet when they feel the urge to have a bowel movement

rather than strictly relying on the schedule and parental

prompt.

Involving the preschool, kindergarten, or school in sched-

uled and rewarded toilet sitting is important. Children who

are apprehensive about completing toilet sits at school bene-

fit from a more private restroom so that they can take their

time and be comfortable with toileting. It also is helpful to

allow an “anytime bathroom pass” for children when they

start school so that they do not withhold stool when they

need to have a bowel movement.

Due to the biopsychosocial nature of functional consti-

pation and fecal incontinence, multidisciplinary or even

interdisciplinary care is becoming more common and is

highly recommended when available. The combination of

medical therapy, behavioral modification, and supportive

counseling has the greatest success in the treatment of

constipation and encopresis. When multidisciplinary or

interdisciplinary care is not readily available, clinicians

can still effectively treat this condition with a basic under-

standing of behavior modification techniques, such as the

use of incentives/rewards and gradual setting of goal related

to effective toileting.


PROGNOSIS

The overall prognosis for functional constipation has not been

completely established. However, a general message for fam-

ilies is that the treatment of constipation and encopresis often

requires many months of medication and behavior modifi-

cation. In addition, relapse of symptoms is very common.

According to a recent systematic review, approximately 60%

of children with functional constipation are symptom-free

between 6 and 12 months after beginning treatment regard-

less of laxative use, with the remaining 40% of children still

experiencing symptoms. (8) In addition, a study in Pediatrics

concluded that 25% of children with functional constipation

continue to experience symptoms into adulthood. (9) Older

school-age children and adolescents who have ongoing con-

stipation and encopresis are even more difficult to treat. All

these points highlight the need for aggressive treatment as

early as possible as well as close follow-up evaluation and

adjustments to the treatment plan. Nonetheless, most chil-

dren with constipation and encopresis can be managed

effectively by the general pediatrician. Indications for referral

to a pediatric gastroenterologist include medical red flags,

trouble with disimpaction, trouble establishing mainte-

nance therapy, and lack of improvement after 6 months

of therapy. Referral to a pediatric behavioral specialist

should be considered if significant conditions are interfering

with treatment, such as attention-deficit/hyperactivity disor-

der, oppositional behaviors, anxiety ormood disorders, family

conflict or parent-child conflict, or problems with adherence

to recommendations.

References for this article are at http://pedsinreview.aappubli-

cations.org/content/36/9/392.full.

SummaryThe following summary statements are based primarily onconsensus and expert opinion due to the lack of relevant clinicalstudies. A recent comprehensive review of the literature by Tabberset al, in the Journal of Pediatric Gastroenterology and Nutrition,identified no moderate- or high-quality evidence regardingtherapeutic interventions for the evaluation and treatment offunctional constipation in infants and children.• The presentation of constipation varies, but constipation shouldbe identified according to an appropriate definition, whichincludes the symptom-based Rome III criteria.

• Constipation is prevalent in children and infrequently a result ofunderlying intestinal or systemic disease.

• Based on limited evidence as well as consensus, history andphysical examination are sufficient to provide a diagnosis offunctional constipation; digital rectal examination, laboratorytests, and abdominal radiography are generally not necessary.

• Treatment of constipation requires four components: education,disimpaction, maintenance therapy, and behavioral modification.




PIR Quiz




1. By what age do children have a pattern and frequency of bowel movements similar tothose of adults?

A. Three years.B. Four years.C. Five years.D. Six years.E. Seven years.

2. Which of the following is more characteristic of behavior by children with delayed boweltraining versus children with encopresis?

A. Have difficulty feeling the indication to stool.B. Generally do not have accidents with formed stool.C. Often use the toilet to pass formed or semiformed stool.D. Usually have regular bowel movements in the diaper or underpants.E. Pass liquid/soft stool in their underpants.

3. A 4-month-old girl presents with substantial straining with bowel movements. She criesand turns red in the face just before she passes a soft stool, after which she relaxes. Whichof the following is the most likely diagnosis for this infant’s signs and symptoms?

A. Anal achalasia.B. Functional constipation.C. Hirschsprung disease.D. Infant dyschezia.E. Neuronal dysplasia.

4. A 3-day-old term infant has had delayed passage of meconium. At 48 hours, he passeda small, thick stool. Which of the following is the most likely diagnosis?

A. Anterior displacement of the anus.B. Celiac disease.C. Cystic fibrosis.D. Hirschsprung disease.E. Hyperthyroidism.

5. An 8-year-old boy with chronic constipation and encopresis has been successfully treatedwith education and disimpaction. Which of the following medications is most commonlyused for maintenance therapy due to its ease of use, titratability, low adverse effect profile,and efficacy?

A. Lactulose.B. Magnesium hydroxide.C. Mineral oil.D. Polyethylene glycol solution.E. Senna.



Patient Safety and Quality Improvement:Terminology

Lucy Pereira-Argenziano, MD,* Fiona H. Levy, MD*

*Department of Pediatrics, NYU School of Medicine, New York, New York.

Education Gap

Medical errors and unintended harm continue to occur, despite

preventive strategies. Understanding terminology and key attributes of

improving safety can lead to creation of systems to reduce medical errors

and preventable harm.

Objectives After completing the article, the reader shouldbeable to:

1. Understand and apply common terms used during discussions of

safety and quality.

2. Describe common types of error and harm in pediatrics.

3. Describe the pediatric response to Institute of Medicine

recommendations.

4. Understand attributes of high-reliability organizations and how their

principles can be used to improve patient safety.

BACKGROUND

The patient safety movement was galvanized by publication of To Err is Human by the

Institute ofMedicine (IOM) in 1999. (1) The report estimated that 44,000 to 98,000

people die in US hospitals each year as a result of medical errors. Equally interest-

ing and perhaps as important to the magnitude of preventable injury occurring to

patients in the United States is the fact that much of the data used as the basis for

these estimates had been published and available in 1991. (2) The economic impact

of medical errors has equally alarming implications for both health systems and

consumers. Researchers analyzed clinical and billing data from a hospital database

containing information from 600 hospitals and ambulatory surgery centers within

the United States for visits in which injury occurred as a result of medical error. (3)

A cost analysis was performed for each injury visit. Extrapolation of the data to the

broader US population estimated the cost of medical errors to the US health-care

system to have been $1 billion in 2009. Because the study focused solely on inpatient

costs ofmedical errors and did not account for societal impacts such as time lost from

work, this is likely an underestimate of the true cost of medical errors.

With the publication of To Err is Human and resulting attention of both the

press and the public, the medical community was held accountable to address

AUTHOR DISCLOSURE Drs Pereira-Argenziano and Levy have disclosed nofinancial relationships relevant to this article.This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.


recommendations for improvement. The stated intent of the

IOM recommendations was to achieve a synergy between

the external pressures of regulatory, governmental, and

purchasing organizations and the internal motivations of

clinicians, organizations, and professional societies work-

ing to improve the safety of care at the point of delivery.

Three of the four key strategic recommendations to achieve

safer care can be broadly summarized as: (1)

1. Develop mandatory and voluntary reporting systems to

allow both the identification of and learning from

medical errors.

2. Encourage external oversight organizations, professional

groups, and group purchasers of health-care to raise

performance standards and set expectations of improved

patient safety.

3. Design and implement safety systems in health-care

organizations to ensure safe practices at the delivery

level.

TERMINOLOGY

Clarifying terminology is important because there is signif-

icant overlap and variation among medical errors, adverse

events, and preventability. Probably the best and most

widespread definitions come from the IOM.

Medical ErrorAmedical error has been defined by the IOM as “a failure to

complete a planned action as intended or the use of a wrong

plan to achieve an aim.” (1) A medical error does not always

lead to patient harm because itmay not reach the patient and

it may not be such a critical aspect in the process of care as to

injure the patient (Figure). However, that statement does not

mean that clinicians should not track and seek to under-

stand all medical errors. A near miss is a medical error that

has the potential to cause patient harm but has not. (4) The

knowledge that something kept the error from reaching the

patient provides an excellent opportunity to learn about

processes of care; understanding how we intentionally or

accidently prevent an error from reaching a patient allows

clinicians to improve safety systems. An adverse event is

a medical error in management or intervention that leads to

patient injury (1)(4) and results in prolonged hospitalization

or the presence of a disability at hospital discharge.

Sentinel EventA sentinel event is a term coined and defined by the Joint

Commission as “an unexpected occurrence involving death

or serious physical or psychological injury, or the risk

thereof.” (5) Individual health-care organizations have the

responsibility of defining serious physical or psychological

injury, but the intent is to capture injuries of permanence and

significance, such as loss of limb or function. The phrase “or

the risk thereof” can be thought of as a near miss, where the

risk and potential consequences of a recurrence may lead to

a serious adverse outcome. Of note, a sentinel event may or

may not be due to a medical error. Once a sentinel event has

been identified, the Joint Commission mandates that an

investigation be immediately undertaken to determine the

root causes that have led to the event as well as implementa-

tion of an action plan andmonitoring tominimize future risk

that this event will recur. The information is reported to the

Joint Commission Sentinel Event Database. Aggregate sen-

tinel event data are reviewed by the Joint Commission for

trends of root causes or risk-reduction strategies. Events that

demonstrate either frequency or high risk are shared with

hospitals and the public via Sentinel Event Alerts. Examples

of pediatric-specific Sentinel Event Alerts include: “Prevent-

ing pediatric medication errors” and “Revised guidance to

prevent kernicterus.” (6) Aggregate data from the Sentinel

Event Database are also used to guide development of

National Patient Safety Goals (NPSG). (5)

MEDICAL ERRORS IN PEDIATRICS

Medical errors can be categorized as diagnostic, treatment,

and preventive. (7) Errors can be further categorized as

preventable and nonpreventable.

Diagnostic ErrorsMalpractice claims have been used to extrapolate the distri-

bution of pediatric medical errors. According to analysis by

the Physician Insurers Association of America, diagnostic

errors in the form of missed or incorrect diagnosis account

for most pediatric malpractice cases. (8) Pneumonia, men-

ingitis, appendicitis, and testicular torsion were among the

diagnoses most frequently associated with diagnostic errors

in medical malpractice claims. (9)(10) In an attempt to

elucidate pediatricians’ perceptions and experiences with

diagnostic errors, Singh et al (11) conducted a multicenter

survey. More than 50% of surveyed pediatricians reported

making a diagnostic error at least once per month, with

misdiagnosis of a “viral illness as a bacterial illness” as the

perceived most frequent diagnostic error. Misdiagnosis of

otitismedia with effusion as acute otitismedia is an example

of a viral illness diagnosed as a bacterial illness.

Treatment ErrorsMedication errors are an example of treatment errors.

The National Coordinating Council for Medication Error


Reporting was convened in 1995 with representation from

multiple interdisciplinary agencies in an attempt to encourage

reporting and prevention of medication errors. (12) The

Council developed an Index for CategorizingMedical Errors

to provide a standard method for categorizing and tracking

errors. The Index classifies medical errors as A through I,

according to whether or not they reached the patient, and if

they reached the patient, the progressive degree of resultant

harm. Medication errors classified in categories E through H

are associated with increasing severity of patient harm, with

the ultimate outcome of death in category I. A chart review

from 12 children’s hospitals throughout the United States

found the incidence of medication errors resulting in patient

harm (category E or greater) to be 11.1 per 100 patients or 15.7

per 1,000 patient-days. (13) Analysis of the events revealed

ordering and monitoring as the stages of medication man-

agement that are most prone to preventable error.

