PIR February2013 Pancreatitis PDF

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contents
Pediatrics in Review Vol.34 No.2 February 2013

ATTENTION ARTISTS AGES 5 TO 16 YEARS
Articles
55
Energy Drinks: What Teenagers (and Their Doctors)

Should Know
Kwabena L. Blankson, Amy M. Thompson, Dale M. Ahrendt,
Vijayalakshmy Patrick
63
79
Childhood Brain Tumors

John Crawford
Pediatric Pancreatitis
Arvind I. Srinath, Mark E. Lowe
91
Complementary, Holistic, and Integrative

Medicine: Acne
Anju Sawni, Amritpal Singh
Index of Suspicion
95
Case 1: Intermittent Swelling and Arm Pain for

2 Years in an Adolescent Girl
Case 2: Tender Nodule in Left Mastoid Area of
a 7-year-old Girl
Case 1: Rhina Castillo, Josue Flores, Randolf Nunez
Case 2: Alfredo Torralbas
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Article
substance abuse
Energy Drinks: What Teenagers (and Their Doctors)

Should Know
Kwabena L. Blankson, MD,*
Amy M. Thompson, DO,
Dale M. Ahrendt, MD,
x
Vijayalakshmy Patrick, MD
Author Disclosure
Drs Blankson,
Thompson, Ahrendt,
and Patrick have
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.
Educational Gap
Hundreds of different energy drinks are available and are marketed to adolescents, carrying the potential for substance abuse that involves caffeine and alcohol. Clinicians
must be educated to deal with their patients use of these products.
Objectives
After reading this article, readers should be able to:
1. Understand the size and scope of the energy drink market and recognize common
energy drink brands.
2. Know that adolescents are high consumers of energy drinks and use them as
performance enhancers.
3. Know the contents of energy drinks and their adverse effects and safety concerns.
4. Know that energy drinks can be a cause of tachycardia, hypertension, obesity, and
other medical problems in adolescents.
5. Know the dangers of mixing energy drinks with alcohol.
6. Understand the relationship between caffeine tolerance/dependence and alcohol
tolerance/dependence.
7. Understand the importance of screening teenagers for energy drink use in the office
setting and offering appropriate counseling.
Introduction
Energy drinks are caffeinated beverages advertised as boosting the immune system, enhancing performance, and creating a buzz or a high. Some of these drinks contain alcohol,
and sometimes consumers mix them with alcoholic beverages. This article reviews current
information about the content, benets, and risks of the use of these energy drinks by
adolescents.
Adolescents are no strangers to energy drinks, and over the past 2 years, media reports have
heightened the awareness of doctors, parents, and lawmakers. In 2010, nine university students in Washington State were hospitalized and one almost died; their illness was attributed
to a fruit-avored, caffeinated alcoholic drink. A month earlier, on a college campus in New
Jersey, 23 students were hospitalized after becoming intoxicated, again reportedly after drinking the same product. Both campuses have since banned this caffeinated alcoholic beverage.
Shortly thereafter, Washington State Attorney General Rob McKenna reected, It's
time to bring an end to the sale of alcoholic energy drinks. They're marketed to kids by
using fruit avors that mask the taste of alcohol, and they have such high levels of stimulants
that people have no idea how inebriated they really are. The Food and Drug Administration (FDA) has issued a strong warning to at least one manufacturer about safety concerns
when alcohol and caffeine are combined in a product. Banning caffeinated alcoholic drinks
would be an important rst step, but it may do little to curb the practice of mixing energy
drinks and alcohol, a xture of the college (and most likely high school) party scene. The
dangers of alcohol use in adolescence are well described in the medical literature, but the
safety of energy drinks is a subject under much debate and the focus of this review.
*Maj, US Air Force, Adolescent Medicine, Naval Medical Center, Portsmouth, VA.
Maj, US Army, Adolescent Medicine Fellow, San Antonio Uniformed Services Health Education Consortium (SAUSHEC), San Antonio, TX.
Lt Col, US Air Force, Program Director, Adolescent Medicine, Fellowship, SAUSHEC, San Antonio, TX.
x
Psychiatrist, Brooke Army Medical Center Associate Professor, University of Texas Health Science Center, San Antonio, TX.
Pediatrics in Review Vol.34 No.2 February 2013 55
substance abuse energy drinks
Marketing and Advertising

Energy drinks were rst introduced in the late 1980s.
Presently, the energy drink market brings in upward of
$5 billion a year, with >200 new brands introduced into
the United States market in 2006. The market's leading
drink accounted for almost 49% of the revenue.
The US energy drink market has grown to its current
size by being focused predominantly on adolescents. One
leading market research company found that teens increased their energy drink consumption by 16% from
2003 to 2008, with 35% of teenagers regularly consuming energy drinks. In one study of energy drink consumption among college students, 50% consumed at least one
to four drinks per month. (1) Reasons for drinking included inadequate amount of sleep, need for energy,
and wanting to mix with alcohol. Although one drink
was sufcient to meet most needs, those who mixed with
alcohol often consumed three or more energy drinks. Almost one in three reported weekly jolt/crash episodes,
including headaches and palpitations. (1)
Energy drinks are marketed to adolescents, specically
males. Energy drink manufacturers allocate a signicant
amount of marketing resources to sports sponsorships,
which include soccer teams, automobile racing teams,
and extreme sports athletes. In a survey of almost 800 college students, 39% drank energy drinks in the past month
(males more than females), and jock identity was associated positively with frequency of energy drink (and energy drink mixed with alcohol) consumption. (2)(3)
Over the 3-year period spanning 20072009, although
Americans were huge consumers of energy drinks, the energy drink market penetration held at at 15% of all adults
aged 18 and older. Energy drink nonusers cited high prices
(48%), too much caffeine (43%), and a general feeling that
energy drinks just are not good for them (43%) as reasons
why they had not consumed any in the past 3 months.
This attitude is forcing the energy drink manufacturers
to come up with new strategies, such as targeting women,
herb and vitamin enthusiasts, the afuent, and youth. (4)
Energy drinks showing a low, no, or reduced calorie
claim have increased from 6% to 11% between 2004
and 2008. Major soft drink manufacturers have begun injecting their own energy drinks into the market or are
becoming distributors, further blurring the lines between
regular carbonated soda and caffeinated energy drinks.
What Is in an Energy Drink?

Caffeine
Most energy drinks contain the same basic ingredients:
guarana, taurine, ginseng, sugars, and B vitamins (ie,
56 Pediatrics in Review Vol.34 No.2 February 2013
riboavin, pyridoxine). Caffeine rarely is listed as an ofcial

ingredient, although all of the top-selling energy drinks contain caffeine. Many of them do not state the quantities of
caffeineor other ingredients, shieldingthisinformation under
the tag proprietary blend. When caffeine content is stated,
often the amount given is not accurate. The FDA regulates
the amount of caffeine in cola beverages. Energy drinks
and cold coffee beverages do not fall under the same jurisdiction. One of the reasons is that caffeine is a substance generally
recognized as safe by the FDA, even though the FDA does
regulate the sale of over-the-counter caffeine-containing
drugs, one of which contains 100 to 200 mg of caffeine.
A 6.5-oz cup of coffee, depending on how it is brewed,
contains 80 to 120 mg of caffeine. A cup of tea contains
approximately 50 mg of caffeine. And a 12-oz cola beverage by law cannot contain more than 65 mg of caffeine.
Even the carbonated fountain sodas sold at fast-food establishments and gas stations contain less than 49 mg of caffeine per 16-oz serving. (5)
The Table names some top-selling energy drinks,
pointing out the volume in each.
The caffeine in 16 oz of leading energy drink brands
ranges from 154 to 280 mg (the equivalent of two to
three cups of coffee). Some energy drinks contain 500
mg or more in a single can. Some of the drinks contain
other stimulants, such as guarana, or additives that can
enhance the effects of caffeine. Several Internet sites provide specic information about caffeine content.
There is not a recommended daily allowance for caffeine, but the American Dietetic Association posits that
women of reproductive age and children should consume
no more than 300 mg of caffeine per day (two to three
cups of coffee). (5) Caffeine use and withdrawal have
Table.
Some Popular Energy Drinks
Energy Drink Brand
Oz per Can
Caffeine*
(total mg)
Red Bull
Monster Energy Assault
Monster Energy XXL
Rockstar
Amp Energy-Lightning
Full Throttle
Wired X505
Cocainea
16
16
24
16
16
16
24
8.4
154
160
240
160
160
144
505
280
*Does not include amounts of other stimulants such as guarana or

additives that can enhance the effects of caffeine. Note the variability in
how many mg of caffeine are present in 1 oz or 1 can.
Visit http://www.energyend.com/the-caffeine-database for others.
a
Briey banned in 2007, renamed No-name, now available again in
United States except in Texas under original name.
substance abuse
been linked to a variety of health effects, including irritability, anxiety, mental confusion, hand and limb tremor,
osteoporosis, digestive problems, nausea, insomnia and
sleepiness, urinary frequency, headache, palpitations, arrhythmias, and elevated blood pressure. (6)
Associations have been shown between caffeine consumption and premature birth, miscarriage, fetal growth
retardation, and decreased birthweight. Withdrawal symptoms have been reported in school-age children who drank
as little as 120 to 145 mg per day (one to two cups of coffee or three to ve sodas) over a 2-week period. (7)
Cardiovascular effects as a result of heavy caffeine use
can be a signicant source of morbidity in athletes. Hypertension and palpitations in the adolescent athlete often
lead to extensive medical evaluations. The diuretic effect
of high levels of caffeine could lead to dehydration in athletes who do not drink enough uids to compensate.
Although the World Anti-Doping Agency (WADA) removed caffeine from its list of banned substances in 2004,
it is reconsidering its ban on caffeine given a recent adverse
outcome in an Australian football league athlete. Athletes
in the league routinely take as many as six caffeine tablets as
a game-day stimulant, and then take a sleeping pill to
come down. A star player in the league was rushed to
the hospital with complications following ingestion of this
pill cocktail. Although WADA has not ofcially banned it
for Olympic athletes, caffeine is well-recognized as an ergogenic aid or a performance enhancer, (8) and it remains
on WADAs closely monitored drug list.
The National Collegiate Athletic Association considers caffeine illegal if found in quantities in the urine that
approximate ve to eight cups of coffee consumed in 1
hour. Depending on the brand, that is the equivalent
of as few as one to three energy drinks.
Caffeine usage patterns have been studied not only in
adolescent athletes, but also in the general teenage population. One study of high school students revealed that
95% consumed caffeine, most of it coming from sodas.
Their rst consumption of the day was in the evening.
Those who drank more coffee expected dependence
symptoms and energy enhancement from caffeine and
also reported more daytime sleepiness and use of caffeine
to get through the day. (9)
Studies of depressed youth show that they use more
caffeine than nondepressed youth, and caffeine likely
exacerbates daily anxiety. (10) In another study, daily
caffeine use was associated with dependence in some
adolescents. The teens actually met Diagnostic and Statistical Manual IV criteria for dependence because they
experienced tolerance, withdrawal, persistent desire, or
unsuccessful efforts to control use, and reported drinking
energy drinks
caffeine despite physical or psychological problems associated with caffeine use. The caffeine intake in these daily
users was only two to three cups of coffee. (6)
In this same study, adolescents who met criteria for marijuana dependence (or any other drug abuse or dependence)
consumed signicantly more caffeine than those not dependent on marijuana or other drugs. Young adolescents are at
risk; a survey of over 5,000 seventh graders showed that
those possessing high caffeine risk (ie, consuming more than
six cups of coffee in the previous month) were more likely to
use tobacco or alcohol by 1-year follow-up. (6)
With alcohol use, the intensity of response diminishes
with repeated administration, leading to tolerance. Higher
doses of alcohol may be needed to attain the initial effect,
planting the seeds of abuse and dependence. Caffeine may
work in the same fashion, and there is evidence that
combining alcohol and caffeine increases alcohol tolerance in comparison with exposures to either drug
alone, which is sobering evidence, given observations
of adolescents mixing energy drinks with alcohol. (11)
Guarana
Guarana, also known as Brazilian cocoa, is a South American plant that is commonly added to energy drinks. It contains a substance called guaranine, which is caffeine, with 1
g of guarana being equivalent to as much as 40 mg of caffeine. (12) Of note, when an energy drink lists its caffeine
content, it is usually not taking into account the guarana,
which has been reported to exert a more prolonged effect
than an equivalent amount of caffeine. In reality, when
a drink is said to contain caffeine plus guarana, it contains
caffeine plus more caffeine. Guarana has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and advantages of guarana may not be known.
Sugars
Most energy drinks contain sugars in the form of sucrose,
glucose, or high fructose corn syrup, with the sugar content
varying from 21 to 34 g per 8 oz. Some adult studies have
shown that glucose combined with caffeine can synergistically enhance athletic and cognitive performance. (13)(14)
One study showed that one specic drink improved performance in a range of mental and physical measures. (15)
The amount of glucose in energy drinks is similar to
that found in sodas and fruit drinks. Users who consume
two to three energy drinks could be taking in 120 to 180
mg of sugar, which is 4 to 6 times the maximum recommended daily intake, according to US Department of Agriculture dietary guidelines. Adolescents who consume
energy drinks in abundance may be at risk for obesity
and dental health problems as a result of high sugar intake.
Taurine
Taurine is one of the most abundant amino acids in
the human body, and it is one of the most common ingredients in energy drinks. The human body can manufacture
taurine on its own from other amino acids, although infants and sick adults must get it from their diet or supplements. Taurine is present in meat, seafood, and milk, and is
purported to have benecial physiologic effects. Most of
these effects cannot be attributed to taurine alone, because
it was mixed with caffeine and other substances.
The amount of taurine consumed by regular intake
of energy drinks far exceeds the amount in a normal diet
(40400 mg/day), although there is limited evidence of
adverse events from taurine use. (12) Some data from animal models suggest that taurine might minimize some of
the adverse effects of alcohol consumption and could, by
extension, encourage greater alcohol consumption. (16)
Ginseng
Ginseng is a root most commonly found in East Asia. It
has been claimed that ginseng improves athletic performance, stimulates the immune system, and improves
mood. Ginseng has been linked to adverse events such
as insomnia, palpitations, tachycardia, hypertension,
edema, headache, vertigo, mania, and estrogen-like effects, such as breast tenderness and amenorrhea. Many
energy drinks do not contain therapeutic doses of ginseng (100200 mg/day), with a user needing to drink
two to four cans of an energy drink to get even the lowest
therapeutic dose. (17) There is little scientic evidence
that ginseng improves physical performance signicantly.
Other Additives
A host of other additives (eg, B vitamins, glucuronolactone, Yohimbe, carnitine, and bitter orange) purport to
have a bevy of positive effects on consumers. Most of the
claims about these ingredients, such as that they reduce
cancer risk, improve sexual performance, and prevent diabetes, lack sufcient scientic evidence. The quantities
of these ingredients found in energy drinks often are
sub- or supratherapeutic, with doses so low or so high
that no one knows what effect they have on the human
body. Even taking into account some of the known physiologic benets, little is known about the effects of daily
consumption of energy drinks on long-term health.
Alcohol
In a recent survey of ten universities in North Carolina,
one-fourth of college students had consumed energy
drinks mixed with alcohol in the past month. (4) These
students were more likely to be younger, white, male,
engaged in athletics, or members of fraternities or sororities. Those who consumed alcohol mixed with energy
drinks (in comparison with those who consumed alcohol
alone) had a signicantly higher prevalence of alcoholrelated consequences including:
Being taken advantage of sexually