Pediatric medication management is especially complex

because of calculations necessary for weight-based dosing,

off-label use of medications, compounding and dilution

needed for medication preparation, and limited ability of

young patients to communicate. (14)(15) Within pediatrics,

patients in the neonatal intensive care unit are particularly

vulnerable due to frequent changes in medication dosing

weights and altered pharmacokinetics leading to variation

in medication metabolism. (14)(16)

Preventive ErrorsPreventive errors encompass failure to provide a prophylac-

tic treatment. Examples of preventive errors have been seen

in perinatal hepatitis B prevention. Neonates born to women

infected with hepatitis B require immunoprophylaxis after

delivery. Without appropriate treatment, approximately

40% of exposed infants are estimated to develop chronic

hepatitis B infection. (17) The Immunization ActionCoalition

reported approximately 500 cases of hepatitis B perinatal

prevention errors between July 1999 and October 2002. (18)

The errors reported included: “infants born to [hepatitis B

surface antigen]HBsAg-positivemothers did not receive both

hepatitis B vaccine and [hepatitis B immune globulin] HBIG

within 12 hours,” “Infants born to mothers of unknown

HBsAg status were not properly prophylaxed,” and “screen-

ing test results were misordered, misinterpreted, mistran-

scribed, or miscommunicated.” In response to the errors

reported, the Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices updated

recommendations to prevent hepatitis B transmission,

including universal hepatitis B vaccination at birth. (19)

The Committee also provided strategies to aid in imple-

mentation of the recommendations, such as the inclusion of

hepatitis B vaccine as a standing order at birth.

Preventable and Nonpreventable Medical ErrorsMedical errors of all types can be further classified as

preventable and nonpreventable. Making this distinction

allows targeted efforts to eradicate preventable errors and

any associated harm, with less focus on nonpreventable

errors. Equally important is the determination of whether

patient harm is preventable or nonpreventable.

An example of nonpreventable error may be an adverse

drug event (ADE), such as a patient without a history of

a medication allergy developing an allergic reaction after

administration of amedication. Although the patientmay be

harmed by the event, the event was not preventable because

the allergy was previously unknown. In contrast, if a patient

has a known medication allergy and the medication is

administered, a preventable error has occurred.

Patient harm may also be designated as preventable or

nonpreventable. Nabhan et al (20) performed a literature

review to determine common themes used to designate

a harm event as preventable. According to these authors,

“presence of an identifiable modifiable cause, reasonable

Figure. Medical errors.


adaption to a process will prevent future recurrence and lack

of adherence to guidelines implies preventability.”

The concept of the preventability of patient harm has led

to a modified and enhanced approach to patient safety in

hospitals. In 2008, Nationwide Children’s Hospital set

a 5-year goal to eliminate preventable harm within their in-

stitution. The journey to elimination of preventable patient

harm included a cultural change based upon the principles

of high-reliability organizations (HROs). (21) HROs are typ-

ically found in the arenas of nuclear power, naval aircraft

carriers, and commercial aviation. (22) Many organizations

have begun to test and study how these cultural under-

pinnings of HROs might be brought to the world of health-

care and improve the safety of patient care. HROs are

governed by five key principles: three of anticipation and

two of containment (Table 1). (23)

To achieve both the preoccupation with failure and the

sensitivity to operations, transparency of information about

the system in which people work is required. Deviations of

performance or errors are transparently shared with mem-

bers of the HRO. To achieve this, Nationwide Children’s

Hospital developed and implemented a Preventable Harm

Index (PHI). (21) The PHI is composed of the number of

harmevents that occur in eight different categories, including

hospital-acquired infections, ADEs, preventable non-intensive

care unit cardiac arrests, significant postsurgical compli-

cations, serious falls, pressure ulcers, and miscellaneous

significant harm and serious safety events. (21) In 2008,

teams were established to work on reducing each category of

patient harm. Through cultural transformation, the work of

quality improvement teams, and the measurement and shar-

ing of the PHI, Nationwide Children’s Hospital experienced

a significant decrease in preventable harm events and pa-

tient mortality. (21) Similar organization-wide initiatives to

decrease preventable harm in children alsowere successful at

institutions such as Cincinnati Children’s Hospital (24) and

Helen DeVos Children’s Hospital. (25)

Interestingly, the designation of harm as nonpreventable

may change over time. Events that are currently determined

to be nonpreventable may become preventable if additional

knowledge is acquired or new standards of care are estab-

lished. (26) An example of preventable harm that previously

was believed to be the price of being sick and in an intensive

care unit and, therefore, nonpreventable is central line-

associated blood stream infections (CLABSI). Central line

insertion and maintenance bundles emerged from collab-

orative efforts and sharing of data. (A bundle is a structured

approach to improving processes of care and patient out-

comes.) As the bundles were tested and the incidence of

CLABSI was significantly decreased, (27) use of bundles as

well as certain components of the bundle have become the

standard of care. The presence of guidelines that have been

found to prevent the occurrence of CLABSI has led to the

designation of CLABSI as preventable harm.

MEDICAL ERRORS UNDERSTOOD THROUGH PROCESSANALYSIS

The occurrence of amedical error is oftenmultifactorial and

requires multiple small deviations to occur in sequence,

leading to the larger event. The Swiss Cheese Model devel-

oped by JamesReason can beused to illustrate howamedical

error occurs. (22) In the model, every step in a process (the

process of care in the case of medical errors) is represented

as a slice of Swiss cheese. Each step in the process can

prevent or facilitate an error reaching a patient and causing

harm.When the process works well, the cheese is intact and

blocks errors from reaching patients. When processes of

care are flawed (represented by holes in the cheese), they

provide avenues for errors to reach the patient and cause

harm. When all of the steps are placed together, if some of

the holes align through the successive layers, the error

reaches the patient. The opportunity to study errors from

the perspective of processes and system analysis after real

and near-miss events allows for redesigning of systems of

care that can prevent the recurrence of adverse or sentinel

events in the future.

TABLE 1. Principles of High-reliabilityOrganizations

Principles of Anticipation:

1. Preoccupation with failure: Identification of failures and signsof system weakness are embraced.

2. Reluctance to simplify: Simplification of factors leading toa failure may lead to missed identification of factors andopportunities for improvement.

3. Sensitivity to operations: Attention is paid to what isoccurring in the system rather that what is supposed to occurand recognition that accidents are the consequence ofmultiple errors.

Principles of Containment:

1. Commitment to resilience: Ability of a system to recover afteran error has occurred.

2. Deference to expertise: Acknowledgement that knowledgeand decision support are needed and sought based on level ofexpertise, not hierarchy.

Adapted from Weick K, Sutcliffe K. Managing the Unexpected. 2ndedition. San Francisco, CA: Copyright (c) 2007 by John Wiley & Sons, Inc.All rights reserved.


The importance of process analysis can be illustrated by

the example of a prescriber making an error when entering

a medication order into a computerized physician order

entry (CPOE) system. Normally the first barrier to keep this

error from reaching the patient might be the CPOE system.

In this case, the CPOE system was not designed with

safeguards for this medication, so the error passes through

the first barrier (it finds the hole in the Swiss cheese). The

next barrier could be a pharmacist who needs to verify all

orders. On this day, a covering pharmacist who is unfamiliar

with pediatrics approves the medication. The error has

moved through two intended barriers or safeguards. Finally,

the medication is picked up by the nurse, who normally

would have checked and rejected the medication. However,

on this day the patient care unit is very busy and loud and the

nurse is continually interruptedwhile checking this unusual

medication before administering it. Thus, a simple error

made by a prescriber passes through all of the safeguards

between the error and the patient.

The next step is to understand how the processes broke

down and allowed this medication error to happen. What is

wrong with the design of CPOE system andwhat needs to be

fixed?What processes are in place to orient new pharmacists

to the pediatric pharmacy to prevent error? How is the

clinical unit designed to ensure that nurses have the unin-

terrupted time and space to check all medications thor-

oughly? Process analysis allows clinicians to determine

the real causes of error (latent failures) and focus on how

to fix systems rather than punish individuals.

DEVELOP REPORTING SYSTEMS FOR MEDICAL ERRORS

The ability to detect and report medical errors is critical to

improving the safety of care. Error reporting via voluntary or

mandatory reporting systems allows for review of factors that

have contributed to an error (actual or near miss), and the

subsequent development of risk-reduction strategies can help

prevent the recurrence of a similar event. (28)(29) Understand-

ing and implementing a plan to address barriers to error

reporting, includingdifficultywith error detection, can enhance

the use of reporting systems and, therefore, learning potential.

Voluntary Error ReportingVoluntary incident reporting systems are used in health-care

to report the occurrence of errors. Frequently, the errors

reported have resulted in little or no patient harm, but they

provide critical information necessary to drive performance

improvement and improve patient safety. (1) Voluntary

reporting systems, although useful, have limitations. In

2004, Tayor et al (30) surveyed 200 physicians and nurses

at a large children’s hospital. Fewer than 50% of the re-

spondents indicated that they completed incident reports on

80% or more of the errors they committed. Approximately

one third of respondents indicated that they completed an

incident report for fewer than 20% of the errors they

committed. When evaluating per discipline, nurses were

more likely to report their errors than physicians.

To understand barriers to the use of voluntary incident

reporting systems, physicians and nurses have been sur-

veyed regarding their practices of and beliefs about error

reporting. (31) The barriers encountered by each discipline

varied. Physicians most frequently identified “lack of feed-

back, incident form takes too long to complete, and a belief

that an event was too trivial” as barriers. Nurses identified

“lack of feedback, a belief that there was no point in reporting

near misses, and forgetting to make a report when ward was

busy” as the most common barriers to error reporting.

Concern about legal implications from the generation of

an error report, (32) lack of physician access to electronic

incident reporting systems, interruption of patient care to

complete incident report, and concern that reporting may

result in punitive action have been identified as additional

barriers to voluntary incident reporting systems. (33)

Physicians surveyed identified changes to voluntary re-

porting systems that may increase reporting of medical

errors. Recommendations include: “education about which

errors should be reported, feedback on a regular basis about

errors reported and about individual events, evidence of

system changes because of reports of errors, and electronic

format for reports.” (30) In addition, the Agency for Health-

care Quality (AHRQ) has recommended key components to

increase the effectiveness of an error reporting system. (34)

The components include: generation of error reports by

a wide range of employees, protecting the confidentiality of

the author of the incident report, implementation of a sys-

tem to review events, performing analysis, implementation

of risk-reduction strategies, and timely feedback to staff.

Enhanced Error DetectionThe strength of a voluntary reporting system is dependent

on the ability to detect medical errors. The Institute for

Healthcare Improvement (IHI) developed trigger tools to

complement error detection. Triggers are occurrences that

may signify the presence of an error if present in a medical

record. Examples of triggers include the use of naloxone,

a rising creatinine value, hyperglycemia, and unexplained

return to surgery. (35) Identification of a trigger prompts

further evaluation of the medical record to determine

whether a medical error has occurred. Evaluation of trigger

tools may be manual or automated. Manual detection


requires that a trained reviewer audit a sample of charts for

the presence of a trigger. If a trigger is identified, the chart

is reviewed in depth to determine if a medical error has

occurred. Currently available pediatric-specific trigger tools

through the IHI include the Pediatric Trigger Toolkit: Mea-

suring Adverse Drug Events in the Children’sHospitals (36)

and Trigger Tool for Measuring Adverse Events in the

Neonatal Intensive Care Unit. (37) Examples of triggers in

the Pediatric Trigger Toolkit include administration of

diphenhydramine, rash, and hyperkalemia. (36)

The Children’s Health Corporation of America devel-

oped and tested a pediatric-specific trigger tool for ADEs.

(13) A manual retrospective chart review was conducted to

identify the presence of triggers. Identified triggers, includ-

ing administration of diphenhydramine, presence of rash,

and hyperkalemia, prompted an in-depth review for ADEs.

The study determined that the mean ADE rate was 11.1 per

100 patients and 15.7 per 1,000 patient-days. Only 3.7% of

the ADEs identified using the trigger tools were also iden-

tified by the voluntary reporting system. (13)

Although manual identification of triggers improves

error detection, it only samples a small number of charts

and is labor intensive. Automated adverse event detection

(AAED) uses algorithms to identify triggers in the electronic

health record on a continual basis, thereby enabling audit-

ing of all charts. As with manual detection, once a trigger is

identified, a chart review is conducted for evaluation of

a potential medical error. Lemon and Stockwell (38) pub-

lished results with use of AAED over a 4-year period. Of the

triggers identified, 34% identified adverse events. Only 3%

of the adverse events found using the AAED were also

identified by the voluntary reporting system.

Mandatory Error ReportingState law may require reporting of sentinel events and

adverse events leading to significant patient harm. The

New York Patient Occurrence Reporting and Tracking

System (NYPORTS) is an example of a state-led manda-

tory reporting system. (39) Requirements for reporting to

NYPORTS include: deaths not related to anticipated disease

progression, medical equipment malfunction or misuse

leading to serious patient harm or death, and discharge of

a patient incapable of making medical decisions to an unau-

thorized person. Trending of NYPORTS data allows for

identification of opportunities for quality improvement

within an institution and throughout the system. Successful

institution of preoperative protocols to decrease the incident

of wrong-site surgery, wrong-site procedure, and procedure

on the wrong patient is an example of an initiative driven by

NYPORTS data. (40)

Mandatory error and adverse event reporting is also used

by the US Food and Drug Administration (FDA). The FDA

is responsible for review of medical equipment to ensure its

safety and effectiveness before approval for use. After

approval, monitoring for device safety with the use of an

event reporting system continues. Mandatory Medical

Device Reporting mandates “device user facilities,” which

include hospitals and outpatient treatment facilities, to

report any serious injuries or deaths that may be attributed

to the use of medical equipment. (41)

Medical Error Reporting to Share Lessons LearnedBecause the occurrence of medical errors at each institution

is relatively small, the knowledge gained through collabo-

ration and sharing of information among institutions can

greatly enhance the speed of error prevention. In 2005,

Congress approved the Patient Safety and Quality Improve-

ment Act. The Act provides confidentiality protection to

members of Patient Safety Organizations (PSOs), allowing

for sharing of medical errors and safety events. Currently,

80 PSOs are listed with the AHRQ. Pediatric PSOs include

Safe Pediatric Health Care PSO, Child Health Patient Safety

Organization, and Wake Up Safe. (42)

Wake Up Safe is a quality improvement initiative of the

Society for Pediatric Anesthesia. The initiative contains

a registry of serious safety events that have occurred in

pediatric anesthesia. The knowledge gained in the analysis

of serious safety events is shared with members of the PSO

and used to drive learning and safety initiatives. (43)

The AHRQ has established common formats, which serve

as a standard for reporting and analyzing patient safety events.

PSOs use common formats for submission and reporting of

events. Common formats are available for falls, health-care-

acquired infections, blood or blood product events,medication

or other substance events, perinatal events, surgery or anes-

thesia events, and venous thromboembolic events. (44)

ENCOURAGE EXTERNAL OVERSIGHT ORGANIZATIONS,PROFESSIONAL GROUPS, AND GROUP PURCHASERSTO RAISE PERFORMANCE STANDARDS AND SETEXPECTATIONS OF IMPROVED PATIENT SAFETY

Standards and expectations for patient safety may be set by

accrediting organizations such as the Joint Commission

through the development of the NPSG. More recently,

the work of pediatric networks, exemplified by the Chil-

dren’sHospitals’ Solutions for Patient Safety (CHSPS), have

applied standard bundles for hospital-acquired conditions

and complementary work on the culture of safety to improve

patient outcomes.


National Patient Safety GoalsIn 2002, the Joint Commission established the NPSG pro-

gram to enhance patient safety across all accredited health-

care organizations (Tables 2 and 3). (45) An advisory group

that includes nurses, physicians, pharmacists, risk manag-

ers, and clinical engineers identifies patient safety concerns

throughout the health-care system and potential solutions.

Specific patient safety goals are established for ambulatory

health-care, behavioral health-care, critical access hospitals,

home care, and hospice. Every 2 years these goals are

reviewed and revised. Once a goal has become an accepted

standard of practice, it and its assigned goal number are

removed, so the goals are not numbered sequentially. Ac-

credited health-care organizations are required to establish

NPSG as organizational priorities and develop policies and

procedures to ensure compliance.

Children’s Hospitals’ Solutions for Patient SafetyIn 2009, the children’s hospitals in Ohio joined together to

create the Ohio Children’s Hospitals’ Solutions for Patient

Safety, a collaborative to improve patient safety. The initial

focus was to decrease surgical site infections and ADEs,

which subsequently expanded to the goal of eliminating

serious harm. The success of the collaborative, which dem-

onstrated a 40% reduction in serious harm events and 55%

reduction in serious safety events, prompted the support of

the Centers for Medicare and Medicaid Services Innovation

Center in 2012, allowing collaboration to spread to hospitals

outside of Ohio. (46) Currently the network, renamed as

CHSPS, comprises more than 80 children’s hospitals

throughout the United States. (47) Current goals of the

network include: “40% reduction in hospital-acquired

conditions, 20% reduction in readmissions, and a 25% re-

duction in serious safety events.” (48) The hospital-acquired

conditions that form the current focus of CHSPS are: CLABSI,

catheter-associated urinary tract infections, ventilator-

associated pneumonias, ADEs, injuries from falls, pressure

ulcers, surgical site infections, preventable readmissions,

venous thromboembolism, and obstetric adverse events.

The shared belief in the principle “All Teach, All Learn”

allows hospital teams to share lessons learned with one

another to promote safety and improved outcomes for all.

IMPLEMENTING SAFETY SYSTEMS IN HEALTH-CAREORGANIZATIONS TO ENSURE SAFE PRACTICES AT THEDELIVERY LEVEL

Health-care organizations strive to create a safe system and

environment for all patients and employees. Despite great

efforts and devotion by members of health-care teams, tools

to ensure safety of care must be developed and imple-

mented. The military and aviation industries perform

incredibly difficult processes under stress yet have imple-

mented processes and protocols to ensure the safety of their

employees and others. (22) Some of the tools that have been

adapted for use in health-care include: checklists, Team-

STEPPS, and CPOE. Fostering a culture of safety within an

organization is an integral component of preventing med-

ical errors and reducing patient harm.

ChecklistsAchecklist contains a listing of tasks thatmust be completed

to ensure accuracy and safety. Checklists have been used in

aviation since the 1960s. The aviation industry realized that

checklists play a vital role in ensuring safety by providing

a list of tasks that must be completed before engine starts,

takeoff, and landing as well as tasks for in-flight procedures

and emergencies. The checklist ensures that the same

TABLE 2. 2015 National Patient Safety Goals forHospitals

Goal 1: Improve the accuracy of patient identification

Goal 2: Improve the effectiveness of communication amongcaregivers

Goal 3: Improve the safety of using medications

Goal 6: Reduce the harm associated with clinical alarm systems

Goal 7: Reduce the risk of health care associated infections

Goal 15: The hospital identifies safety risks inherent in its population

UP 01: Universal Protocol for Preventing Wrong Site, WrongProcedure, and Wrong Person Surgery

Adapted from The Joint Commission. Hospital: 2015 National PatientSafety Goals. http://www.jointcommission.org/hap_2015_npsgs.Accessed Aug. 6, 2015.

TABLE 3. 2015 National Patient Safety Goals forAmbulatory Care

Goal 1: Improve the accuracy of patient identification

Goal 3: Improve the safety of using medications

Goal 7: Reduce the risk of health care associated infections

UP 01 Universal Protocol for Preventing Wrong Site, WrongProcedure, and Wrong Person Surgery

Adapted from The Joint Commission. Hospital: 2015 National PatientSafety Goals. http://www.jointcommission.org/ahc_2015_npsgs/.Accessed Aug. 6, 2015.


http://www.jointcommission.org/hap_2015_npsgs

http://www.jointcommission.org/ahc_2015_npsgs/

process is followed consistently each time without reliance

on human memory, allows for mutual checking, and en-

hances communication among crew members. (49)

The role and importance of checklists in ensuring safety

has been recognized by the health-care industry. In 2007,

The World Health Organization launched the Safe Surgery

Saves Lives Campaign in response to an estimated 7 million

surgical complications per year worldwide. The initial study

included hospital representation from Toronto, Canada;

NewDelhi, India; Amman, Jordan; Auckland, New Zealand;

Manila, The Philippines; Ifakara, Tanzania; London, United

Kingdom; and Seattle, Washington. A surgical checklist was

developed for completion at transition points throughout

the surgical procedure, including before administration of

anesthesia, before skin incision, and at completion of pro-

cedure. Through consistent use of the surgical checklist, the

rate of major complications and mortality decreased by

more than one-third in each of the eight centers. (50)(51)

TeamSTEPPSComplete, timely, and effective communication is critical to

ensuring patient safety. Unfortunately, communication is

frequently the root cause of sentinel events. (52) The US

Department of Defense and AHRQ have worked collabora-

tively to develop TeamSTEPPS, a system to enhance com-

munication and teamwork. (53) Some critical times of

information exchange include handoff, change in clinical

status, and whenever a team member has a safety concern.

TeamSTEPPS provides health-care teams with tools and

common language to foster timely and effective communi-

cation as well as a culture of mutual respect and support. An

example of a tool to organize presentation of information

that requires immediate response is SBAR: Situation, Back-

ground, Assessment, and Recommendation/Response.

Computerized Provider Order EntryMedication prescription and administration pose a signifi-

cant risk to the pediatric population. Pediatric patients are at

increased risk for harm due to factors such as weight-based

dosing, use of off-labelmedications, large dosing range based

on indication for medications, and limited ability of the

patient to communicate. Most medication errors occur at

the time of prescription. (14)(15) CPOE systems used in

conjunction with clinical decisions improve medication

safety by eliminating illegibility of orders and transcription

errors, providing support formedication selection and adher-

ence to guidelines, and delivering alerts for dosing outside of

the accepted range. A meta-analysis conducted to review the

effect of CPOE on prescription errors, ADEs, and mortality

showed that prescription errors were significantly decreased

after the introduction of CPOE, but ADEs andmortality were

not. (54) Longhurst et al (55) published results from a quater-

nary care children’s hospital documenting that the monthly

adjusted mortality rate decreased by 20% with the introduc-

tion of a commercially available CPOE. With continued

evolution of commercially available pediatric-specific CPOE

systems and clinical decision support, the contribution of

these systems to medication safety should expand.

Culture of SafetyCHSPS maintains that the development of a culture of

safety is essential to reducing patient harm. A culture of

safety incorporates principles learned from HROs, such as

sensitivity to operations, preoccupation with failure, and

reluctance to simplify. By following these principles, the

organizational expectation becomes that all employees have

a personal responsibility to maintain the safety of all pa-

tients. (56)

MEDICAL ERROR DISCLOSURE

Despitemany efforts,medical errors continue to occurwithin

pediatric practices. Once a medical error has been detected,

the medical team must face the difficult task of disclosure to

the patient and family. Patients desire disclosure of errors that

have caused themharm. They request information, including

why it happened, how the error can be corrected, and how the

error can be prevented in the future. In addition, patients

have stated that disclosure of medical errors by physicians

helps build their trust in the clinician. (57) A survey to

examine parental preferences for error disclosure and legal

action was conducted on a sample of parents who presented

to an emergency department with a child. The responses

revealed that 36% of parents were less likely to seek legal

action if a medical error was disclosed by a physician. (58)

Physician perceptions regarding medical error may dif-

fer from that of their patients. Although physicians agree

that medical errors resulting in harm should be disclosed to

their patients, they hesitate to do so because of fear of

litigation. Physicians may find themselves “choosing their

words carefully” in an attempt to discuss the adverse event

without explicitly mentioning that an error has occurred.

The act of apologizing has also been an area of concern due

to the perception that an apology creates a legal liability and

may be damaging to the physician’s reputation. (59)

The IHI provides recommendations for disclosure of

adverse events to ensure that the patient and family remain

at the center of communication. (60) Among the recom-

mendations are: clear communication about the event that

includes how it happened and what will be done to prevent


this occurrence in the future, appointment of a staff mem-

ber as the family support person who is available 24/7,

assurances that any new information obtained from inves-

tigation of the event is shared with the family in a timely

manner, and addressing all patient and family concerns as

soon as possible.