Taking advantage of another sexually
Riding in a car with a driver under the inuence of alcohol
Being hurt or injured
Requiring medical treatment
Another study of college students showed that energy

drink users (in comparison with nonusers) had heavier alcohol consumption patterns and were more likely to have
used other drugs (such as marijuana and prescription
drugs), both concurrently and in the year preceding assessment. (18)
From the bold, colorful cans, to the edgy names, energy drinks are marketed in a language teenagers know
well. Sales messaging for a popular energy drink includes
references to house parties and jungle juice, the latter
being a term for various improvised alcoholic beverages;
both allusions have strong associations with underage
binge drinking.
Some of the most popular energy drinks are manufactured already mixed with alcohol. These alcohol-containing
energy drinks share close resemblance to their non
alcohol-containing counterparts. And, in most cases,
the alcohol-containing spinoff is less expensive. Energy
drink manufacturers may be blurring the lines between
their drinks and alcoholic beverages, and the teenage consumer might experience brand confusion.
How much alcohol is in an alcohol-containing energy
drink? The alcohol by volume (ABV) determination is
one measure of the amount of alcohol in a beverage. The
ABV content of one 23.5-oz can of a popular alcoholcontaining energy drink is 12%. The ABV content of a
domestic 12-oz beer ranges from 4.2% to 5%. The ABV
of a standard wine bottle is approximately 12%.
The strength of an alcoholic beverage is best understood in terms of units of alcohol, when ABV and the volume of the drink are known. One unit of alcohol is the
amount of alcohol that an average healthy adult can metabolize in 1 hour. A unit of alcohol can be calculated
with a simple formula:
ABV=1; 000 amount milliliters
strength of drink in units of alcohol
The number of units of alcohol in different alcoholic
beverages is as follows:
substance abuse
Large glass of wine: 3 units

12-oz can of beer: 1.75 units
Single shot of liquor (whisky, rum, vodka): approximately 1 unit
In the case of one popular alcohol-containing energy
drink, the determination of units of alcohol is as follows:
(12% ABV/1,000) 695 mL (w23.5 oz) = 8.3 units.
Thus, a can of this drink has essentially the same strength
as an entire bottle of wine (9 units); with its estimated
500 mg of caffeine, consuming it is comparable to drinking almost a 6-pack of beer plus ve cups of coffee. Other
23.5-oz caffeinated alcoholic beverages range between
6.5% ABV and 12% ABV. Thus, drinking two to three
of these drinks at a party could amount to drinking
two to three bottles of wine/6 packs of beer, and 10
to 15 cups of coffee.
Mixing these caffeinated alcoholic beverages with additional alcohol, as was done by the nine college students
in Washington State, could be especially dangerous,
given their already high alcohol content. This practice
demonstrates either a poor understanding of the amount
of alcohol in the mixed beverage or a disregard of the
danger altogether.
Adolescents who combine energy drinks with alcohol
perceive less of an effect from alcohol. (19)(20) For example, one study noted that young adults who consumed
energy drinks with alcohol felt fewer symptoms such as
headache, weakness, and impaired muscular coordination. (19) But these participants still were impaired in
terms of motor coordination and visual reaction time.
The study by OBrien reported that 15% of adolescents
mixed energy drinks with alcohol to drink more and
not feel as drunk, and 5% of teens did not want to look
as drunk. (4)
Thus, there is the grave danger that adolescents may
feel unimpaired, when they are just as impaired as a person
with the same blood alcohol level, and subsequently may
drink much more than they intended to and attempt to
drive themselves and others home. One high-potency
drink might provide the rush of ve cups of coffee; but
the sobering reality is that the adolescent is now, as
one school ofcial stated, a wide-awake drunk.
Discussion
Clinician Intervention
What can the medical provider do? First and foremost, as
with any other sensitive issue in the adolescent patient,
the clinician must ask in the rst place whether energy
drinks are being consumed. How the question is asked
is equally important. You dont drink energy drinks,
energy drinks
do you? may not facilitate open discussion with the teenage patient.
The HEEADSSS interview (Home, Education, Eating, Activities, Drugs/Alcohol abuse, Sexual activity,
Safety, Suicide/Depression) provides an easy method
and effective tool for examining the important spheres
of adolescence that affect health and well-being. (21) Under the E, many clinicians address education, eating, and
exercise, with sleep going hand-in-hand with these issues.
During this interview would also be a perfect time to
ask about energy drink use, either to stay up late to study,
to get going in the morning, or to enhance athletic performance. Under the D, providers should ask about drug
use, caffeine intake, and energy drinks, because studies
have shown a connection between heavy caffeine use
and illicit substance use. The interviewer also can ask
about alcohol use, segueing into specic questions on alcohol mixed with energy drinks, based on a positive response. An opportunity for education might present
itself; we suspect many teens will have no idea how much
alcohol and caffeine they are consuming when they ingest
these energy drinks.
The CRAFFT pneumonic has been validated as an appropriate screening tool for substance abuse in adolescents. (22) It is a series of six questions developed to
screen adolescents for high-risk alcohol and other drug
use disorders. Have you ever ridden in a CAR driven
by yourself or someone who had been using alcohol or
drugs? Do you ever use alcohol/drugs to RELAX, feel
better about yourself, or t in? Do you ever use alcohol/drugs while you are ALONE? Do you ever FORGET
things you did while using alcohol/drugs? Do your family or FRIENDS ever tell you that you should cut down
on your drinking/drug use? Have you gotten into
TROUBLE while you were using alcohol/drugs? Adding energy drinks mixed with alcohol to the questioning
could be useful.
College student drinkers who report mixing alcohol
with energy drinks are at increased risk for alcohol-related
consequences. Of great concern, students who report consuming energy drinks mixed with alcohol were more than
twice as likely to ride in a car with an intoxicated driver. (4)
Because teenagers who consume alcohol mixed with energy drinks underestimate their degree of intoxication, it
is critical to educate all teens properly, as both drivers
and passengers. If the person driving a teenager home says
he is sober but has been drinking alcohol mixed with energy drinks, the teen passenger can assume the driver may
be gauging his level of sobriety inaccurately.
Clinicians should not be shy about bringing up this
issue with their teenage patients. As with discussing
sexuality, there is little proof that talking about the issue

will encourage dangerous activity or behavior. Rather,
education should be protective. Teenagers already know
about mixing energy drinks with alcohol; adults (and specically primary care providers) need more education.
Some college students, in the wake of the ban of a popular
alcohol-mixed energy drink, proceeded to stock up, while
others posted web videos about how to manufacture
a homemade version of the same drink, using hard candy,
malt liquor, and energy drink. In addition, there is a popular website describing over 200 alcoholic beverages that
call for energy drinks as an ingredient.
Clinicians can apply the concepts of motivational interviewing in their discussions of energy drink consumption. A discussion of motivational interviewing with video
can be found in Pediatrics in Review (Barnes AJ, Gold
MA. Promoting Healthy Behaviors in Pediatrics: Motivational Interviewing. Pediatr Rev. 2012;33(9):e57e68).
[www.pedsinreview.org/content/33/9/e57.full].
Education
Pediatricians should discuss energy drink consumption
with their adolescent patients. (23) Evidence suggests that
energy drinks may provide some therapeutic benet (increased wakefulness, focus, performance-enhanced exercise). But given the unknown levels of caffeine and
other poorly studied additives, there is signicant risk associated with energy drink consumption that may outweigh the benets in the adolescent consumer.
Energy drinks contain high, unregulated amounts of
caffeine that may lead to signicant morbidity in adolescents (cardiovascular effects, withdrawal symptoms, mixing
with alcohol, association with substance dependence).
Additives such as guarana, ginseng, taurine, carnitine,
and bitter orange are not regulated by the FDA, and
their short- and long-term side effects are incompletely
understood.
Little is known about potential negative interactions
between energy drinks and common medications taken
by adolescents, such as stimulants, antidepressants, and
atypical antipsychotics, and there are case reports of energy drink consumption associated with new-onset seizures and manic episodes. (17) When mixed with alcohol,
energy drinks present serious potential for harm and
abuse. In-ofce counseling on daily exercise, early bedtime, and healthy dieting appropriately addresses some
of the goals that underlie the reasons why adolescents
choose to consume energy drinks.
Primary care clinicians should be aware that abnormal
vital signs (tachycardia, hypertension), insomnia, anxiety, palpitations, and headache are all potential effects
of energy drink consumption. By educating themselves,

adolescents, and parents about the potentially dangerous
consequences of energy drink consumption, pediatricians may prevent unnecessary evaluation of symptoms
due to energy drink effects and halt the needless hospitalization of young adults who mix energy drinks with
alcohol.
Summary
The energy drink industry has successfully marketed
their products to adolescents.
There is great concern over the safety and negative
health effects of energy drinks, given their high
caffeine content and the common practice
on college campuses of mixing energy drinks with
alcohol.
Knowledge about the safety of energy drinks in the
adolescent population is lacking.
Caffeine use is associated with a variety of health
effects, such as palpitations, anxiety, insomnia,
digestive problems, elevated blood pressure,
dehydration, and more. Caffeine is the major ingredient
in most energy drinks, but none of the drinks
state its exact caffeine content and these products
are not FDA-regulated. Top-selling energy drinks
may contain the equivalent of two or three cups of
coffee and more caffeine than FDA-regulated alertness
pills.
Heavy energy drink consumption can cause significant
morbidity in adolescents that often leads to extensive
medical evaluations.
Recent news reports about events on college campuses
remind us that adolescents frequently combine energy
drinks and alcohol, but many young people fail to
appreciate the strength of an alcohol-mixed energy
drink. A can of a caffeinated alcoholic beverage may be
equivalent to drinking a bottle of wine and a few cups of
coffee. Consuming more than one of these drinks (or
mixing them with additional alcohol) can be very
dangerous.
One-quarter of college student drinkers report
mixing energy drinks with alcohol and are at increased
risk for alcohol-related consequences. As clinicians, we
must be aware of this behavior and educate teens
properly.
The HEADSSS interview provides an easy method for
examining the spheres of adolescence that affect
overall health. This interview is a perfect avenue for
asking about energy drinks and alcohol-mixed energy
drinks, assessing risk-taking behaviors, and providing
counseling.
CRAFFT is an excellent screening tool for substance
use and abuse and another avenue for assessing
energy drink abuse (mixing energy drinks with
alcohol).
substance abuse
References
1. Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T,
Barber-Heidal K. A survey of energy drink consumption patterns
among college students. Nutr J. 2007;6(6):35
2. Miller KE. Wired: energy drinks, jock identity, masculine norms,
and risk taking. J Am Coll Health. 2008;56(5):481489
3. Miller KE. Energy drinks, race, and problem behaviors among
college students. J Adolesc Health. 2008;43(5):490497
4. OBrien MC, McCoy TP, Rhodes SD, Wagoner A, Wolfson M.
Caffeinated cocktails: energy drink consumption, high-risk drinking, and alcohol-related consequences among college students.
Acad Emerg Med. 2008;15(5):453460
5. McCusker RR, Goldberger BA, Cone EJ. Caffeine content of
energy drinks, carbonated sodas, and other beverages. J Anal
Toxicol. 2006;30(2):112114
6. Bernstein GA, Carroll ME, Thuras PD, Cosgrove KP, Roth ME.
Caffeine dependence in teenagers. Drug Alcohol Depend. 2002;66(1):
16
7. Bernstein GA, Carroll ME, Dean NW, Crosby RD, Perwien AR,
Benowitz NL. Caffeine withdrawal in normal school-age children.
J Am Acad Child Adolesc Psychiatry. 1998;37(8):858865
8. Ahrendt DM. Ergogenic aids: counseling the athlete. Am Fam
Physician. 2001;63(5):913922
9. Bryant Ludden A, Wolfson AR. Understanding adolescent
caffeine use: connecting use patterns with expectancies, reasons,
and sleep. Health Educ Behav. 2010;37(3):330342
10. Whalen DJ, Silk JS, Semel M, et al. Caffeine consumption,
sleep, and affect in the natural environments of depressed youth and
healthy controls. J Pediatr Psychol. 2008;33(4):358367
11. Fillmore MT. Alcohol tolerance in humans is enhanced by
prior caffeine antagonism of alcohol-induced impairment. Exp Clin
Psychopharmacol. 2003;11(1):917
12. Finnegan D. The health effects of stimulant drinks. Nutr Bull.
2003;28:147155
13. Scholey AB, Kennedy DO. Cognitive and physiological effects
of an energy drink: an evaluation of the whole drink and of
energy drinks
glucose, caffeine and herbal avouring fractions. Psychopharmacology (Berl). 2004;176(3-4):320330

14. Rao A, Hu H, Nobre AC. The effects of combined caffeine and
glucose drinks on attention in the human brain. Nutr Neurosci.
2005;8(3):141153
15. Alford C, Cox H, Wescott R. The effects of red bull energy
drink on human performance and mood. Amino Acids. 2001;21(2):
139150
16. Quertemont E, Lallemand F, Colombo G, De Witte P. Taurine
and ethanol preference: a microdialysis study using Sardinian
alcohol-preferring and non-preferring rats. Eur Neuropsychopharmacol. 2000;10(5):377383
17. Clauson KA, Shields KM, McQueen CE, Persad N. Safety
issues associated with commercially available energy drinks. J Am
Pharm Assoc (2003). 2008;48(3):e55e63, quiz e64e67
18. Arria AM, Caldeira KM, Kasperski SJ, et al. Increased alcohol
consumption, nonmedical prescription drug use, and illicit drug use
are associated with energy drink consumption among college
students. J Addict Med. 2010;4(2):7480
19. Ferreira SE, de Mello MT, Pompia S, de Souza-Formigoni
ML. Effects of energy drink ingestion on alcohol intoxication.
Alcohol Clin Exp Res. 2006;30(4):598605
20. Marczinski CA, Fillmore MT. Clubgoers and their trendy
cocktails: implications of mixing caffeine into alcohol on information processing and subjective reports of intoxication. Exp Clin
Psychopharmacol. 2006;14(4):450458
21. Goldenring J, Rosen D. Getting into adolescent heads: an
essential update. Contemp Pediatr. 2004;21(1):6490
22. Knight JR, Sherritt L, Shrier LA, Harris SK, Chang G.
Validity of the CRAFFT substance abuse screening test among
adolescent clinic patients. Arch Pediatr Adolesc Med. 2002;156
(6):607614
23. Committee on Nutrition and the Council on Sports Medicine
and Fitness. Sports drinks and energy drinks for children and
adolescents: are they appropriate? Pediatrics. 2011;127(6):1182
1189
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1. A 17-year-old boy participates on his high school track team, and he takes honors classes. He performs well
both athletically and academically, but his mother is concerned that he is not sleeping well, that he seems
irritable, and that he complains of headaches on the weekend. He goes to sleep between 1 and 2 AM and wakes
at 6 AM to prepare for school. He drinks soda in the evenings to stay awake to finish homework. This boys
symptoms are most likely related to ingestion of:
A. Alcohol.
B. Caffeine.
C. Carnitine.
D. Sucrose.
E. Taurine.
2. A 15-year-old boy plays soccer and has started drinking energy drinks without alcohol every afternoon before
soccer practice. His mother is concerned that these drinks are not healthy, and she would like your opinion on
these drinks. You are most likely to tell this boys mother that:
A. Energy drinks can contain the same amount of caffeine in 16 oz as 3 cups of coffee.
B. The benefit of the vitamin additives in the energy drink offsets the adverse effects of caffeine.
C. The National Collegiate Athletic Association has banned consumption of any caffeine as a performanceenhancing drug.
D. There is no clear evidence that energy drinks adversely affect health.
E. You have no significant concerns as long as he continues drinking brands that do not contain alcohol.
3. You see a 16-year-old girl who runs on the track team. During a HEEADSSS evaluation, she tells you that she
has started drinking alcohol on the weekends with her teammates. You ask her what form of alcohol she is
drinking, and she states that she prefers drinking alcohol-containing energy drinks. She notes that she does not
get as drunk as her peers who drink beer. You are most likely to respond that the alcohol effects in these drinks is:
A. Diminished by the sugar content.
B. Does not affect motor coordination.
C. Lower than in a can of beer.
D. Masked by caffeine effects.
E. Similar to a glass of wine.
4. You are the physician for your nephews high school football team. One of the team trainers encourages the
team members to drink a nonalcoholic energy drink before each game to enhance their athletic performance.
A.
B.
C.
D.
E.
Caffeine in the drinks adversely affects cognition.

Ingestion of the drinks is associated with hypertension in athletes.
Only benefit to the drinks is improved hydration.
Teams performance will likely be impaired by the energy drinks.
Vitamin content in the drinks is beneficial to the athletes.
5. A 17-year-old patient tells you that he consumes energy drinks on a regular basis because they contain all
kinds of ingredients that are good for your health. Your response to him is:
A. Ginseng will improve athletic performance and has no adverse effects.
B. Research shows that the quantities of several additives in energy drinks is just the right amount needed to
reduce the risk of cancer and diabetes.
C. The addition of taurine is good because adolescents do not get enough in their diet.
D. The main ingredient is caffeine and regulation of caffeine content by the Food and Drug Administration is
done for cola but not for energy drinks.
E. The sugars in energy drinks reduce body fat.
Article
central nervous system
Childhood Brain Tumors

John Crawford, MD, MS*
Author Disclosure
Dr Crawford has
disclosed no financial
Educational Gap
Brain tumors are the most common solid tumor of childhood and the No. 1 cause of death
among all childhood cancers. The pediatrician is pivotal in both the diagnosis and longterm management of brain tumors. A lack of awareness of the clinical signs and symptoms of brain tumors may delay diagnosis and worsen patient outcomes.
relationships relevant
to this article. This
commentary does
an unapproved/
Objectives
After completing this article, readers should be able to:
1. Recognize the presenting signs of brain tumor (eg, headache, deteriorating school
performance, ataxia, emesis).
2. Recognize the signs and symptoms of craniopharyngioma.
device.
Introduction
Each year, more than 4,000 brain and central nervous system (CNS) tumors are reported in
children age 0 to 19 years in the United States, according to the most recent data from the
Central Brain Tumor Registry of the United States. (1) Although the incidence of ve per
100,000 person-years is rare compared with other childhood malignancies, brain tumors are
the most common solid tumor of childhood. Most importantly, brain tumors are the No. 1
cause of death among all childhood cancers, according to surveillance, epidemiology, and
survival data. (2) Childhood brain tumors represent an anatomically and biologically diverse
group of neoplasms that can present with both common and unusual symptoms. A lack of
awareness of the clinical signs and symptoms of brain tumors may lead to a delayed diagnosis
by clinicians.
The pediatrician is pivotal in both the diagnosis and long-term management of brain tumors. This primary carefocused review will offer a practical overview of childhood brain tumors, including diagnosis, classication, management, and both early and late effects. Potential
late effects of therapy include neurocognitive decits, endocrinopathies, vasculopathies, and development of secondary neoplasms. A greater awareness of the clinical and neurologic warning
signs associated with the presence of a brain tumor may allow earlier diagnosis and possibly
affect outcomes.
Brain Tumor Classification, Epidemiology, and Pathogenesis