SECOND VICTIMS

The Hippocratic Oath states, “I will prescribe regimens for

the good of my patients according to my ability and my

judgment and never do harm to anyone.” The concept that

a physician will never do harm and, in essence, never

commit a medical error creates professional and societal

pressure. Unfortunately, when a medical error resulting in

patient harm does occur, the emotional and psychological

effects on the clinician can be profound. Anger, fear, guilt,

and self-doubt are common. The designation of “second

victim” recognizesmedical professionals involved inmedical

errors who experience difficulty in copingwith emotions. (61)

Providing appropriate support to second victims is crit-

ically important. Many institutions have readily available

employee assistance programs, but clinicians may be reluc-

tant to seek resources. (59) Additional programs have been

developed specifically to lend support to second victims.

Medically Induced Trauma Support Services is an organi-

zation established by a patient and a physician involved in

a medical error that had caused harm to the patient. The

organization provides A Toolkit for Building a Clinician and

Staff Support Program aswell as support services to clinicians

involved in a medical error. (62)

Colleague support for second victims is also important,

although it can be challenging. Victims often need support

and understanding following an adverse event. Simply

asking how he or she feels and listening can be comforting

and alleviate concerns and feelings of being shunned. In

addition, exchanging personal experiences with errors can

be reassuring. (61)

Another program developed to lend support to clinicians

in deeply stressful situations is Code Lavender. (63) Code

Lavender is a hospital response team that is deployed to care

for patients, parents, and clinicians in times of emotional

stress and fatigue. The team may consist of nurses, chap-

lains, social workers, and other clinicians. The tools they use

may include imagery, Reiki (Japanese technique for stress

reduction and relaxation), meditation, and music therapy.

CONCLUSION

Quality improvement initiatives and implementation of

safety systems have resulted in a decrease in patient harm,

although harmful events continue to occur. (13)(14)(18)(21)

(38)(64) Improved detection and reporting ofmedical errors

allows review of factors that contribute to the error and

implementation of risk reduction strategies. (28)(29) The

development of pediatric networks and collaboratives enable

shared learning and can expedite the rate of change. (24)(27)

(46)(50)(51) In addition, the recognition of cultural trans-

formation as a key component of a successful patient safety

program has further enhanced the work to prevent patient

harm. (21)(25)(26)(28)

References for this article are at http://pedsinreview.aappublications.

org/content/36/9/403.full.

Summary• Case study data continue to demonstrate instances ofunintended harm to pediatric patients. (13)(14)(18)(21)(38)(63)

• On the basis of strong evidence, pediatric networks andimprovement collaborative mechanisms improve quality andsafety of care. (24)(27)(46)(50)(51)

• Increasingly, case studies are demonstrating culture change asa necessary component to improving pediatric patient safety. (21)(25)(26)(28)

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and click on the Data Supplement for this article.




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PIR Quiz




1. As you prepare a lecture on patient safety for third-year medical students, you decide tobegin by defining the terminology used nationally by governmental agencies as well as bythe local hospital administration. Themost accurate description of amedical error is that it:

A. Always injures the patient.B. Does not require investigation if patient harm has not occurred.C. Is a mistake that always reaches and causes harm to the patient.D. Is characterized by the use of a wrong plan to achieve a desired aim.E. Offers little to learn if the error was intercepted and prevented from reaching

a patient.

2. A fourth-year medical student is completing a quality improvement project as part of hisgraduation requirements. He is interested in a career in pediatrics and recently completeda sub-internship on the general pediatric ward. He is interested in educating medicalstudents and residents onmedical errors among pediatric patients. Which of the followinginformation is most correct in support of his research?

A. Although incorrectly interpreting viral as bacterial illness is common, pediatriciansrarely report this diagnostic error.

B. In a multicenter survey conducted by Singh et al, nearly 50% of surveyedpediatricians reported making a diagnostic error at least once a year.

C. In a multicenter study conducted by Singh et al, the most frequent diagnostic errorwas misinterpretation of complete blood cell count indices.

D. The most common diagnoses in pediatric medical malpractice claims areintussusceptions and suspected child abuse.

E. Most pediatric malpractice claims result from missed or incorrect diagnoses.

3. You are conducting rounds on a 4-day-old preterm infant who was born at 26 weeks’gestation. The infant is maintained on mechanical ventilation and nothing by mouth.You are preparing to write the medication order for a second course of indomethacinfor treatment of a patent ductus arteriosus. Which of the following is not a factor thatincreases the difficulty in pediatric medication management?

A. Altered pharmacokinetics in preterm infants.B. Calculations necessary for weight-based dosing.C. Frequent changes in weight that require changes in dosing.D. Limited ability of parents to communicate with physicians.E. Off-label use of medications.

4. A pediatric nephrologist diagnoses nephrotic syndrome in an 11-year-old boy based onclinical symptoms of gross edema, pleural effusions with dyspnea, proteinuria, and fatigue.He admits the boy to the nephrology ward to begin a course of corticosteroid therapy. Theboy has no known drug allergies documented in his medical records. After the initial doseof corticosteroid, he develops an allergic reaction. Which of the following most accuratelydescribes the type of error that occurred?

A. A diagnostic error made by the pediatric nephrologist.B. A nonpreventable medical error.C. A preventable medical error.D. Not a treatment error because it did not result in patient death.E. Not a medical error.

5. During ward rounds last week, one of the general pediatricians wrote orders forvancomycin and cefotaxime to treat orbital cellulitis in a 3-year-old girl. Afteradministration of the antibiotics, clinicians discovered that the child received an overdoseof vancomycin. Voluntary error reporting revealed that the medication had been orderedincorrectly by the physician, and the error was overlooked by pharmacy and nursing.Which of the following is a common reason cited by both physicians and nurses as a barrierto voluntary error reporting?



A. Belief that the event was too trivial to make a formal report.B. Forgetting to file a report.C. Incident form takes excessive amount of time to complete.D. Lack of feedback.E. Not necessary to report near misses.


Priyanka Rao, MD,* Jennifer Stojan, MD*

*University of Michigan Mott Children’s Hospital, Ann Arbor, MI.

PRESENTATION

A 7-month-old previously healthy boy presents with a diffuse rash. Three months

ago he developed an erythematous perioral rash that spread to his trunk and

extremities. The rash persisted despite treatment with numerous corticosteroid

creams, antibiotic courses, and antifungal treatments. The rash is not pruritic or

painful, and he has been afebrile. He has also had hair loss.

The boy has no history of diarrhea, viral respiratory tract infections, acute otitis

media, or other rashes. He is growing and developing appropriately and is up-to-

date on his immunizations. He breastfeeds without difficulty and in the last

month has begun to eat a small amount of soft, age-appropriate foods. His general

skin care consists of three to four baths per week with lukewarm water. He is

moisturizedwith petroleum immediately following his baths.His family has been

trying tar shampoo and uses fragrance-free laundry detergent.

On physical examination, his vital signs are all within age-appropriate ranges,

and he appears well. His weight is 8.5 kg (31st percentile), length is 70 cm (41st

percentile), and head circumference 45 cm (51st percentile). The rash covers 70%

of his body surface and consists of orange-hued, flaking, erythematous plaques

on his bilateral malar surfaces, neck creases, wrists, elbows, palms, bilateral groin

creases, and scrotum (Figs 1 and 2). Small erythematous papules cover his scalp

and upper trunk, but no there are blisters (Fig 3). He has areas of decreased hair

density. Other findings on his physical examination are normal.

Dermatology is consulted and a punch biopsy performed. Laboratory tests are

obtained to evaluate for nutritional deficiencies.

DISCUSSION

Initial laboratory results included: all electrolytes within appropriate range,

vitamin B12 308 pg/mL (227.2 pmol/L) (normal, 211–911 pg/mL [115.7–672.1

pmol/L]), and zinc less than 10 mg/dL (1.5 mmol/L) (normal, 55–150 mg/dL [8.4–

23.0 mmol/L]). A punch biopsy revealed numerous changes consistent with

a general nutritional deficiency, including confluent parakeratosis with serum

crust and neutrophils in the stratum corneum, spongiosis and keratinocytes

with pale cytoplasm and clear vacuoles in the upper epidermis, and perivascular

lymphohistiocytic infiltrate in the upper dermis. Histopathologic changes on

biopsy in combination with laboratory studies provided the basis for a diagnosis of

zinc deficiency dermatitis. The infant was started on 5 mg/kg per day zinc sulfate

supplementation (equivalent to 1 mg/kg per day of elemental zinc) and skin care

1 Intractable Rash in a 7-month-old Boy

EDITORS NOTE

We invite readers to contribute case

presentations and discussions. Please use

the Submit and Track My Manuscript link

on the Pediatrics in Review homepage:

http://pedsinreview.aappublications.org.

AUTHOR DISCLOSURE Drs Rao and Stojanhave disclosed no financial relationshipsrelevant to this article. This commentary doesnot contain a discussion of an unapproved/investigative use of a commercial product/device.


http://mc.manuscriptcentral.com/pir

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with triamcinolone cream 0.1% in water-washable base

(excluding groin, axillae, and intertriginous folds) covered

with a sauna suit to prevent further skin breakdown. He did

well and his rash resolved within 2 months of starting zinc

supplementation.

Differential DiagnosisAlthough zinc deficiency was apparent in this case, several

other diagnoses should be considered in the differential

diagnosis for the type of rash described for this infant. These

include other nutritional deficiencies such as biotin, a blis-

tering disorder such as linear immunoglobulin A disease,

severe eczema, or an infiltrative disorder such as Langer-

hans cell histiocytosis.

The ConditionZinc deficiency may have numerous clinical manifestations.

Patients typically present with cutaneous eruptions surround-

ing mucous membranes, often with an erythematous base

and a peeling superficial layer, as seen in this infant.However,

they may also present with nonspecific dermatitis, alopecia,

delayed wound healing, increased allergic sensitivity, diar-

rhea, slowing of growth, neurosensory changes, and impaired

concentration. The causes of zinc deficiency may be divided

into four categories: inadequate intake, excessive losses,

malabsorption, and increased demand. Inadequate intake

is typically seen in infants ages 7 to 12 months who are

exclusively breastfed and may be a result of low zinc levels

in the breast milk due to zinc deficiency in the mother or

a genetic mutation that results in sequestration of zinc in

the mammary tissue lysosomes. In older children, zinc de-

ficiency may result from inadequate intake in solid foods.

Excessive loss of zinc that can lead to deficiency is seen with

digestive fluid losses (severe diarrhea) or increased urinary

elimination (renal disease, diabetes mellitus, or diuretics).

Malabsorption is seen with acrodermatitis enteropathica,

a rare autosomal recessive disorder with a genetic mutation

that prevents zinc absorption. Increased demand is seen in

lactating and pregnant women as well as preterm infants.

Diagnosis is based on results of history, physical exam-

ination, and laboratory testing. A serum zinc concentration

is the gold standard laboratory test. Of note, serum must be

properly collected in acid-washed plastic tubes to prevent

contamination from glass. However, up to 60% of serum

zinc is bound to albumin and, therefore, serum values

should be corrected based on albumin values. Cutaneous

histopathology is also useful in solidifying a diagnosis.

Findings on skin biopsy include confluent parakeratosis,

focal spongiosis, and epidermal acanthosis. If more chronic

lesions are present, cytoplastic pallor, reticular degenera-

tion, and necrosis of keratinocytes may be appreciated. This

patient’s source of zinc deficiency was determined to be

Figure 1. Orange-hued, flaking erythematous plaques on bilateral malarsurfaces and neck creases.

Figure 2. Erythematous plaques on groin creases and scrotum.

Figures 3. Erythematous papules covering the scalp and upper trunk.


zinc-deficient breast milk; his mother’s serum zinc concen-

tration was less than 10 mg/dL (1.5 mmol/L).

ManagementZinc supplementation is the required treatment regardless

of the cause of the deficiency. Approximately 70% of patients

respond within 6 months to supplementation. For children

with acquired zinc deficiency, the recommended daily dose

of elemental zinc is 0.5 to 1mg/kg to replenish stores, which

takes approximately 6 months. However, the child who has

acrodermatitis enteropathica may need as much as 3 mg/kg

per day of elemental zinc throughout his or her lifetime.

Lessons for the Clinician• Zinc deficiency should be considered in the differential

diagnosis of a rash for breastfed infants, especially when

the rash is resistant to antibiotic or corticosteroid cream

treatments.• A rash that surroundsmucousmembranes (mouth, anus)

should raise suspicion for zinc deficiency.• Treatment for zinc deficiency is supplementa-

tion. If zinc values increase, no further evaluation is

necessary.

Suggested Readings for this article are at http://pedsinreview.

aappublications.org/content/36/9/414.full.




Lina Merjaneh, MD,* Lillian R. Meacham, MD*

*Division of Endocrinology and Diabetes, Department of Pediatrics, Emory University

School of Medicine, Atlanta, GA.

PRESENTATION

A 17-year-old boy presents to the emergency department with a 3-day history of

watery and explosive diarrhea, vomiting, abdominal pain, progressive weakness,

and light-headedness. Other family members had diarrhea a few days before and

all have recovered.

On physical examination, the lethargic and dehydrated teen has a blood

pressure of 85/45 mm Hg, heart rate of 120 beats/min, and respiratory rate

of 24 breaths/min. His height is 163 cm (4th percentile) and weight is 55 kg

(10th percentile). He has dry mucous membranes and sunken eyes with left

exotropia. His abdomen is soft and nontender with hyperactive bowels sounds.

His pubic hair and genitalia are at Sexual Maturity Rating 1. He has cold

extremities, with a capillary refill of 4 seconds. The rest of the physical findings

are normal.

Initial laboratory evaluation shows metabolic acidosis with pH of 7.24,

bicarbonate of 15 mEq/L (15 mmol/L), sodium of 139 mEq/L (139 mmol/L),

potassium of 4.6 mEq/L (4.6 mmol/L), glucose of 83 mg/dL (4.6 mmol/L),

blood urea nitrogen of 31 mg/dL (11.1 mmol/L), and creatinine of 1.4 mg/dL

(123.8 mmol/L). He receives aggressive fluid resuscitation with 4 L normal

saline without significant improvement. He requires dopamine infusion for 2

days in the pediatric intensive care unit to maintain his blood pressure in the

normal range.

After stabilization and on further questioning, he reports having a longstand-

ing history of a lazy left eye. He also reports poor growth since age 12 years.

Ophthalmologic examination reveals left eye exotropia with very low vision, right

hemi-field defect in the left eye, and left optic nerve pallor with increased cupping.

Further laboratory evaluation and imaging reveal the diagnosis.

DISCUSSION

Endocrine evaluation, as outlined in the Table, revealed panhypopituitarism. The

diagnosis of central adrenal insufficiency, the likely cause of the recalcitrant

presenting hypotension, was based on the lowmorning cortisol concentration and

poor response to the low- and high-dose adrenocorticotropin hormone stimula-

tion. The boy also had hypogonadotropic hypogonadism with low gonadotropin

and testosterone values and central hypothyroidism with low thyroid hormone

2 Cardiovascular Shock Following AcuteGastroenteritis in a 17-year-old Boy

AUTHOR DISCLOSURE Drs Merjaneh andMeacham have disclosed no financialrelationships relevant to this article. Thiscommentary does contain a discussion of anunapproved/investigative use ofa commercial product/device.


concentrations despite themild elevation in thyrotropin that

would be expected to be much higher in the case of primary

hypothyroidism. He was also suspected to have growth hor-

mone deficiency based on a low insulinlike growth factor 1,

insulinlike growth factor binding protein 3, and delayed

bone age. Brain magnetic resonance imaging showed

absence of the pituitary infundibulum, decreased volume

of the pituitary gland, ectopic neurohypophysis, and dimin-

ished volume of the left optic nerve, with severe thinning of

the optic chiasm most notable on the left (Figs 1 and 2).

These findings were consistent with the diagnosis of septo-

optic dysplasia (SOD).

Viral gastroenteritis severe enough to result in hypoten-

sion that requires pressor support and admission to the

intensive care unit is unusual for a healthy adolescent. The

viral gastroenteritis did not appear exceptionally virulent

because other affected family members recovered quickly.

This unusual course combined with short stature and

absence of puberty raised suspicion for hypopituitarism.

The presence of optic nerve hypoplasia (ONH) made the

diagnosis of SOD likely.

Physiologic replacement of hydrocortisone (10 mg/m2

per day) was started. Thyroid replacement began with

a slowly advancing dose of thyroid hormone. The boy was

discharged home after clinical improvement in blood

pressure and diarrhea with instructions to triple his hydro-

cortisone dose in case of acute illness. He was provided with

injectable hydrocortisone to administer in case of vomiting

and severe illness and told to proceed to an emergency

department for administration of parenteral corticosteroids

if this occurred. Plans were made for growth hormone

testing and outpatient testosterone replacement.

The ConditionSOD is a rare congenital disorder with incidence of 1 in

10,000 live births and an equal prevalence in males and

females. The diagnosis can be made when two or more

features of the classic triad are present: ONH, pituitary

hormone abnormalities, and midline brain defects, includ-

ing agenesis of the septum pellucidum or corpus callosum.

SOD is caused by mutations in genes involved in early

development and patterning of the forebrain and pituitary

that result in this association of neuroanatomic findings.

SOD is a phenotypically variable disorder with a wide

spectrum of clinical presentations. Visual impairment is

present in 23% of patients. Developmental delay is seen in

57% of patients with bilateral ONH and 32% of those with

unilateral ONH. The primary findings are hypopituitarism

(62%–80%), with growth hormone deficiency being the

most common abnormality, followed by adrenal, thyroid,

TABLE. Hormonal Evaluation of Patient

TESTING PATIENT’S RESULTSEXPECTED NORMAL VALUES FORA 17-YEAR-OLD MALE

Pituitary-Adrenal Axis

Screening tests AM cortisol < 0.8 mg/dL (22.1 nmol/L) 3–19 mg/dL (82.8–524.2 nmol/L)

Stimulation test Low-dose ACTH Peak cortisol 5.3 mg/dL (146.2 nmol/L) > 18 mg/dL (496.6 nmol/L)High-dose ACTH Peak cortisol 7.9 mg/dL (218.0 nmol/L) > 18 mg/dL (496.6 nmol/L)

Pituitary-Gonadal Axis

Screening tests LH 0.35 mIU/mL (0.35 IU/L) 0.57–12.07 mIU/mL (0.57–12.07 IU/L)FSH 0.72 mIU/mL (0.72 IU/L) 0.95–11.95 mIU/mL (0.95–11.95 IU/L)Testosterone < 2 ng/dL (0.07 nmol/L) 117–1,218 ng/dL (4.1–42.3 nmol/L)

Pituitary-Thyroid Axis

Screening tests TSH 6.36 mIU/mL 0.60–3.60 mIU/mLFree T4 0.71 ng/dL (9.14 pmol/L) 0.79–1.34 ng/dL (10.2–17.3 pmol/L)

Growth Hormone*

Screening tests IGF1 < 10 ng/mL (1.3 nmol/L) SMR 1: 52–391 ng/mL 6.8–51.2 nmol/L)IGFBP3 832 ng/mL (109 nmol/L) SMR 1:1,878–6,190 ng/mL (246.0–810.9 nmol/L)Bone age 13 years 17 years – 15.4 months

ACTH¼adrenocorticotropin hormone, FSH¼follicle-stimulating hormone, IGF¼insulinlike growth factor, IGFBP¼insulinlike growth factor binding protein,LH¼luteinizing hormone, SMR¼Sexual Maturity Rating, TSH¼thyrotropin, T4¼thyroxine.*Growth hormone evaluation with stimulation testing is planned in the outpatient setting.


and gonadotropin deficiencies. The clinical features of

endocrinopathies are not always evident in early childhood

because hormone deficiencies can evolve with time. Better

outcomes are associated with earlier diagnoses; untreated

hormonal deficiencies may result in abnormalities of growth

and development. The presence of unrecognized adrenal

insufficiency places the patient at risk of hypoglycemia,

adrenal crises, and subsequent death.

SOD should be suspected in the newborn period in

infants who have hypoglycemia, jaundice, microphallus,

and abnormal eye movements. A newborn screen that is

based on primary thyrotropin measurements might not

detect central hypothyroidism because thyrotropin values

are usually normal or only mildly elevated. SOD should be

suspected during childhood when a child who has visual

abnormalities presents with growth failure. ONH is the

third most common cause of vision impairment in children

younger than 3 years in the United States. Many children

with ONH do not actually have hypopituitarism, but con-

sultation with a pediatric endocrinologist is warranted for

any child with ONH, especially if there is any associated

growth delay.

When SOD is suspected, evaluation for hormone defi-

ciencies can be performed as outlined in the Table and brain

magnetic resonance imaging (MRI) should be performed.

Findings on MRI consistent with SOD include: hypoplasia

of the optic nerves and optic chiasm, agenesis of the septum

pellucidum, and abnormalities of the corpus callosum and the

pituitary gland.MRIfindings vary considerably amongpatients.

ManagementHormone replacement therapy is tailored for the specific

deficiencies. Of note, cortisol must be replaced before

starting any other hormone therapy. Thyroid hormone

replacement in an adrenally insufficient child could pre-

cipitate an adrenal crisis by accelerating cortisol metabolism

and increasing the metabolic rate. Furthermore, growth

hormone replacement might worsen a preexisting thyroid

or adrenal insufficiency by modulating thyroid hormone or

cortisol metabolism. Early diagnosis of SOD can facilitate

early interventions for hormone deficiencies, visual impair-

ment, and developmental delay and may favorably improve

health outcomes in patients by decreasing associated mor-

bidity and mortality.

Lessons for the Clinician• Septo-optic dysplasia is a phenotypically variable disorder

with a wide spectrum of clinical presentations. Hormone

deficiencies might not be present at diagnosis but may

evolve with time.

• Referral to endocrinology is required for any child with

abnormalities of vision and growth failure or delayed

puberty.• In the case of multiple pituitary hormone deficiencies,

cortisol must be replaced before any other hormone.• Patients should receive clear instructions about stress

dosing during times of acute illness.



Figure 2. Brain magnetic resonance imaging coronal T2-weightedimage demonstrates severe volume loss of the left optic nerve (arrow).

Figure 1. Brain magnetic resonance imaging sagittal T1-weightedimage demonstrates absence of pituitary infundibulum (bold arrow)and severe thinning of the adenohypophysis (solid arrow) in addition toectopic neurohypophysis (dashed arrow).


http://pedsinreview.aappublications.org/content/36/9/417.full


Tiffany J. Herd, MD,* Hillary S. Lawrence, MD,† Michelle A. Manalang, MD,‡

Laura S. Plummer, MD,x Lei Shao, MD,* Kimberly A Horii, MD*

*Department of Dermatology, Children’s Mercy Hospital & Clinics, Kansas City, MO.†Department of Dermatology, The University of Oklahoma College of Medicine, Oklahoma City, OK.‡Departments of Dermatology and Hematology/Oncology, Children’s Mercy Hospital & Clinics, Kansas

City, MO.xDepartments of Dermatology and Ophthalmology, Children’s Mercy Hospital & Clinics, Kansas City, MO.

PRESENTATION

A 12-day-old girl presents to the dermatology clinic with ptosis, edema, and purple

discoloration of the right upper eyelid. She was born at 38 weeks’ gestation via an

uncomplicated vaginal delivery. The findings were noted at birth and initially

attributed to birth trauma. However, the lesion had slightly grown since birth and

was still present at 10 days of age, prompting a presumed diagnosis of infantile

hemangioma (IH) of the eyelid by the referring ophthalmologist.