The current classication of primary brain tumors is based on histologic criteria presented by
the World Health Organization (WHO). (3) Brain tumors are broadly classied according to
the cell of origin and most commonly are neuroepithelial derived. WHO classication categories of primary brain tumors
include tumors of the neuroepithelium, cranial nerves, meninAbbreviations
ges, and sella, as well as those of hematopoietic and germ cell
origin.
CNS: central nervous system
Among the neuroepithelial tumors, gliomas are the most
CSF: cerebrospinal uid
common brain tumors of childhood, occurring at an incidence
CT:
computed tomography
of 1.16 per 100,000 person-years. (1) Gliomas are astrocyteMRI: magnetic resonance imaging
derived tumors and are graded 1 through 4, according to
NF-1: neurobromatosis type 1
increasing degree of aggressiveness. Juvenile pilocytic astrocyNF-2: neurobromatosis type 2
toma and diffuse brillary astrocytoma represent the majority of
WHO: World Health Organization
low-grade gliomas (WHO grades I and II), whereas anaplastic
*University of California San Diego and Rady Childrens Hospital, San Diego, CA.
brain tumors
astrocytoma and glioblastoma multiforme represent the malignant variants (WHO grades III and IV).
Although there is no histologic distinction between
adult and pediatric gliomas, there are striking differences
in their epidemiology. Glioblastoma multiforme represents
the most common glioma of adulthood (3.19 per 100,000
person-years), whereas juvenile pilocytic astrocytoma is the
most common glioma of childhood (0.8 per 100,000 person-years). (1)
Three commonly encountered neurogenetic syndromes
diagnosed in childhood (neurobromatosis type 1 [NF-1],
neurobromatosis type 2 [NF-2], and tuberous sclerosis)
have a predisposition for low-grade glioma formation
based on their respective genetic mutations. In the case
of NF-1, children may develop low-grade gliomas of the
optic pathway, cerebrum, cerebellum, and spinal cord.
Children who have NF-2 are also at risk for glioma formation but more commonly develop meningiomas, ependymomas, and acoustic schwannomas. Children who have
tuberous sclerosis may develop subependymal giant cell astrocytomas (WHO grade I) that can obstruct the foramen
of Monro, leading to obstructive hydrocephalus.
Aside from a few genetic syndromes with a predisposition for developing CNS tumors (ie, NF-1, NF-2, tuberous sclerosis, Li-Fraumeni syndrome, Gardner syndrome,
Turcot syndrome, Gorlin syndrome), brain tumor pathogenesis is largely unknown. Brain tumor genesis is most
likely a consequence of inherited, acquired, and epigenetic
phenomena.
In general, patient characteristics such as age and gender
are not associated with a predisposition to a brain tumor,
with a few exceptions. For instance, CNS germ cell tumors
occur more commonly in boys (twofold), and pituitary tumors are more common in girls (threefold). Although environmental and other epigenetic causes are under intense
investigation, there is no proven cause of childhood brain
tumors aside from the known associated genetic syndromes
mentioned earlier.
Tumors of young children (age 04 years) most commonly are of embryonal origin and often are located in
the posterior fossa. The differential diagnosis of posterior
fossa tumors in this age group, listed by decreasing frequency, include medulloblastoma, juvenile pilocytic astrocytoma, ependymoma, and atypical teratoid rhabdoid
tumor. In older children, juvenile pilocytic astrocytoma is
the most common posterior fossa tumor, followed by
medulloblastoma.
Across all ages, medulloblastoma (WHO grade IV) is
the most common malignant brain tumor of childhood
(0.51 per 100,000 person-years) and the most common
primary brain tumor in children age 0 to 4 years.
Medulloblastoma is derived from tumor stem cells of

the external granular layer of the cerebellum and can be
categorized according to distinct histologic variants (classic, nodular desmoplastic, and anaplastic large-cell). Recent studies have divided medulloblastoma into distinct
molecular subgroups that can potentially be used to predict survival and provide risk-adapted therapies. (4)(5)
A histopathologic and neuroradiographic mimicker of
medulloblastoma, the atypical teratoid rhabdoid tumor is
a highly malignant tumor related to the rhabdoid tumor
of the kidney that most often occurs in children age younger than 2 years. (6) Atypical teratoid rhabdoid tumor is
categorized molecularly by a mutation/deletion of the
hSNF5/INI-1 gene on chromosome 22q11.2 and can occur outside of the CNS in the kidney and soft tissues.
Atypical teratoid rhabdoid tumors can occur in both infratentorial and supratentorial locations. The diagnosis is conrmed by an immunohistochemical lack of INI-1 protein
expression that distinguishes it from the histologically
similar medulloblastoma. The distinction between medulloblastoma and atypical teratoid tumor is critically important
because atypical teratoid rhabdoid tumors can be more aggressive, may have poorer survival rates, and may require
more aggressive therapy than classic medulloblastomas.
Ependymomas are the second most common embryonal tumor of childhood (0.29 per 100,000 person-years)
and are derived from ependymal cells within the CNS.
Ependymoma can be of varying grades (WHO grades I
and III) and locations. They are found more commonly
in the posterior fossa; however, these tumors also can occur in the supratentorial region and in the spinal cord.
With more than 30 histopathologic classications of
primary pediatric brain tumors, establishing a diagnosis
can be challenging even for the most experienced pediatric
neuropathologist. The current WHO classication system
is helpful with regard to establishing a uniform guideline
for brain tumor classication and grading, but it is by
no means complete. Advances in molecular genetics have
improved our ability to classify brain tumors based on biologic markers but likely will not replace our current histopathologic classication for many years. Unfortunately,
not all brain tumors are created equal, making diagnostic and management strategies nonuniform and highly individualized at times.
The morbidity and mortality associated with childhood brain tumors are multifactorial and depend not only
on tumor pathology but also on location and treatment.
Figure 1 lists some of the more common pediatric brain
tumors according to neuroanatomic location. This list is
far from exhaustive and is meant to demonstrate the diversity of tumor types based on location. It is also meant
brain tumors
and symptoms, should alert the clinician

to the likelihood of cerebrospinal uid
(CSF) obstruction secondary to a brain tumor. In 15% of children newly diagnosed
as having a brain tumor, papilledema also
may be present.
The triad of headache, nausea or vomiting, and gait imbalance is the most
common presentation of posterior fossa
tumors and is usually accompanied by
early morning vomiting as the dening
feature. The pathophysiology of early
morning vomiting is related to nocturnal hypoventilation, hypercarbia, vasodilation of cerebral vessels, increased
cerebral blood volume, and increased
CSF production, all during recumbent
sleep. Posterior fossa tumors also may
present with head tilt and torticollis, particularly when there is invasion of the
Figure 1. Common pediatric brain tumor subtypes according to anatomic location.
foramen of Luschka.
One of the most difcult presenting
signs
of
pediatric
brain
tumors to detect clinically is a visual
to provide the primary care physician with a general difeld
decit.
These
defects
can be associated with a variety
ferential diagnosis in children suspected of having a brain
of
suprasellar
and
optic
pathway
tumors, including craniotumor in the context of abnormal results on neurologic
pharyngioma,
optic
glioma,
and
low-grade glioma, to
examination.
name a few. Often, the visual eld decits in children
are subacute or chronic and are not readily noticed by
the child or caregiver, regardless of age, until progression
Signs and Symptoms
to extreme papilledema and subsequent optic nerve pallor
The presenting signs and symptoms of pediatric brain tuor infarction develops.
mors can be incredibly diverse and elusive to the patient,
parent, and clinician alike. In general, symptoms arise from
Similar to visual eld decits, signs and symptoms rethe neuroanatomic pathways that are disrupted by the tulated to endocrine dysfunction may be present several
months before a diagnosis of a brain tumor is made.
mor, as illustrated in Fig 2. The most common symptom
The more common signs of endocrine dysfunction associreported by children with a newly diagnosed brain tumor is
ated with brain tumors include precocious or delayed puheadache. Headache occurs in approximately one third of
berty, anorexia, and excessive urination. These symptoms
pediatric patients newly diagnosed as having brain tumors.
localize to a tumor in the region of the hypothalamic(7) Headache in the absence of other symptoms associated
pituitary axis and include pituitary adenomas, germinomas,
with normal neurologic ndings does not have reliable
positive predictive value in the diagnosis of a brain tumor.
and low-grade gliomas.
Therefore, the presence of headache alone should not be
The presence of a new-onset seizure, particularly of focal
onset, may be seen in up to 40% of children diagnosed with
a red ag for this diagnosis.
cortical-based tumors. (7) Although seizures are a common
Nausea and vomiting may occur in approximately one
presenting feature of brain tumors, the vast majority of seithird of children newly diagnosed as having a brain tumor.
zures are due to other systemic or genetic inuences. Over(7) However, children who have systemic illnesses such as
all,
a new childhood brain tumor is associated with less than
gastroenteritis, viral meningitis, and childhood migraine all
4% of all new-onset seizure presentations.
can present with similar symptoms, and these are far more
common illnesses than brain tumors.
Occasionally, patients may present with tics, tremors,
Children will often present with the triad of headache,
movement disorders, or learning disabilities that can be
confused with other postinfectious, demyelinating, or neunausea or vomiting, and gait imbalance that develops over
rodegenerative diseases. CNS germinomas or low-grade
weeks to months. This triad, with progression of signs
brain tumors
Neurologic Examination
A thorough neurologic examination is
of paramount signicance in the assessment of a child suspected of having a
brain tumor. The majority of children
diagnosed as having a brain tumor have
abnormal ndings on neurologic examination at presentation. (7) In a busy
pediatric practice, a focused history
and neurologic examination based on
symptoms can be adequate to raise
suspicion of a brain tumor. The key
components of the neurologic examination include evaluation of mental
status, cranial nerves, motor skills, sensation, reexes, coordination, and gait
(Table 2).
In terms of mental status, an increased degree of encephalopathy will
most likely prompt emergent neuroimFigure 2. Common symptoms of pediatric brain tumors according to anatomic location. aging. However, in patients who have
chronic hydrocephalus secondary to
a
midbrain
tectum
low-grade glioma, a history of slow
gliomas of the basal ganglia, midbrain, or deep white
but
steady
decline
in
school performance may be the only
matter in particular are associated with atypical symptoms.
warning
sign.
Young children who have brain tumors often are the
Examining extraocular movements can be a sensitive
most challenging patients to diagnose. These children
component
of brain tumor detection, particularly in cases
will present with macrocephaly (40%), vomiting (30%),
of
midbrain,
pineal, cerebellar, and brainstem tumors. Parirritability (25%), and lethargy (20%). (7) Macrocephaly
inaud
syndrome,
a constellation of ndings that include
usually is detected on routine health visit screenings
paralysis
of
upgaze,
pupils that are mid-dilated and poorly
and must be distinguished from other familial, traumatic,
reactive
to
direct
light,
convergence or retraction nystagand neurogenetic causes. Two signs that can be overmus,
and
eyelid
retraction,
is commonly seen with dorsal
looked in young children are failure to thrive and early
midbrain
tumors.
Children
who have cerebellar tumors,
handedness. In the case of failure to thrive, children
especially
with
involvement
of
the oculonodular lobe, will
may have a prolonged history of poor weight gain withpresent
with
nystagmus
in
any
direction. Limited upgaze
out an identiable cause, and despite an exhaustive gasor
upgaze
nystagmus
is
always
pathologic and should
trointestinal evaluation, eventually neuroimaging reveals
prompt
further
evaluation.
a midline tumor. In cases of diencephalic syndrome (a
Another syndrome presenting with abnormal eye
constellation of severe emaciation, normal or precocious
movements
worth mentioning in the context of pediatric
intellectual development, and normal linear growth),
neuro-oncology
is opsoclonus myoclonus syndrome.
a hypothalamic/chiasmatic tumor is present on neuroiThis
syndrome
represents
a paraneoplastic phenomenon
maging that is almost always a low-grade glioma (with
characterized
by
involuntary
conjugate eye movements of
or without hydrocephalus). Remarkably, after treatment
large
amplitude
and
myoclonic
jerks; it is usually associwith surgery or chemotherapy, there is marked improveated
with
an
extra-CNS
neuroblastoma.
These children
ment in weight gain that correlates with tumor shrinkage.
can
present
with
a
cerebellar
syndrome
(eg,
fast oscillatEarly or changing handedness can be a sign of upper moing nystagmus, tremor, ataxia, dysmetria, irritability) in
tor neuron injury and may be seen with both corticalthe absence of neuroimaging ndings that may mimic
based and spinal cord tumors. A list of some of the more
common warning signs in the presentation of childhood
a postinfectious syndrome.
brain tumors that may warrant neuroimaging is shown in
As mentioned, visual eld abnormalities are common in
Table 1.
tumors involving the optic pathway (eg, nerves, chiasm,
brain tumors
Signs and Symptoms Associated With