Physical examination shows awell-appearingneonate.Growth parameters include

a weight of 3.4 kg (25th-50th percentile) and length of 51 cm (25th-50th percentile).

Her temperature is 36.6°C (97.9°F), heart rate is 168 beats/min, respiratory rate is 49

breaths/min, blood pressure is 80/46 mm Hg, and oxygen saturation is 100% in

room air. Examination of the eyelid shows a 6.0 � 5.5-cm firm, violaceous growth

involving the entire upper right eyelid with complete ptosis (Fig 1).

The neonate is hospitalized for further evaluation. Ultrasonography reveals

a hypervascular solid and cystic mass concerning for a sarcoma or vascular tumor.

Magnetic resonance imaging of the orbits shows an encapsulated mass confined to

the preseptal soft tissues of the right orbit, with focal areas of hemorrhage and

findings suggestive of high cellularity (Fig 2A). Excisional biopsy reveals the

diagnosis.

DISCUSSION

The histology resembled a malignant, undifferentiated, small round cell tumor

composed of densely cellular sheets of primitive spindle cells with little pleo-

morphism and no tumor necrosis. Although the tumor was largely undifferen-

tiated, immunohistochemistry revealed both epithelial and mesenchymal

markers, including cytokeratin, CAM5.2, and Vimentin. The tumor cells were

negative for Glut-1, synaptophysin, CD99, myogenin, CD31, CD34, CD45, EMA,

and WT-1 (C terminus). Fluorescence in situ hybridization studies were negative

for ETV6/NTRK3 gene rearrangement, seen in infantile fibrosarcoma. Histologic

and cytogenetic studies excluded rhabdomyosarcoma, Ewing sarcoma/primitive

neuroectodermal tumor (PNET), infantile fibrosarcoma, and neuroblastoma.

3 A Vascular-appearing Eyelid Mass ina Neonate

AUTHOR DISCLOSURE Drs Herd, Lawrence,Manalang, Plummer, Shao, and Horii havedisclosed no financial relationships relevant tothis article. This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.


Glut-1, a specific marker of IH, was also lacking, thereby

excluding IH as the diagnosis. The final pathologic diagno-

sis, also reviewed by an outside consultant, was a malignant

undifferentiated soft-tissue tumor.

Differential DiagnosisThe differential diagnosis of soft-tissue masses of the orbit

is broad. Although IHs are the most common periocular

soft-tissue tumors, other soft-tissue sarcomas, including

rhabdomyosarcoma, Ewing sarcoma/PNET, and infantile

fibrosarcoma, should be considered. Further possible diag-

noses include lacrimal gland lesions, neuroblastoma, leuke-

mia,malignant rhabdoid tumor, Langerhans cell histiocytosis,

other vascular tumors, dacryocystoceles, and infection.

Described clinical features may distinguish IHs from

malignant lesions. Among the characteristics believed to be

concerning for malignant lesion are congenital lesions,

rapid growth, ulceration, fixation to deep fascia, firm texture,

size greater than 3 cm, and mass immobility. Because some

of these features may be present in IH, making a definitive

diagnosis based solely on the clinical appearance is not

always possible. In 2006, Frieden et al suggested that a “fully

formed” congenital tumor should exclude IH as a diagnostic

possibility. Furthermore, lesions that grow beyond the ex-

pected period of proliferation for IHs should raise concern

for malignant soft-tissue tumors or other vascular tumors.

Imaging with ultrasonography ormagnetic resonance imag-

ing may be useful. If the diagnosis in an atypical case is

unclear, biopsy may be needed for histologic diagnosis.

Biopsy is often necessary for histologic and immunohisto-

chemical evaluation of soft-tissue tumors to delineate a diag-

nosis. Molecular testing may also have diagnostic value.

The ConditionMalignant undifferentiated tumors are a heterogenous

group of neoplasms with little or no morphologic evidence

Figures 1. A violaceous growth involving theentire upper right eyelid (A) with completeptosis (B).

Figure 2. A. Multiplanar post-contrastT1-weightedmagnetic resonance imaging of theorbits shows an enhancing, heterogenous massanterior to the right globe, with dense cellularityand fluid levels suggestive of hemorrhage orcystic change. B. Clinical appearance at2-½ months of age following excisional biopsyand chemotherapy.


of differentiation that cannot be further classified based on

histologic features. Malignant undifferentiated tumors

exhibit unpredictable clinical behavior. These may be

present at birth or develop over time. Size may remain

stable or tumors may undergo rapid proliferation beyond

the period of growth anticipated for IHs, which may serve

as a diagnostic clue. Atypical clinical characteristics or

growth patterns of a presumed IH may warrant further

investigation.

Similar cases of soft-tissue tumors mimicking IHs have

been reported. In 2006, three cases of congenital vascular-

appearing tumors diagnosed as ulcerated IH and treated

with systemic corticosteroids were described. After reeval-

uation of unusual characteristics, including congenital pres-

ence and ulceration present at birth, tissue was obtained for

pathology, leading to the diagnosis of a congenital infantile

fibrosarcoma in each instance. A recently reported case of

congenital infantile fibrosarcoma of the lip that underwent

rapid proliferation was treated as a presumed IH. Because

of the refractory response to therapy, biopsy was per-

formed, confirming the diagnosis. To our knowledge, no

case has been reported describing a malignant undifferen-

tiated soft-tissue tumor misdiagnosed as IH of the eyelid in

a neonate.

ManagementMalignant undifferentiated tumors often require full exci-

sion and possibly chemotherapy and radiation. Treatment is

multidisciplinary and may include ophthalmology, derma-

tology, oncology, and pathology services to ensure optimal

therapy. The girl in this case underwent evaluation

for metastatic disease, which was negative. Treatment

was initiated with a sarcoma-based chemotherapy protocol

(ifosfamide, etoposide, vincristine, doxorubicin, and cyclo-

phosphamide) and proton therapy. She had an excellent

clinical response to treatment by 2-½months of age (Fig 2B).

Lessons for the Clinician• Cutaneous malignant soft-tissue tumors can clinically

mimic infantile hemangiomas, which poses a diagnostic

dilemma because treatment and prognosis drastically

differ between the two conditions.

• Clinicians should consider diagnostic possibilities other

than infantile hemangioma if the clinical history, behavior,

or appearance of the lesion is not typical; atypical growth

pattern or lack of response to treatment should raise

suspicion for a possible malignant soft-tissue tumor.



CorrectionIn the July 2015 article “Dehydration: Isonatremic, Hyponatremic, and Hypernatremic Recognition and Management”

(Powers KS. Pediatrics in Review. 2015;36(7): 274–285, doi: 10.1542/pir.36-7-274), key phrases were deleted from the

Question 1 answer options, which should begin as follows:

A. In hypernatremic dehydration …

B. In hypernatremic dehydration …

C. In hyponatremic dehydration …

D. In hyponatremic dehydration …

E. In hyponatremic dehydration …

The phrases have been restored in the online quizzes, a correction has been attached to the article online. The journal

regrets the copyediting error.




Monica Liao, MD,* Philip Magcalas, MD,* Patricia Hopkins-Braddock, MD*

*Children’s Hospital at Albany Medical Center, Albany, NY.

PRESENTATION

A 6-year-old Caucasian boy with a past medical history of eczema presents to the

pediatric emergency department with 12 days of worsening bilateral anterolateral

leg pain and edema that has resulted in refusal to ambulate. His mother noted an

atypical rash on the boy’s anterior shins, which has persisted despite application

of hydrocortisone cream. Other symptoms include low energy, low-grade fever,

nausea, poor oral intake, and persistently dry and bleeding lips. Immunizations

are up-to-date, and he has had no sick contacts. The only medication he has

received is ibuprofen for pain. Developmental milestones are appropriate for age,

and the boy has no dietary restrictions. The only finding of note in the family

is rheumatoid arthritis in the paternal great-grandmother. The boy has been

evaluated by his primary care physician, and laboratory results, including com-

plete blood cell count, Lyme studies, antinuclear antibody, and C-reactive protein,

are within normal limits. He has a slightly elevated erythrocyte sedimentation rate

of 33 mm/hr (normal, 0–15 mm/hr). Bilateral lower extremity radiographs are

negative for any fractures or indications of trauma.

Physical examination reveals erythematous, cracked, and bleeding lips with mild

oropharyngeal erythema. Other positive findings include nontender cervical lymph-

adenopathy as well as salmon-colored, erythematous, dry macules on the lateral

thighs and anterior shins. Bilateral lower extremities are diffusely tender to palpation,

with mild nonpitting edema. The child cries when attempting to stand and bear

weight. Initial laboratory results in the emergency department reveal a serum calcium

of 13.9 mg/dL (3.5 mmol/L) (normal 8.6–10.3 mg/dL [2.2–2.6 mmol/L]) and ionized

calcium of 6.6 mg/dL (1.65 mmol/L) (normal 4.6–5.3 mg/dL [1.14–1.33 mmol/L]).

DISCUSSION

Because of concern for a malignant process causing bone pain, urine metanephrines

were assessed and determined to be within normal limits. Imaging and procedures

performed to evaluate formalignancy included chest radiograph, bonemarrow biopsy,

magnetic resonance imaging of the spine, computed tomography scanof thehead, and

a technetium-99mbone scan. The bone scan (Figure) revealed increased uptake in the

bilateral forearms, proximal femurs, tibias, and kidneys, consistent with metabolic

bone disease. In investigating a possible endocrinologic cause for the patient’s

hypercalcemia, parathyroid hormone values were found to be low, while thyrotropin,

free thyroxine, and vitamin D values were within normal limits.

4 How Much Is Too Much? A Case ofHypercalcemia in a 6-year-old Boy

EDITOR’S NOTE

This case was selected for publication from

the 10 finalists in the 2014 Clinical Case

Presentation program for residents held

by the Resident Section of the American

Academy of Pediatrics. Dr Liao, a resident

from Children’s Hospital at Albany

Medical Center, wrote this case report.

Choosing which case to publish involved

considerations of the teaching value and

excellence of writing but also the content

needs of the journal. Another case will

be chosen from the finalists presented at

this year’s AAP National Conference and

Exhibition and published in the September

2016 issue of Pediatrics in Review.

AUTHOR DISCLOSURE Drs Liao, Magcalas,and Hopkins-Braddock have disclosed nofinancial relationships relevant to this article.This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.


Hypercalcemia persisted despite hydration and treatment

with calcitonin, which reduces calcium concentrations by

inhibiting parathyroid hormone activity. The boy subsequently

received pamidronate, a bisphosphonate that reduces bone

resorption and turnover by inhibiting osteoclast activity. He

also underwent diuresis with furosemide. Potassium and

magnesium repletion were provided as necessary. With this

therapy, his symptoms, including cheilosis, bone pain, and

inability to bear weight, improved grossly. During the boy’s

hospital stay, the parents revealed that they had taken him to

a natural health practitioner 6 months ago for eczema, and he

had been taking nutritional supplements since. These supple-

ments were not formulated for children, and many contained

vitaminA,with one containing 39,000 IUof vitaminAper pill.

With therapy, calcium values decreased gradually. At dis-

charge, his ionized calcium value was 5.2mg/dL (1.3mmol/L).

The boy was sent home with magnesium oxide and a low-

dairy diet. His electrolytes and calcium concentrations were

evaluated regularly. He resumed a regular diet 2months after

his electrolyte values normalized, but he continued to have

persistent hypotonia and required outpatient physical therapy

for months before he fully regained his strength.

Differential DiagnosisThe differential diagnosis for a child with bone pain, refusal

to bear weight, peripheral edema, and rash is both broad and

challenging. Potential diagnoses include accidental and non-

accidental trauma, osteomyelitis, myositis, septic arthritis,

postinfectious myalgias, and chronic kidney disease. Given

the involvement of this patient’s bilateral lower extremities,

rheumatologic conditions such as juvenile dermatomyositis

and juvenile polymyositis were also considered. The concur-

rent hypercalcemia also raised concern for possible malig-

nancy or derangements of parathyroid hormone activity.

The ConditionVitamin A is an essential fat-soluble micronutrient that has

significant effects on vision, cell proliferation, immunity,

growth, and reproduction. It is used in the treatment of skin

conditions such as acne and keratosis follicularis. Acute

vitamin A toxicity usually affects the central nervous system

and skin, with signs and symptoms of headaches, vomiting,

dry skin, and lip fissuring. Chronic toxicity may progress

to include ataxia, liver injury, and, particularly in children,

bone demineralization. The mechanisms behind the effects

of vitamin Atoxicity are not well-understood butmay involve

angiogenic factors, bone resorption, and competition with

vitamin D, leading to hypercalcemia. In addition to being

fat-soluble, vitamin A is subject to varying rates of excretion

and resorption. Therefore, serum concentrations do not

necessarily correlate with those in the tissues.

The recommended daily allowance of vitamin A is between

1,000 and 5,000 IU. However, acute toxicity can occur in

children with intakes as low as 1,500 IU/kg per day. This boy

was found to be taking more than 39,000 IU per day, which

is 1,860 IU/kg per day for more than 6 months.

Treatment and PrognosisIf toxicity is suspected, supplementation should be stopped

and vitamin A intake from the diet restricted. Much of the

Figure. Technetium-99m bone scan shows increased uptake in both forearms, proximal femurs, tibias, and kidneys.


symptomatology is strongly related to hypercalcemia, and this

boy was treated with hydration and calcitonin.When refractory

to these interventions, diuretics and bisphosphonatesmay also

be used. This boy responded well to therapy with both furo-

semide and pamidronate. Otherwise, pain and any other

concurrent electrolyte derangements are the focus of therapy.

Limiting intake of vitamin A and controlling hypercal-

cemia are generally believed to have a favorable outcome,

but the effects of toxicity are not quickly corrected. The

condition is rare enough that long-term effects have not

been extensively described. However, chronic ingestion of

excessive vitamin A can cause permanent damage, includ-

ing liver cirrhosis or failure. Patients should be monitored

for stability on an outpatient basis.

Lessons for the Clinician• The symptoms of hypervitaminosis A are suggestive of

other serious illnesses, such as malignancies, rheuma-

tologic disorders, or infection, necessitating extensive

evaluation and close outpatient follow-up evaluations.• Vitamin A is fat-soluble, and toxicity can occur even in the

absence of elevated blood concentrations.• Dietary and medication history should address all

nutritional supplements.• Patients should be educated on the potential ad-

verse effects of supplements, ideally before initiating

treatment.






Head GrowthMary Elizabeth Wroblewski, MD,* Joyce Bevington, MD, PhD,* Cathi Badik, MD**University of Toledo College of Medicine and Life Sciences, Toledo, OH.

Evaluation of head size and shape is a routine part of the infant and toddler health

supervision visit. Maximal occipitofrontal circumference is the best correlate for

brain growth and is plotted on a Centers for Disease Control and Prevention

growth chart normalized for age and gender up to 36months of age.Microcephaly

and macrocephaly are defined as a head circumference less than two standard

deviations and greater than two standard deviations from the norm, respectively.

For bothmicro- andmacrocephaly, it is important to document parental head size

because the size may represent a trait that can be hereditary. If the child’s head

size is not congruent with familial sizes, a full history (including prenatal, birth,

past medical, and family) in addition to a physical examination focused on

identifying dysmorphic features and a neurologic examination are warranted.

Microcephaly may be due to cessation of brain growth or abnormal brain

development. Considerations include intrauterine infections such as rubella,

cytomegalovirus, or toxoplasmosis as well as possible genetic ormetabolic causes.

Among the causes of macrocephaly are increased intracranial pressure, hydro-

cephalus, intracranial hemorrhage, mass, or genetic causes.

Children who have abnormal head size, whether present at birth or acquired

over time, should be evaluated with neuroimaging. When an infant’s anterior

fontanelle is still open, brain ultrasonography may be sufficient, but if it is closed,

brain computed tomography (CT) scan or magnetic resonance imaging (MRI) is

indicated to detect any abnormalities in the brain parenchyma or ventricles or the

presence of a space-occupying lesion. Infants who have microcephaly at birth

should be tested for rubella, toxoplasmosis, and cytomegalovirus infections and

inborn errors of metabolism, if appropriate. A genetic panel is available to evaluate

the causes ofmicrocephaly because some causesmay have geneticmarkers. More

than 100 syndromes have been associated with increased head size, the most

common of which is Soto syndrome. If a cause of abnormal head size can be

determined, genetic counseling can be offered to the patient’s family.

Head shape also should be evaluated, whether it is associated with a normal or

abnormal head circumference. An abnormally shaped or flattened, asymmetri-

cally shaped head is referred to as plagiocephalic. Flattening or asymmetry can be

due to many causes, the most common of which is positioning that can cause

molding of the skull, often referred to as positional or deformational plagio-

cephaly. Because flattening due to positional plagiocephaly can improve with

time, the prevalence is age-dependent.

Plagiocephaly due to premature closure of one or more suture lines is

termed craniosynostosis. The incidence of craniosynostosis is as high as 1 in

1,700 live births. When viewed from above, closures of the sutures have the

following appearances:• Sagittal suture closure results in an elongated skull

• Metopic suture closure results in a triangular skull

AUTHOR DISCLOSURE Drs Wroblewski,Bevington, and Badik have disclosed nofinancial relationships relevant to this article.This commentary does not containa discussion of an unapproved/investigativeuse of a commercial product/device.

Microcephaly Syndromes. Abuelo D. SeminPediatr Neurol. 2007;14(3):118–127.

Macrocephaly Syndromes. Haskins Olney A.Semin Pediatr Neurol. 2007;14(3):128–135.

Positional Plagiocephaly: An Analysis of theLiterature on the Effectiveness of CurrentGuidelines. Shweikeh F, Nuno M, DaielpourM, Kreiger MD, Drazin D. Neurosurg Focus.2013;35(4):1–9.

Evidence-based Care of the Child withDeformational Plagiocephaly, Part 1:Assessment and Diagnosis. Looman WS,Kack Flannery AB. J Pediatr Health Care.2012;26(4):243–250.

Evidence-based Medicine:Craniosynostosis. Fearon JA. Plast ReconstrSurg. 2014;133(5):1261–1275.


in

Brief

• Coronal suture closure results in a reduced anterior-

posterior skull length on the side with the closed suture

• Lambdoid suture closure results in flattening of the

affected side, reduced posterior skull height, and con-

tralateral parietal bossing

Differentiating craniosynostosis from abnormal head

shape due to external forces is important, especially in light

of the American Academy of Pediatrics (AAP) “Back To

Sleep” campaign, which has led to an increase in positional

molding and flattening of the back of the skull. Factors that

may help to differentiate between the two are the normal

posterior skull height and lack of parietal bossing in posi-

tional plagiocephaly.

Both positional plagiocephaly and craniosynostosis can

be diagnosed clinically based on a history of head position-

ing and skull shape. The current reference standard for

diagnosis of craniosynostosis is head CT scan with three-

dimensional reconstruction of the skull. With concerns

about radiation dosing in pediatric patients, though, some

researchers have shown that physical examination by a spe-

cialist, such as a neurosurgeon or physical therapist, with

specific anthropomorphic skull measurements may be as

accurate as CT scan at diagnosing and classifying different

types of craniosynostoses.

Treatment of positional plagiocephaly depends on the

severity of the deformity and the age of the patient. Surgical

intervention is not recommended because the results are

merely cosmetic and the surgery is fraught with risk. If the

deformity is present after 6 months of age, use of a helmet

orthosis may be considered, but this has been shown to be

no more effective than no intervention in resolving deform-

ities. Physical therapy may also be useful. In response to the

“Back To Sleep” campaign, the AAP recommends daily

“tummy time” as well, not only to improve development

of motor skills, but also to decrease the amount of time that

the occiput experiences molding forces. Unlike positional

plagiocephaly, craniosynostoses usually require surgical

intervention to allow the brain to continue to grow without

restriction.

All infants and toddlers with abnormal head size or shape

need to be monitored over time for changes in other growth

parameters, delays in developmental milestones, and evi-

dence of syndromic features. Children with microcephaly

especially are at increased risk for epilepsy and cerebral

palsy.

COMMENTS: The longitudinal measurement of head

growth is an important component of primary care visits.

Accurate measurement is essential but can be challenging

in young infants who are moving frequently and have a full

head of hair or braided hair that can contribute to falsely

larger readings. Plotting the head circumference on a growth

curve is essential to determine changes that may not be

apparent by physical examination alone. An acute increase

in head circumference requires more urgent evaluation

because acute onset of hydrocephalus or intracranial hem-

orrhage may require more urgent assessment and interven-

tion. When contemplating neuroimaging, it is important to

consider the best test balanced against radiation exposure.

If an infant’s anterior fontanelle is still open, head ultraso-

nography may be sufficient as a first-line imaging study. If

the fontanelle is too small or closed, brain CT scan or MRI

may be needed. Brain MRI is preferable if it can be obtained

in an appropriate time frame because it is associated with

less radiation exposure than CTscan and offers more details

of parenchymal and anatomic changes.

– Janet Serwint, MDAssociate Editor, In Brief

ANSWER KEY FOR SEPTEMBER 2015 PEDIATRICS IN REVIEW:Pediatric Fever of Unknown Origin: 1. B; 2. B; 3. D; 4. C; 5. C.

Constipation and Encopresis in Childhood: 1. B; 2. D; 3. D; 4. C; 5. D.

Patient Safety and Quality Improvement: Terminology: 1. D; 2. E; 3. D; 4. B; 5. D.


Newborn With a Facial VascularBirthmark

Brian M. Faux, MD,*† Abraham W. Suhr, MD,‡ David T. Hsieh, MD*†

*Department of Pediatrics, †Division of Pediatric Neurology, ‡Department of Ophthalmology, San

Antonio Military Medical Center, Ft Sam Houston, TX.

PRESENTATION

After an unremarkable pregnancy, a term baby boy is delivered without compli-

cations. The newborn examination is notable only for a flat facial vascular birthmark

involving nearly the entire distribution of the left trigeminal nerve, with some

patchy involvement of the left upper torso, as well as involvement of the right upper

eyelid (Fig 1). The patient otherwise acts well and has no abnormal movements. No

notable similar dermatologic findings are reported within the family.

The clinician discusses the possibility of ophthalmologic and neurologic

complications with the family. They choose to defer neuroimaging. Ophthalmol-

ogy consultation initially reveals suspicious findings for glaucoma, with mildly

elevated intraocular pressure in both eyes and myopic cycloplegic refraction. The

infant initially is closely observed because both optic nerves appear healthy, but by

age 3 months, therapy for glaucoma is initiated.

At age 5 months, the boy presents in status epilepticus with generalized clonic

convulsions, which are aborted with intravenous lorazepam.

DIAGNOSIS

Upon hospital admission, magnetic resonance imaging (MRI) of the brain reveals

diffuse leptomeningeal enhancement of the left temporal and parietal lobes and

prominence of the left choroid plexus (Fig 2), confirming the clinical diagnosis of

Sturge-Weber syndrome (SWS). After a hospital course of progressive mental

status improvement without recurrence of seizures, the boy is discharged on

phenobarbital and later transitioned to oxcarbazepine.

SWS is a sporadic congenital neurocutaneous syndrome that is characterized

by cutaneous capillary malformations in the distribution of the trigeminal nerve,

particularly in the V1 distribution, with associated findings of glaucoma and

cerebral venous malformations. SWS is caused by an activating somatic mutation

of the GNAQ gene, whose gene product Gaq plays an important role in cell

proliferation, although much research is still needed to better understand the

developmental processes affected by GNAQ mutations. SWS occurs in approx-

imately 1 in 20,000 of the population. Because SWS is due to a somatic mutation,

it is not inherited.