Delayed Diagnosis of Childhood Brain Tumors
cranial neuropathies that would

raise suspicion for a brainstem tumor and prompt immediate
neuroimaging.
Signs and Symptoms
Tumor Location
In terms of motor testing, the
Early morning vomiting, recurrent
Posterior fossa, ventricular system
most important procedure is to asvomiting, enlarging head
sess for possible asymmetries in bulk,
Failure to thrive, anorexia
Suprasellar, hypothalamic
tone, and strength. Children who
Visual complaints, abnormal eye
Optic pathway, suprasellar, brain
have longstanding upper motor neumovements
stem, posterior fossa
ron injury secondary to a low-grade
Tics, tremor, movement disorder
Basal ganglia, thalamus, midbrain
Early handedness
Cortex, subcortical, brain stem, spinal
cortical, subcortical, or brainstem tucord
mor involving the cortical spinal
Facial nerve palsy
Brain stem, cerebellar pontine angle
tracts will have increased tone as well
Hearing loss
Cerebellar pontine angle
as hemiatrophy of the affected limb.
Precocious puberty, nocturnal enuresis
Suprasellar
These physical ndings can provide
Head tilt, torticollis
Cerebellar pontine angle,
cervicomedullary junction
useful clinical insight with regard to
tumor grade and biologic behavior,
because hemiatrophy and hypertonia
represent longstanding upper motor
neuron injury and correlate with low-grade tumor patholtracts, thalamus, radiation, visual cortex) and, if not tested
ogy. In young children, in whom individual muscle groups
for, can be missed. (8) The easiest way to assess visual elds
are difcult to test, one can look for hand preference when
in young patients is to use two colorful objects. While
grasping for objects. In older children, the presence of
maintaining central xation with one object, the second
object should be placed in each of the four quadrants while
a pronator drift when the arms are extended in supination
monitoring for tracking. In older, more cooperative pawith the hands open is a sensitive test for extremity
weakness.
tients, it is necessary that each eye be tested individually
Asymmetries in sensation (cold, light touch, and pinwhile maintaining central xation to test accurately for viprick) can be clues to cortical tumors, spinal cord tumors,
sual elds.
and, in the case of facial sensation, dysfunction of the diA fundoscopic examination is crucial not only in assessvisions of the trigeminal nerve located throughout the
ing for papilledema but also in detecting disc pallor, combrain stem.
monly seen in tumors involving the optic nerve and chiasm
and indicative of optic nerve damage. Both the conEvaluation of reexes can be very helpful, especially if
ventional and panoptic ophthalmoscope may be used to
there are asymmetries. The upper extremity reexes (biceps, triceps, and brachioradialis) generally are more difperform the fundoscopic examination. The panoptic ophcult to obtain in young children; however, asymmetries are
thalmoscope allows for visualization of the entire disc and
pathologic and can be clues to tumor location. In the
generally is regarded as more user-friendly than the conlower extremities, asymmetries in the patellar and Achilles
ventional ophthalmoscope. Regardless of the equipment
reexes are generally associated with a Babinski response,
used, in an uncooperative or young child, a formal dilated
indicative of upper motor neuron dysfunction.
examination performed by an ophthalmologist may be required to obtain accurate results.
Coordination testing is extremely important in children
Patients aficted with brainstem tumors can present
who have suspected cerebellar and brainstem tumors. The
classic nger-to-nose testing must be performed to assess for
with a multitude of cranial neuropathies. Facial nerve
cerebellar dysmetria. It is critical for the child to extend the
palsy is a common presentation of most brainstem tuextremity fully and reach for the examiners nger. Cerebelmors involving the pons. Often confused with having
lar testing can be done in both the arms and the legs. AlterBells palsy, these patients may have other cranial neunatively, the patient may hold out a nger and mirror the
ropathies (eg, esotropia, decreased hearing, drooling,
examiners nger movements in the extended position. This
dysphagia) specically involving abducens, vestibulocochlear, glossopharyngeal, vagus, and hypoglossal
mirror testing is extremely sensitive in assessing cerebellar
nerves in isolation or in various combinations. Any padysfunction, and in the case of patients who have cerebellar
tumors, will result in an overshoot of the movement. A
tient presenting with new-onset facial palsy should have
rather quick and sensitive screening test that can be
a thorough neurologic examination to exclude other
Table 1.
brain tumors
Key Components of the Neurologic Examination in a Child Who

Has a Suspected CNS Tumor
Table 2.
Examination
Pertinent Findings Suggestive of a Tumor
Mental status (level of alertness, speech and language)

Cranial nerve 2 (visual fields, fundoscopic examination)
Cranial nerves 3, 4, 6 (extraocular movements, efferent
pupillary function)
Cranial nerve 7 (facial symmetry)
Encephalopathy, progressive neurocognitive decline

Visual field deficit, papilledema
Nystagmus (upgaze in particular), gaze paralysis in any
direction, mid-position, poorly reactive pupils
Facial weakness (upper versus lower motor neuron
distribution)
Decreased hearing to finger rub (unilateral or bilateral),
vertigo
Drooling, dysphagia
Cranial nerve 8 (hearing, balance)

Cranial nerves 9, 10, 12 (palate elevation, swallowing,
tongue movements)
Motor examination (bulk, tone, proximal and distal strength)
Reflexes (biceps, triceps, brachioradialis, patellar, Achilles)
Cerebellar function (finger to nose testing, mirror testing,
rapid finger and toe tapping)
Gait (heel, toe, tandem straight line)
Sensory examination
performed easily is to have the child rapidly tap his ngers

against his thumbs and his feet on the oor. Asymmetries of
these ne motor movements may be indicative of cerebellar
dysfunction, focal motor weakness, or both.
Gait assessment is an important part of the neurologic
examination and can be accomplished solely by observation. Patients who have cerebellar tumors, particularly those
involving the midline cerebellum, will exhibit a classic widebased ataxic gait, as well as an inability to perform tandem
straight-line walking. Children who have cortical spinal
tract involvement will exhibit a hemiparetic gait, with circumduction of the leg and asymmetries in the swing phase
of the arms. In all cases of gait disturbance, it is important to
consider spinal cord tumors in the differential diagnosis.
Finally, it is always prudent to perform a thorough skin
examination, looking for neurocutaneous stigmata of disease. In particular, the presence of caf au lait macules and
axillary freckling should raise suspicion for neurobromatosis
and trigger fundoscopic examination and assessment for visual decits (NF-1) and hearing decits (NF-2). Patients
who have ash leaf spots, shagreen patches, and facial angiomatosis should undergo head circumference measurement
and a fundoscopic examination. In children who have
known or suspected tuberous sclerosis who present with
headache, vomiting, or irritability, the diagnosis of obstructive hydrocephalus secondary to a subependymal giant cell
astrocytoma should be considered.
Early handedness, delayed motor milestones, pronator drift,

focal changes in tone with associated atrophy
Hyperreflexia with Babinski sign
Dysmetria, overshoot on mirror testing, marked asymmetry
of finger and/or toe tapping (must be differentiated from
weakness)
Wide-based unsteady gait, inability to perform straight-line
test, circumduction of gait
Sensory deficits in a focal anatomic distribution
Neuroimaging Features of Childhood Brain

Tumors
Any child who has an abnormal result on neurologic examination in the setting of the aforementioned symptoms
should have neuroimaging to rule out a brain tumor. The
choice of neuroimaging depends on the urgency of the
symptoms and the degree of neurologic abnormality. Children who manifest altered mental status, behavioral changes,
or cognitive decline associated with headache, nausea, vomiting, and ataxia in the absence of infection should be referred to the emergency department. In these situations,
a noncontrast computed tomography (CT) scan of the head
generally is performed based on availability and urgency.
It is important to note that some tumors, particularly
tumors of the brainstem, cerebellum, and suprasellar region as well as inltrative tumors of the white matter,
can be missed on CT neuroimaging. Figure 3 shows examples of the CT appearances of various pediatric brain tumors with their associated signs and symptoms. CT
neuroimaging is sensitive in detecting both blood and calcication and continues to have a role in the ongoing management of pediatric brain tumors, often because there
may be no sedation requirement because the length of
time for the procedure is short. Both coronal and sagittal
reformatting of CT sequences are available at most centers
and can provide additional anatomic information.
A CT scan with contrast is rarely necessary in the emergency setting of a patient suspected of having a brain tumor unless an infectious cause (eg, cerebral abscess) is in
the differential diagnosis. Despite the utility of a CT scan
in the emergency setting, magnetic resonance imaging
(MRI) is the standard of care for all children who have
a known or suspected brain tumor. MRI is the most sensitive neuroimaging modality for detecting a brain tumor,
with and without intravenous gadolinium contrast. Although not every CNS tumor shows enhancement, the gadolinium is particularly helpful in detecting those patients
who have disseminated leptomeningeal metastatic disease
at presentation. Therefore, all children who have newly
discovered brain tumors on neuroimaging should routinely have an MRI with contrast of the entire spinal axis.
Occasionally, abnormalities will be encountered on an
MRI that could be consistent with other disorders, such
as demyelinating or postinfectious diseases, which may involve the deep white matter, basal ganglia, or thalamus.
Under these circumstances, additional MRI sequences,
brain tumors
such as MRI perfusion and spectroscopy, can be used to

differentiate tumor from mimickers. Although not used
routinely in every case, it is hoped that additional MRI sequences can be used reliably to distinguish a tumor from
radiation necrosis and help to predict responses to radiation, chemotherapy, or biologic therapy.
Although the MRI is an extremely valuable tool in the
practice of neuro-oncology, it has its limitations. For example, in patients who have orthodontic braces, there is
often magnetic susceptibility artifact that can limit the interpretation of suprasellar tumors in particular. In small
children, sedation is required to obtain an adequate study
because motion artifact is common in this age group.
MRIs have been notoriously ineffective at detecting
blood and mineralization; however, this limitation is circumvented with newer sequences, including susceptibility weighted imaging. The most signicant limitation of
MRI is its inability to render a pathologic diagnosis. Although there are specic neuroimaging features of the various pediatric brain tumor subtypes, there is tremendous
Figure 3. Computerized tomography neuroimaging findings and associated symptoms of childhood brain tumors.
brain tumors
overlap, and therefore a specic diagnosis cannot be achieved

based on MRI appearance alone.
With the exception of the CNS germinoma, which can
display elevations of serum and CSF markers (a-fetoprotein
and b-human chorionic gonadotropin), the nal diagnosis of a brain tumor is made by histologic examination
after biopsy or resection.
Examples of MRI neuroimaging features of pediatric
brain tumors with associated symptoms are shown in Fig 4.
Acute Management of the Newly Diagnosed

Patient
The management of the child newly diagnosed as having
a brain tumor usually begins in the emergency department after neuroimaging. In general, the management
of neuro-oncology patients is no different from that of
patients who have other acute neurologic emergencies.
Establishing an airway, sufcient breathing, and effective
circulation remain the most crucial immediate priorities.
In cases of acute obstructive hydrocephalus with herniation syndrome, emergent neurosurgical consultation
for either surgical resection or emergent temporizing
ventricular decompression is required. Preoperative laboratory testing should include a complete blood cell count,
coagulation studies, and blood type and cross-matching.
In the case of suprasellar tumors, it is extremely helpful to
obtain baseline electrolytes and endocrine studies before
surgery, because patients who have large suprasellar tumors often have multiple endocrinopathies of both anterior and posterior pituitary function.
A baseline ophthalmologic evaluation, including visual
eld testing and fundoscopic evaluation, is important in
preoperative evaluations because most patients do not
complain of visual eld decits at presentation. Depending on the degree of vasogenic edema, intravenous corticosteroids with a gastrointestinal-protective agent are
given conventionally before and after surgery. Although
there is little evidence to support the use of corticosteroids with regard to overall outcome, corticosteroids
can relieve headache, nausea, and vomiting and remain
a generally accepted treatment.
If the diagnosis is based on CT imaging alone, a preoperative MRI of the brain and spine (with and without
gadolinium) is necessary for surgical planning and staging. A general schematic of acute management strategies
in patients newly diagnosed with a brain tumor is listed in
Table 3.
Equally important in the management of newly diagnosed patients is providing psychosocial support during
the initial conrmation of the diagnosis. It is beyond
the scope of the primary care physician or emergency department team to discuss tumor histology, treatment
strategies, and outcomes. However, it is important to
keep the patients (when appropriate) and parents informed of the diagnostic process. This task generally is
performed best in a conference room setting, where neuroimages can be reviewed with the family and the neurosurgical/neuro-oncology team may be introduced.
It is common for parents to have extraordinary guilt
when a brain tumor is diagnosed. It must be emphasized
that brain tumors occur in children of all ages, races, and
geographic locations, and there is no single cause for developing a brain tumor, a disorder that cannot be prevented.
Parents and clinicians often are plagued with guilt by
delayed diagnosis due to unusual or vague symptoms.
There has been no study to date that has correlated early
detection of pediatric brain tumors with changes in overall or event-free survival. Children generally present for
medical attention when their neurologic symptoms impede their ability to play.
Social workers, child life specialists, and neuropsychologists provide critical support to families and patients
during diagnosis and throughout the course of care.
Once a pathologic diagnosis is rmly established, a multidisciplinary conference is required to review the diagnosis, treatment plan, and prognosis.
Therapeutic Strategies and Outcomes

Neurosurgery generally is the rst and most important intervention for children newly diagnosed as having a brain
tumor. The ultimate goal of surgery is to obtain a complete resection without postoperative complications.
Sometimes a complete resection is not feasible due to tumor location, in which case a subtotal resection or biopsy
is performed. In children who have posterior fossa tumors
(eg, medulloblastoma, juvenile pilocytic astrocytoma,
ependymoma), a gross total resection correlates with improved event-free and overall survival.
However, the posterior fossa is a potentially dangerous
location and prone to postoperative complications. Posterior fossa mutism syndrome, a constellation of mutism,
hypotonia, and irritability, can occur in the immediate
postoperative period and is presumed to be due to midline cerebellum connection disruption. Posterior fossa
mutism can be partially or completely reversible over
weeks to months and has been reported with varying degrees of severity in up to 10% to 20% of children who undergo posterior fossa surgery.
In children who have cortical-based tumors (eg, lowgrade astrocytoma, ependymoma, oligodendroglioma,
brain tumors
Figure 4. Magnetic resonance imaging findings and associated symptoms of childhood brain tumors. CNS[central nervous system.
mixed glioneuronal tumors), the goal is to achieve gross

total resection. In those patients who have high-grade tumors of any location, maximum tumor resection and adjuvant therapy are required, based on the high rate of
reoccurrence and dissemination. In children who have
deep-seated tumors (ie, thalamic, basal ganglia, pinealtectal tumors), a biopsy often is sufcient to achieve a diagnosis, and tumor debulking is performed in cases in
which there is signicant mass effect.
In the case of CNS germinoma, a diagnosis can be
made on the basis of elevation of serum or CSF tumor
markers (a-fetoprotein and b-human chorionic gonadotropin) alone. A biopsy, although generally favored, is
not always required to establish a diagnosis of
CNS germinoma. A gross total resection in children
who have extensive craniopharyngiomas can be curative; however, gross total resection is often associated with resulting visual eld decits and multiple
endocrinopathies.
Children diagnosed with tectal or pineal tumors often

undergo a biopsy approach, given the potential risk of
surgical morbidity, and frequently also receive a CSF diversional procedure (ventricular peritoneal shunt versus
endoscopic third ventriculostomy) in cases of obstructive
hydrocephalus. The decision to place a shunt in a child
who has a malignant brain tumor with associated hydrocephalus sometimes is based on medical necessity, but the
procedure carries a 5% to 7% risk of extraneural seeding.
Those who have large posterior fossa tumors frequently
require a CSF diversional procedure because prolonged
CSF obstruction is associated with papilledema and potential optic nerve infarction.
Despite the precarious location of the tumor, children
who have brainstem tumors can undergo safe resection to
achieve cure in cases of dorsal exophytic cervicomedullary
tumors. Patients who have diffuse intrinsic pontine glioma, the most malignant of childhood brain tumors,
generally do not undergo biopsy unless enrolled in
brain tumors
the patient, pathologic diagnosis,

degree of residual tumor, presence
Table 3.
or absence of dissemination, and
availability of clinical trials. If the
reader is interested in the manageAirway, breathing, circulation stabilization
ment of a specic tumor type, there
Neurosurgery/neuro-oncology consultation
are numerous textbooks, published
NPO
Presurgical laboratory tests (electrolytes, CBC, coagulation studies, blood type and
clinical trials, and review articles that
cross-matching)
outline the evidence-based manageIntravenous steroids (dexamethasone) with GI-protective agent
ment strategies and controversies of
Magnetic resonance imaging of the brain and spine with and without intravenous
specic pediatric tumor subtypes.
contrast
For tumors of low-grade histoPreoperative endocrine laboratory tests for suprasellar tumors
Ophthalmologic examination
logic type in which gross total resecSeizure prophylaxis for patients presenting with or at high risk for convulsions
tion is achieved, no further treatment
Social work consultation
is necessary. Children who have residual low-grade tumors generally
Lumbar puncture for CSF cytology and tumor markers (for suspected CNS
are observed for progression. If they
germinoma) is generally performed 7 to 10 days postoperatively if there are no
contraindications.
demonstrate growth on surveillance
neuroimaging (every 46 months),
CBCcomplete blood cell count, CNScentral nervous system, CSFcerebrospinal uid,
GIgastrointestinal, NPOnothing by mouth.
they are treated with further surgery,
chemotherapy, or radiation therapy,
depending on age, tumor location,
degree of recurrence, and symptoms. Children who have
a clinical trial, because the diagnosis can be made by the
appearance of a characteristic expansile mass centered in
malignant gliomas require radiation therapy postoperathe pons with minimal or no contrast enhancement on
tively, in combination with the experimental biologic
agents (eg, molecular-based targeted therapy) or oral cheMRI. Occasionally, a biopsy is warranted in these cases,
motherapy agents such as temozolomide. The most promespecially when there are focal, well-dened enhancing
inent role of chemotherapy is in children who have
lesions, to exclude infectious or demyelinating mimickers
embryonal tumors or CNS germinomas and in younger
of brainstem gliomas.
children who have progressive low-grade gliomas.
An additional tumor, optic nerve glioma, can be diagBased on strong research evidence, (1) it has been shown
nosed on the basis of neuroradiographic features alone.
These tumors often are low-grade gliomas associated with
that a combination of chemotherapy involving either a twoNF-1 and are seen easily on dedicated MRI sequences of
drug regimen (carboplatin and vincristine) or a four-drug
regimen (procarbazine, thioguanine, lomustine, and vincristhe optic nerves. Very rarely, meningiomas and metastatic
tine) can improve event-free survival in children diagnosed
disease can present with optic nerve pathology. Children
with progressive low-grade glioma. (9)
diagnosed as having optic nerve gliomas (with or without
In children who have embryonal tumors (medulloblasneurobromatosis) are treated conservatively with observatoma, ependymoma, or atypical teratoid rhabdoid tution but undergo chemotherapy if they demonstrate visual
mors), chemotherapy is often used in conjunction with
dysfunction or tumor progression. In summary, the
outcome for children who have brain tumors is very much
either focal or craniospinal radiation, depending on the
dependent on skilled neurosurgical management to
age, degree of dissemination, and tumor pathology. In
children who have average-risk medulloblastoma (age
achieve a gross total resection whenever feasible, and such
>3 years, <1.5-cm2 residual disease, nondisseminated dismanagement remains the ultimate goal for successful
ease, and nonanaplastic histology), a combination of cratreatment.
niospinal radiation with adjuvant chemotherapy followed
Once neurosurgical intervention and sufcient healing
by maintenance chemotherapy is used. Chemotherapy
of surgical wounds are achieved, additional treatments
can be used either at standard doses or at higher doses
may be required, including chemotherapy, radiation therto achieve greater CNS penetration that would require auapy, or a combination of both. These adjunct therapies
tologous stem cell support secondary to myeloablative
are chosen based on the pathologic diagnosis and amount
chemotherapy. Current trials are underway to investigate
of residual tumor. The nonsurgical management of childthe utility of a reduced dose of craniospinal radiation to
hood brain tumors is complex and depends on the age of
General Management Strategy of Newly

Diagnosed Pediatric Brain Tumors
prevent long-term sequelae of radiation therapy without

compromising survival.
Patients who have high-risk medulloblastomas require
high-dose craniospinal radiation of 3,600 cGy with a posterior fossa boost, whereas patients who have average-risk
medulloblastomas require either 1,800 or 2,340 cGy of
craniospinal radiation with a similar posterior fossa
boost. Current management strategies of children who
have average-risk medulloblastomas have led to improvements of 5-year event-free survival that approach 85% in
multiple international studies. Patients who have highrisk medulloblastomas, unfortunately, have much lower
survival rates (40%65%) and are the focus of intense
investigation.
The results of adjuvant chemotherapy in patients who
have posterior fossa ependymoma are less convincing than
for medulloblastoma. Children can achieve durable responses to postoperative radiation alone. Previous studies
in young children who delayed or avoided radiation demonstrated recurrence of ependymoma in up to two thirds
of children treated with chemotherapy alone. Phase III
clinical trials are being conducted to determine whether
a combination of focal radiation and chemotherapy will
have synergistic effects.
Children younger than 3 years provide additional challenges for the clinician, regardless of the tumor histology.
The long-term effects of craniospinal and possibly even
focal radiation have led to various management strategies
to avoid or delay radiation therapy. In children who have
embryonal tumors, higher doses of chemotherapy to
achieve greater CNS penetrability have been used to delay or avoid radiation in a subset of children who have
embryonal tumors. However, high-dose chemotherapy
regimens are myeloablative, require autologous stem cell
rescue during therapy, and have been associated with
treatment-related morbidity and mortality in a small percentage of patients. One management strategy currently
under investigation is to treat young children who
have posterior fossa embyronal tumors with adjuvant
methotrexate-based chemotherapy followed by involvedeld-only radiation therapy, with the option of using
craniospinal therapy for progressive disease.
Children who have CNS germinomas can be cured by
using a combination of chemotherapy and involved-eld
lower dose radiation that involves the ventricular system, attaining cure rates of greater than 90%. The malignant counterpart of a CNS germinoma, the nongerminomatous germ
cell tumor (embyronal, immature teratoma, choriocarcinoma, and mixed germ cell tumor), requires a combination
of chemotherapy and craniospinal radiation and is associated with approximately 20% lower 5-year overall survival.
brain tumors
Children diagnosed with diffuse intrinsic pontine glioma have the worst survival rate, with greater than 90%
mortality by 2 years despite radiation therapy and use of
investigational agents. A variety of radiosensitizing biologic and chemotherapic agents have been used alone
and in various combinations without improvement in
survival. It is important to realize that not every brainstem tumor carries this dismal prognosis. Children
who have exophytic brainstem tumors can be cured
with surgery or radiation therapy. Children who have
focal brainstem tumors can become long-term survivors
and presumptively have tumors with low-grade
pathologic characteristics. Children who have high-grade
gliomas in general have similar poor survival rates as
the adult patients and are the focus of numerous clinical
trials.
Because cranial and craniospinal radiation is commonly used in both initial treatment regimens and salvage
therapy at relapse, clinicians should be aware of the two
major types of radiation treatments: photon and proton
beam radiation. Both photon and proton beam irradiation use high-energy irradiation to create free radicals
that deliver preferential damage to tumor DNA because
tumor cells do not have competent enzymatic repair
capabilities. Both modalities use frameless stereotactic
navigation to provide three-dimensional conformal intensity-modulated radiation, in which radiation beams
are formed to match the tumor shape. During intensity-modulated radiation therapy, the intensity of radiation is changed during treatment to spare normal
surrounding tissues.
The concern for photon beam radiation is that there
can be damage to normal surrounding tissue due to
the intrinsic properties of the high-energy particle. This
effect is important when targeting sensitive areas such
as the cochlea, temporal lobes, and, in the case of spinal
irradiation, the abdominal cavity.
Because of the physical nature of the proton, the radiation dosage deposited inadvertently in normal tissues
(termed the exit dose) is less and therefore may spare vital
organs. Children who have suprasellar and malignant
posterior fossa tumors theoretically are good candidates
for proton beam therapy from a neurocognitive standpoint. (10) Only a small number of proton beam centers
exist in the United States, however, and therefore not
every child can be treated with proton beam irradiation. Ongoing studies are being performed to determine whether there are any benets of proton beam
therapy with regard to survival or incidence of late
effects, but these studies will not be completed for many
years.
brain tumors
Management of Progressive or Recurrent