Clinical Features and DiagnosisThe skin findings of SWS derive from aberrant ectatic dermal blood vessels

resulting in capillary malformations (port-wine stains). Most patients born with

AUTHOR DISCLOSURE Drs Faux, Suhr, andHsieh have disclosed no financialrelationships relevant to this article. Thiscommentary does not contain a discussion ofan unapproved/investigative use ofa commercial product/device.

e30 Pediatrics in Review

facial port-wine stains, however, do not have SWS. Of all

patients born with facial port-wine stains, approximately 8%

to 15% have SWS. Affected patients have skin findings

involving the distribution of the first trigeminal nerve

branch, at minimum, but often have extension into the

second or third branches.More recent literature emphasizes

that port-wine stain involvement of the embryologic vascu-

lar distribution of the forehead, rather than the trigemi-

nal neural innervation, confers the highest risk of SWS,

although this proposal is still being investigated. In most

case series, bilaterality of facial port-wine stain lesions is

associated with a higher risk of neurologic involvement.

Rarely, patients who have SWS do not have skin lesions. The

birthmarks typically appear as pale-pink macular lesions at

birth andmay evolve into a darker red-purple over time, with

both head and neck and sometimes truncal involvement

possible.

Eye findings of SWS also derive from ectatic capillary

venous vascular malformations, resulting in glaucoma due

to impaired episcleral venous outflow aswell as a component

of primary trabecular meshwork maldevelopment. These

malformations cause increased intraocular pressure, which

contributes to glaucomatous optic neuropathy. A rapid rise

in intraocular pressure in children younger than age 2 years

can cause an abnormally large eye, termed buphthalmos,

clinically manifesting as enlarged corneal diameters, tears

in the posterior layer of the cornea, and axial myopia. The

eye ipsilateral to the port-wine stain is most commonly

affected, but bilateral glaucoma can also occur. Glaucoma

occurs in approximately 30% to 70% of those affected by

SWS, with up to 40% of patients developing glaucoma later

in childhood or adolescence.

Leptomeningeal venous angiomatosis, a cerebral venous

malformation, is one aspect of brain involvement that

typically, but not exclusively, occurs ipsilateral to the port-

wine stain. Most commonly, the parietal-occipital lobe is

involved, but frontal and temporal lobe involvement is also

possible. The sluggish flow through these redundant vessels

can result in a spectrum of disease ranging from seizures,

stroke, and headache to cognitive and behavioral problems.

Epilepsy presents in more than 85% of all patients who

have SWS, with most becoming symptomatic within the

Figure 1. A port-wine birthmark involved nearly the entire (V1, V2, V3)distribution of the left trigeminal nerve, the upper eyelid, and partly theV1 distribution of the right trigeminal nerve.

Figure 2. T1-weighted axial brain magneticresonance imaging with gadolinium contrastreveals diffuse left temporal and parietalleptomeningeal enhancement (white arrow)and prominence of the left choroid plexus(black arrow).

Vol. 36 No. 9 SEPTEMBER 2015 e31

first 2 years after birth. Earlier onset of epilepsy is associated

with a worse cognitive prognosis. The seizures tend to be

focal motor in origin but may also secondarily generalize

from a focal nidus. In many patients, the seizures tend to

cluster, with long seizure-free periods, particularly cluster-

ing around times of intercurrent illness. In addition to

seizures, headaches with migrainous features occur in about

one third of patients.

Strokelike episodes with hemianesthesia, hemiparesis,

and hemianopsia also occur in patients with SWS. These

episodes tend to cluster around times of minor head trauma

but may also be brought on by prolonged seizures, with

a hypothesized inability of the abnormal vasculature to

autoregulate to the increased metabolic demand at these

times.

Intellectual disability ranging from borderline to severe

is seen in more than 50% of patients with SWS. Behavioral

issues such as attention-deficit/hyperactivity disorder are

also common.

Finally, endocrinologic disorders such as central hypo-

thyroidism (2.4% of patients) and growth hormone defi-

ciency (0.54%) are possible.

The diagnosis of SWS is clinical, requiring two of three

criteria: facial port-wine birthmark, increased intraocular

pressure, and leptomeningeal angiomatosis. Routine oph-

thalmology assessments are needed to identify ocular man-

ifestations. MRI is the most sensitive neuroimaging

modality. MRI can be used before symptom onset but is

sometimes delayed until after age 1 year due to possible

false-negative findings in infancy, the need for sedation and

its intrinsic risks, and the large number of patients with

visible facial birthmarks who do not have SWS. If MRI is

undertaken, intravenous contrast is required to highlight

the abnormal vasculature. In addition, susceptibility-weighted

imaging sequences are recommended to supplement the

sensitivity of neuroimaging. Additional findings can include

dilated deep-draining venous vessels, cortical and subcortical

calcifications, white matter abnormalities consistent with

gliosis, and hemiatrophy of the brain.

TreatmentThe port-wine stain in patients with SWS is primarily a cos-

metic issue, but the possible significant psychosocial effects

are a tangible concern. Thus, treatment with a tunable dye

laser should be offered to patients. Repeated treatments over

several months are often required.

All children who have SWS need initial and regular sur-

veillance examinations by an ophthalmologist for evidence of

glaucoma, refractive error, or amblyopia. Symptoms such as

ocular pain or visual disturbance should prompt urgent

referral to an ophthalmologist. When glaucoma is diag-

nosed, management can consist initially of medical treat-

ment with topical eyedrops to reduce intraocular pressures.

Many patients may also require surgical techniques to lower

intraocular pressure. Patients also should be seen by a pedi-

atric ophthalmologist for amblyopia monitoring, preven-

tion, and or treatment.

Themanagement of epilepsy in children with SWS starts

with behavioral adjustments, including good sleep hygiene,

fever control during illnesses, and avoidance of known

triggers. For example, pressure equalizer tubes for those

who have SWS and recurrent otitis media has been reported

to improve seizure control. However, seizure management

most often consists of standard anticonvulsant medications.

The choice of anticonvulsant medication often depends, in

part, upon the patient’s seizure type, comorbidities, and

family preferences in consultation with the treating neurol-

ogist. Although there is a theoretical concern of glaucoma

with the use of topiramate, this adverse effect is rarely

reported in SWS. In addition, the possibility of an associ-

ation between oxcarbazepine and hypothyroidism in SWS

has been raised, but this relationship remains uncertain.

Because the benefits of starting anticonvulsant medications

prophylactically, ie, before the onset of epilepsy, in SWShave

not been proven, most patients do not begin such treatment

unless epilepsy has been diagnosed.

Seizure control is especially important in patients with

SWS due to functional radiographic evidence of ictal hypo-

perfusion to affected cortical regions during seizures, which

has been hypothesized to contribute to cortical injury and

atrophy. Thus, a clear seizure action plan is imperative that

includes home-based abortive medications such as rectal

valium to minimize the occurrence and duration of status

epilepticus in patients who are susceptible to prolonged

seizures. For patients whose epilepsy is refractory to anti-

convulsant medications, dietary treatments such as the

ketogenic diet, modified Atkins diet, or low-glycemic index

treatment should be considered. Finally, the possibility of

epilepsy surgery should be explored in medication-

refractory patients and can consist of either focal resections

or hemispherectomy. Although earlier surgery has been sug-

gested to be associated with improved long-term outcome,

further evidence and study is needed.

Retrospective data suggest that daily low-dose aspirin

(3–5 mg/kg) appears to be safe and can prevent and reduce

the number of strokelike episodes in patients with SWS.

In addition, patients with SWS who are taking daily aspirin

therapy can receive the additional benefit of improved

seizure control. The benefit of starting aspirin therapy

before the onset of strokelike symptoms is uncertain. As


with all children receiving chronic aspirin therapy, patients

should be reminded to obtain all vaccinations, especially

influenza, due to the theoretical risk of Reye syndrome.

Chronic migraine headaches can negatively affect quality

of life and should be treated with standard therapy. Such

therapy should include behavior modification (routine sleep

hygiene, good hydration), psychological techniques (relax-

ation therapies), andmedications as needed. Medical therapy

for headaches can include standard pediatric daily prophy-

lactic medications and the judicious use of abortive medi-

cations. The use of triptans to abort migraines is associated

with a theoretical vascular risk in SWS, although in the

published literature, some patients with SWS have reported

triptan use without self-reported adverse events.

Educational and social supports are as important to address

as medical treatments. Neuropsychological and educational

testing can identify areas of need for educational support.

Furthermore, families should be encouraged to join national

organizations such as the Sturge-Weber Foundation (www.

sturge-weber.org).

More recently, patients with SWS have been found to

have a higher risk than the general population for endocrine

abnormalities. Thus, those who have signs and symptoms of

hypothyroidism or growth hormone deficiency should be

referred to an endocrinologist for consideration of therapy

with thyroxine or growth hormone replacement. Finally,

with the recent discovery of the somatic mutation GNAQ as

a known cause of SWS, there is hope that future therapies

based on the gene’s downstream protein products may pos-

sibly help prevent and treat SWS.

Patient CourseThe boy is now 4 years old (Fig 3). He has received multiple

pulse-laser treatments of his facial port-wine stain that have

been successful in fading the lesion.Hehasdevelopedbilateral

glaucoma that is treated with topical drops and surgically

implanted drains. Due to intermittent seizure clustering, he

has undergone slow titration of his oxcarbazepine doses until

the seizures stabilized clinically. After a prolonged episode of

right hemiparesis in the setting of a seizure cluster, daily

aspirin therapy was recently initiated. Although not clinically

symptomatic for hypothyroidism, the boy has had his serum

thyrotropin and free thyroxine routinely screened,with normal

results thus far. Possible migraine headaches have been

suspected due to occasional episodes of holding his head,

but these episodes do not occur often enough to initiate daily

medication prophylaxis at this time. Hyperactive and defiant

behaviors have been managed with both behavioral therapy

and medications.

Note: The view(s) expressed herein are those of the author(s)

and do not reflect the official policy or position of Brooke Army

Medical Center, the U.S. Army Medical Department, the U.S.

Army Office of the Surgeon General, the Department of the

Army, the Department of the Air Force and Department of

Defense or the U.S. Government.

Figure 3. The child at age 4 years.

Summary• Sturge-Weber syndrome is characterized by facial port-winestains that involve either the V1 trigeminal distribution or theforehead embryologic vascular distribution, glaucoma, andcerebral vascular malformations.

• Neurologic complications can include epilepsy, migraineheadaches, strokelike episodes, and learning and behavioraldifficulties.

• Identification and treatment of Sturge-Weber syndromecomplications are directed toward the goal of improved quality oflife.

• The recently described associated somatic activating mutation inGNAQ raises hope for potential novel treatments and a preventivecure.

Vol. 36 No. 9 SEPTEMBER 2015 e33

http://www.sturge-weber.org

http://www.sturge-weber.org

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Irving ND, Lim JH, Cohen B, Ferenc LM, Comi AM. Sturge-Webersyndrome: ear, nose, and throat issues and neurologic status.Pediatr Neurol. 2010;43(4):241–244

Lo W, Marchuk DA, Ball KL, et al; Brain Vascular MalformationConsortium National Sturge-Weber Syndrome Workgroup.Updates and future horizons on the understanding, diagnosis, andtreatment of Sturge-Weber syndrome brain involvement. Dev MedChild Neurol. 2012;54(3):214–223

Miller RS, Ball KL, Comi AM, Germain-Lee EL. Growth hormonedeficiency in Sturge-Weber syndrome. Arch Dis Child. 2006;91(4):340–341

Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome andport-wine stains caused by somatic mutation in GNAQ. N Engl JMed. 2013;368(21):1971–1979

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Waelchli R, Aylett SE, RobinsonK, ChongWK,Martinez AE, Kinsler VA.New vascular classification of port-wine stains: improvingprediction of Sturge-Weber risk. Br J Dermatol. 2014;171(4):861–867


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