Disease
The management of progressive brain tumor disease poses
signicant challenges, and pediatricians should be aware of
the issues that patients and families face. Despite combined
surgery, chemotherapy, and radiation treatments, a significant proportion of children will have progressive or recurrent disease. The risk of disease recurrence is dependent on
the patients age, tumor pathology, extent of resection,
and previous treatment. In children who experience local
relapse, surgery generally is offered, depending on the anatomic site of relapse. If patients have not received radiation therapy to the affected area, radiation generally is
offered. Even when a patient has received previous radiation, radiosurgery techniques (stereotactic, highly focused
radiation) have been used to prolong survival.
Most commonly, as with other malignancies, children
who experience progressive or recurrent disease are offered enrollment in clinical trials. Most clinical trials of
treatments for recurrent childhood brain cancer involve
Phase I studies, designed to test a new drugs safety
and tolerability. The decision to enroll in a clinical trial
is a personal one and involves myriad factors, including
geography, tolerability and mode of delivery of the
agents, and quality of life. All clinical trials in the United
States and many international trials are registered on
www.clinicaltrials.gov. These clinical trials can be researched by patients, families, and clinicians. Each trial
consists of both inclusionary and exclusionary criteria that
must be met before enrollment.
Neuro-oncology therapy is changing constantly, and
new clinical trials are added weekly. In patients for whom
clinical trials are not an option, combinations of biologic
and chemotherapic regimens, with or without radiation,
have been used, with varying degrees of success in delaying the progression of the disease.
Acute and Subacute Effects of Treatment

The primary care physician should understand the acute
and long-term effects of brain tumor treatment. Patients
may have acute treatment-related effects from surgery,
radiation, and chemotherapy, depending on the tumor
type and therapy received. In the case of surgery, patients
can experience headaches after the surgical procedure.
Headaches generally are relieved with anti-inammatory
medications; however, if fever is present, an abscess or infection due to CSF leak must be considered.
Children receiving chemotherapy might experience allergic reactions or acute neurologic complaints, such as
foot drop or cranial neuropathies. Children who have
CNS tumors may experience seizures at any time during

their treatment. Administering nonenzyme-inducing
anticonvulsants (eg, levetiracetam) whenever possible is
a requirement for many clinical trials involving investigational drugs.
Children undergoing cranial radiation may experience
fatigue, nausea, or vomiting during their treatment. On
occasion, stimulant and nonstimulant medications can
be used to treat radiation somnolence. In the case of radiation or chemotherapy-related emesis, antiemetic medications or low-dose corticosteroids can be very helpful in
controlling symptoms.
The neuro-oncology team manages the usual adverse
effects of chemotherapy on the hematopoietic system
(neutropenia, anemia, and thrombocytopenia); however,
it is crucial that the primary care physician be aware of
when the patient is undergoing treatment to recognize
potential complications of therapy. In children who are
receiving craniospinal radiation, complete blood cell
counts are performed weekly because of the risk for anemia associated with marrow disruption due to radiation.
Late Effects of Treatment

Improved patient survival has presented a new era of late
effects of tumor therapies that the primary care provider
must be able to recognize. As with other pediatric malignancies, treatment with chemotherapy poses a potential
risk for future hematogenous malignancies. In children
who have received craniospinal radiation, subsequent
thyroid cancers, skin cancers, meningiomas, and secondary high-grade gliomas all have been reported. (11) Under these circumstances, a compelling argument can be
made for performing yearly MRI examinations in children who have undergone previous cranial radiation
and are long-term survivors.
Children who have received any form of chemotherapy
for the treatment for a brain tumor are at risk for both hematogenous and systemic secondary malignancies. Highfrequency hearing loss is extremely prevalent in children
who have received platinum-based chemotherapies, and
such children must have routine audiometric evaluations.
Other potential late effects of chemotherapy on organ
function include disruption of cardiac, renal, pulmonary,
and hepatic function. The effect of chemotherapy on fertility of both genders is the subject of current investigation.
Radiation therapy, despite its critical role in the management of pediatric brain tumors, has the highest number of
long-term sequelae that the primary care physician should
recognize. (12)(13)(14)(15) The most common, and perhaps most signicant, effect of radiation therapy is its
impact on neurocognition. Children younger than 8 years

are at the highest risk for radiation-related neurocognitive
injury. Those patients who receive craniospinal radiation
are at risk for declines in IQ of 2 to 4 points per year
(1020 points overall), depending on radiation dosage, tumor location, and age of the child. Subsequently, these
children often have difculty with learning and memory
and may require special education services. Studies are ongoing to determine whether pharmacologic interventions
have any impact on improving neurocognition in this population of children.
Endocrinopathies are commonly seen in patients who
have received either whole brain or suprasellar boosts of radiation. Although the hypothalamic-pituitary axis hormones often are measured before, during, and after
therapy, the long-term consequences of treatment-related
endocrinopathies acquired during childhood are unknown.
Another important long-term neurologic complication specic to children who have received cranial radiation is neurovascular disease. Depending on the radiation
dose and location, children are at increased risk for cerebral vasculopathy, including Moyamoya disease, which
increases the risk for a future stroke. The mechanism of
radiation-related vasculopathy is not entirely known but
is different from the atherosclerotic or cardioembolic
pathophysiology of stroke seen in adults. Unfortunately,
pharmacologic intervention is difcult to apply due to the
lack of data on whether preventive therapy (eg, aspirin,
cholesterol-lowering drugs, antiplatelet agents) decreases
the risk of radiation-associated childhood strokes.
Children who have been treated with either chemotherapy or radiation therapy for a brain tumor may have
chronic headaches. These headaches can have features of
migraines, tension-type headaches, cluster headaches, or
a combination of all three. The exact pathophysiologic
mechanism and true incidence are not fully understood.
A certain proportion of patients will develop chronic daily
headaches and require both prophylactic and abortive
headache regimens. Unfortunately, in some cases, it is
difcult to determine whether the headache is related
to the disease or to the sequelae of treatment. It is important to recognize that headaches could be a sign of disease recurrence and may be present before there is
MRI evidence of progressive or recurrent disease. A thorough headache history may be helpful in distinguishing
whether there is a change in the headache pattern from
baseline that warrants neuroimaging.
Less understood late effects of brain tumor treatment
are depression and other psychosocial consequences. A
wide range of patients of all ages, with all tumor types,
tumor locations, and therapies, are at risk for depression.
brain tumors
It is unclear whether this condition is due to a direct effect of the tumor diagnosis or of therapy. Regardless, patients should be screened routinely for signs and symptoms
of depression. Screening can be performed by both the
neuro-oncology team and the pediatrician. When depression is suspected, a referral to child psychiatry or initiation
of antidepressant therapy may be warranted. In terms of
the psychosocial consequences of brain tumors, a high divorce rate among parents, disrupted sibling relationships,
and problems with peer-to-peer interactions have been observed. A summary of the common late effects of brain tumor therapy is shown in Table 4.
Future of Pediatric Neuro-Oncology

The eld of pediatric neuro-oncology is evolving rapidly,
thanks in part to the advances in molecular biology. Many
common primary brain tumors now can be categorized
according to molecular markers, which someday soon
will serve as the basis of risk stratication in clinical trials.
Our improved knowledge of the molecular mechanisms
of neuro-oncogenesis has led to the discovery of an enormous number of molecular-targeted therapies (ie, biologic agents) that currently are being studied in clinical
trials for recurrent or refractory disease. These drugs
are designed specically to disrupt known tumor-specic
molecular signaling pathways. It is the hope that one day,
more specic targeted biologic therapies will replace conventional chemotherapy or radiation in the treatment of
childhood brain tumors.
One of the great limitations in achieving success of biologic-based treatments is the ability of these drugs to cross
the bloodbrain barrier. To overcome this gatekeeper,
a number of treatment strategies, including gene-based delivery systems, immunotherapies, and convection-based
drug delivery, currently are being investigated.
Advances in radiation oncology are necessary for improving neurocognitive outcomes without sacricing therapeutic efcacy. It is unknown whether proton beam
therapy will be superior to conventional photon beam therapy, and results may not be known for many years. An improved understanding of the molecular mechanisms of
radiation-related neurocognitive injury will allow for the development and implementation of neuroprotective agents at
the initiation of therapy. Likewise, advances in neuroimaging will allow detection of tumor reoccurrence earlier and more accurate differentiation of treatment-related
changes from disease reoccurrence.
Determining the genetic underpinnings of neurooncologic disease includes understanding epigenetic factors that govern neuro-oncogenesis. Today, a variety of
mouse models exist that spontaneously and at great
brain tumors
Potential Late Effects of

Pediatric Brain Tumor Therapy
Table 4.
1. Endocrinopathy (hypothyroidism, growth hormone

deficiency, corticotropin deficiency, precocious or
delayed puberty, diabetes insipidus)
2. Secondary neoplasms (hematogeneous, skin, thyroid,
CNS)
3. Cerebral vasculopathy (stroke, Moyamoya disease,
angiitis)
4. Neurocognitive effects (learning, memory, IQ)
5. Sensorineural hearing loss
6. Scoliosis
7. Osteopenia
8. Primary headache disorder
9. Epilepsy
10. Infertility/dysmenorrhea
11. Depression/anxiety
12. Obesity/diabetes
13. Neuropathy
14. Ocular effects (vision loss, amblyopia, cataracts)
15. Cardiomyopathy
16. Renal insufficiency
CNScentral nervous system.
frequency form brain tumors similar to childhood disease.

Primary tumor cell cultures have been established for a variety of pediatric brain tumors and are being used to study
individual tumor growth patterns, as well as the potential
responsiveness of tumors to a variety of chemotherapeutic and biologic therapies. As our knowledge of the role of
stem cells in disease formation and progression improves,
innovative stem cell therapies may play a role in the future
of neuro-oncologic treatment. It is our belief that one or
all of these advances in molecular medicine will allow us
to achieve individualized brain tumor therapies for our
patients and give the best hope for cure.
Role of the Pediatrician

Pediatric brain tumors are a rare but serious disease of
childhood that require a multidisciplinary approach to diagnosis, ongoing management, and recognition of late
effects of treatment. The role of the pediatrician is extremely important in all aspects of brain tumor management. A heightened awareness of the signs and symptoms
of childhood brain tumors in conjunction with a focused
neurologic examination may lead to an earlier diagnosis.
Children who are long-term survivors of brain tumors face
unique challenges with regard to a multitude of potential
late effects of therapy and therefore require meticulous
continuity of care beyond childhood and into adulthood.
The pediatrician serves as a crucial liaison between pediatric and adult medicine in providing continuity of care. It is
the hope that improved understanding of the biology of
disease will translate into novel therapies and improved
survivals of children diagnosed with brain tumors.
Summary
Based on strong evidence, brain tumors, although rare,
are the No. 1 cause of death among all childhood
cancers.
Based on consensus, the morbidity and mortality
associated with childhood brain tumors are
determined by many factors, particularly tumor
pathology, anatomic location, and treatment.
Based on strong evidence, headache occurs in
approximately one third of patients newly diagnosed
with pediatric brain tumors.
Based on consensus, brain tumors are managed by
surgery, chemotherapy, or radiation, depending on
tumor type, location and dissemination, and age.
Based on strong evidence, in treating brain tumors,
chemotherapy places the child at risk for future
malignancies and radiation therapy places the child at
risk for developing neurocognitive deficits.
References
1. CBTRUS, Central Brain Tumor Registry of the United States.
CBTRUS statistical report: primary brain and central nervous
system tumors diagnosed in the United States in 2004-2008.
Available at: www.cbtrus.org. Accessed July 12, 2012
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer
Statistics Review, 1975-2008, Bethesda, MD: National Cancer
Institute. Available at: http://seer.cancer.gov/csr/1975_2008/.
Accessed July 12, 2012
3. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO
classication of tumours of the central nervous system. Acta
Neuropathol. 2007;114(2):97109
4. Leary SE, Olson JM. The molecular classication of medulloblastoma: driving the next generation clinical trials. Curr Opin
Pediatr. 2012;24(1):3339
5. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of
medulloblastoma: an international meta-analysis of transcriptome,
genetic aberrations, and clinical data of WNT, SHH, Group 3, and
Group 4 medulloblastomas. Acta Neuropathol. 2012;123(4):
473484
6. Ginn KF, Gajjar A. Atypical teratoid rhaboid tumor: current
therapy and future directions. Front Oncol. 2012;2:114
7. Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D.
Presentation of childhood CNS tumours: a systematic review and
meta-analysis. Lancet Oncol. 2007;8(8):685695
8. Harbert MJ, Yeh-Nayre LA, OHalloran HS, Levy ML, and
Crawford JR. Unrecognized visual eld decits in children with
primary central nervous system brain tumors. J Neurooncol. 2012;
107(3):545549
9. Ater JL, Zhou T, Holmes E, et al. Randomized study of two

chemotherapy regimens for treatment of low-grade glioma in
young children: a report from the Childrens Oncology Group.
J Clin Oncol. 2012;30(21):26412647
10. Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U.
Proton versus photon radiotherapy for common pediatric brain
tumors: comparison of models of dose characteristics and their
relationship to cognitive function. Pediatr Blood Cancer. 2008;51
(1):110117
11. Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes
among adult survivors of childhood central nervous system
malignancies in the Childhood Cancer Survivor Study. J Natl
Cancer Inst. 2009;101(13):946958
12. Reimers TS, Ehrenfels S, Mortensen EL, et al. Cognitive
decits in long-term survivors of childhood brain tumors:
identication of predictive factors. Med Pediatr Oncol. 2003;40
(1):2634
brain tumors
13. Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ.
Change in neurocognitive functioning after treatment with cranial
radiation in childhood. J Clin Oncol. 2004;22(4):706713
14. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE.
Late neurocognitive sequelae in survivors of brain tumours in
childhood. Lancet Oncol. 2004;5(7):399408
15. Armstrong GT, Stovall M, Robison LL. Long-term effects of
radiation exposure among adult survivors of childhood cancer:
results from the Childhood Cancer Survivor Study. Radiat Res.
2010;174(6):840850
Suggested Reading
Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors.
New York, NY: Springer-Verlag; 2010
Keating RF, Goodrich JT, Packer RJ, eds. Tumors of the Pediatric
Nervous System. New York, NY: Thieme Medical Publishers Inc;
2001
PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit

level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to
successfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level
of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.
1. The symptom that most warrants emergent neuroimaging for a suspected brain tumor in a previously well 4year-old child is:
A. Episodic vomiting.
B. Newly discovered myopia.
C. Occasional isolated headache.
D. Progressive ataxia.
E. Single generalized seizure.
2. A 3-year-old boy presents with a 4-week history of headache, morning vomiting, and a wide-based gait. His
examination reveals papilledema, ataxia, and dysmetria. He is most likely to have a:
A. Craniopharyngioma.
B. Frontal lobe glioma.
C. Medulloblastoma.
D. Migraine headache.
E. Optic glioma.
3. A 6-year-old girl has been noted to have progressive deterioration of her coordination over the past month and
is no longer interested in play. On examination, you note palsy of her left abducens and facial nerves. You
suspect a brainstem glioma. The best choice as an initial neuroimaging study is:
A. Head computed tomography scan with contrast.
B. Head computed tomography scan without contrast.
C. Lumbar puncture for opening pressure.
D. Magnetic resonance imaging spectroscopy.
E. Magnetic resonance imaging with and without contrast.
brain tumors
4. Neurosurgery is an integral part of diagnosis and management of most brain tumors. However, there are two
types of brain tumors for which surgery is not required to establish a diagnosis. Diffuse intrinsic pontine glioma
is one. The other is:
A. Choroid plexus carcinoma.
B. Central nervous system germinoma.
C. Medulloblastoma.
D. Optic glioma.
E. Supratentorial ependymoma.
5. The parents of a 12-year-old boy who has received both chemotherapy and radiation for a brain tumor ask you
about late sequelae of those treatments. You explain that hematogenous and secondary systemic malignancies
are a threat to any child receiving chemotherapy, whereas the most common effect specifically attributable to
radiation therapy is:
A. Cerebral vasculopathy.
B. Chronic headache.
C. Depression.
D. Impaired learning.
E. Seizures.
Article
gastrointestinal disorders
Pediatric Pancreatitis
Arvind I. Srinath, MD,*
Mark E. Lowe, MD, PhD
Author Disclosure
Drs Srinath and Lowe
have disclosed no
financial relationships
Educational Gaps
1. The incidence of acute pancreatitis has increased in pediatric patients over the past
two decades, approaching the incidence in adults.
2. While pancreatic rest, antiemetics, analgesia, fluid support, and monitoring for
complications remain the mainstays of acute pancreatitis management, clinicians
should know that approaches to pancreatic rest and fluid management have changed,
as have long-time teachings on the use of opiods and the institution of nutrition.
relevant to this article.

This commentary does
not contain
a discussion of an
unapproved/
device.
Objectives
After completing this article, readers should be able to:
1.
2.
3.
4.
Differentiate between acute and chronic pancreatitis.

Know how to diagnose acute pancreatitis.
List common causes for acute, recurrent, and chronic pancreatitis.
Explain the utility of clinical symptoms, biochemical testing, and radiographic
imaging in diagnosing acute and chronic pancreatitis.
5. Understand the management of acute pancreatitis and chronic pancreatitis.
Introduction
Abbreviations
Pancreatitis is an inammatory condition of the pancreas. Two major forms of pancreatitis,

acute and chronic, are recognized. Acute pancreatitis is a reversible process, whereas
chronic pancreatitis (CP) is irreversible. Acute pancreatitis is more prevalent, and most patients have a single episode of pancreatitis. A small number of patients have recurrent episodes of acute pancreatitis and are at risk of developing CP.
Pancreatitis in pediatric patients is an increasingly recognized disorder. Although standard diagnostic criteria for pancreatitis exist, their intricacies deserve close attention, especially in pediatrics. Research over the past decade has demonstrated differences between
pancreatitis in children and adults, particularly in presentation, etiology, prognosis, and nature of acute recurrent pancreatitis (ARP). Many of the traditional thoughts about management have been challenged,
and the treatment of pancreatitis is evolving.
acute recurrent pancreatitis

cystic brosis transmembrane conductance
regulator
CP:
chronic pancreatitis
CT:
computed tomography
ERCP:
endoscopic retrograde cholangiopancreatography
EUS:
endoscopic ultrasound
IgG4:
immunoglobulin G4
MRCP: magnetic resonance cholangiopancreatography
PRSS-1: cationic trypsinogen gene
SPINK-1: serine protease inhibitor Kazal type 1
TPN:
total parenteral nutrition
ARP:
CFTR:
Acute Pancreatitis in Pediatrics

Epidemiology
Acute pancreatitis occurs in all age groups, even in infants. Recent studies from the United States, Mexico, and Australia
have reported an increasing incidence of pediatric acute pancreatitis over the past 2 decades. (1) Currently, the best estimates suggest that there are 3.6 to 13.2 pediatric cases per
100,000 individuals per year, an incidence that approaches
the incidence of disease in adults. Much of the increased diagnosis of acute pancreatitis results from greater physician
awareness, as evidenced by a concurrent increase in biochemical testing (amylase and lipase levels) for pancreatitis.
*Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Childrens Hospital of Pittsburgh of University of Pittsburgh
Medical Center (UPMC), Pittsburgh, PA.
Director, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Vice Chairman of Pediatrics, Childrens Hospital of
Pittsburgh of UPMC, Pittsburgh, PA.
pancreatitis
Pathophysiology
Acute pancreatitis results from injury of the pancreas
and a subsequent inammatory response that may involve adjacent and distant tissues and organs. The prevailing theory of the pathophysiology of pancreatitis
includes several distinct steps. First, an event initiates
a process of acinar cell injury. The cell injury produces
pancreatic edema and a local inammatory response,
with release of inammatory mediators. The production of cytokines and chemokines provoke a systemic
inammatory response. The magnitude of this inammatory response determines the clinical severity of
acute pancreatitis and can lead to complications such
as pancreatic necrosis, shock, and distant organ
failure.
Much current research focuses on the nature of the acinar cell injury. The prevailing model is that nonphysiologic calcium signals initiate the premature intracellular
activation of trypsinogen to trypsin (Fig 1). Trypsin, in
turn, activates other digestive proenzymes. The activated
digestive enzymes then mediate acinar cell injury. Recently, this autodigestion model has been challenged.
In some, if not all, patients with pancreatitis, an aberrant
unfolded protein response and the resultant endoplasmic
reticulum stress may initiate apoptotic pathways and inammatory signals. (2)
Causes of Acute
Pancreatitis in Children
Table 1.
Common
Biliary disorders
Systemic conditions
Medications
Trauma
Idiopathic
Less common
Infection
Metabolic diseases
Genetic/hereditary disorders
Rare
Autoimmune pancreatitis
Anatomic pancreaticobiliary abnormalities
Etiology
The disorders associated with pancreatitis fall into several broad categories (Table 1). The prevalence of different causes varies greatly among studies of acute
pancreatitis in childhood. The variation likely results
from the inherent limitations of retrospective studies,
the bias or experience of the clinicians caring for children
who have pancreatitis, incomplete investigations for
causes, the greater number of patients recognized to have pancreatitis, and the recognition of new
etiologies in childhood.
BILIARY DISEASE. Gallstone pancreatitis is a more common cause of
acute pancreatitis in children than
previously believed. Gallstone pancreatitis or other biliary disease should
be suspected if the patient has elevations in transaminase levels and/or
hyperbilirubinemia.
Figure 1. Pathophysiology of acute pancreatitis. Multiple causes of acute pancreatitis can

lead to abnormal intra-acinii calcium signaling. This signaling leads to intra-acinar
zymogen activation and resulting pancreatic injury and cytokine response, as well as
potential systemic inflammatory response. Ca2D[calcium. Reprinted with permission from
Bai HX, Lowe ME, Husain SZ. What have we learned about acute pancreatitis in children? J
Pediatr Gastroenterol Nutr. 2011;52(3):263 (License Number: 2886070809948).
SYSTEMIC ILLNESS. In recent studies, acute pancreatitis associated with

systemic illnesses accounted for more
than 20% of reported cases. Typically, these children were in an intensive care unit. Pertinent associations
include sepsis, shock (alone or
with sepsis), hemolytic uremic syndrome, and systemic lupus erythematosus. Of these diseases,
hemolytic uremic syndrome has had
the highest prevalence. (3)(4) The
pathophysiologic mechanism is uncertain, although it is

likely multifactorial. Inammatory bowel disease can cause
pancreatitis due to periampullary obstructive small intestinal disease, cholelithiasis, associated primary sclerosing
cholangitis, and the effects of immunomodulating medications (mesalamine and 6-mercaptopurine). It is not
unusual for infectious symptoms to be temporally associated with the onset of acute pancreatitis. With a few exceptions, such as the mumps virus, few viruses clearly cause
acute pancreatitis. (3)
MEDICATIONS. A variety of medications increase the
risk for pancreatitis. Commonly reported associations
implicate L-asparaginase, valproic acid, azathioprine,
mercaptopurine, and mesalamine as triggers of pancreatitis. (3) The mechanism behind medicationassociated pancreatitis is unclear. In susceptible patients,
the medication or its metabolites likely disrupt acinar cell
metabolism.
TRAUMA. Although the prevalence of pancreatitis associated with trauma is probably not as high as previously
thought, trauma remains an important cause of pancreatitis. Most often, unintentional blunt trauma causes damage
to the pancreas, but child abuse can result in traumatic
pancreatitis as well. (5)
pancreatitis
duct, and histologic features. In children, IgG4 elevation

may not be present, even with typical histology. In general, and regardless of serum IgG4 status, pediatric (and
adult) patients with type 1 or type 2 autoimmune pancreatitis respond to corticosteroid therapy. (6)
ANATOMIC PANCREATOBILIARY ABNORMALITIES. Pancreaticobiliary abnormalities such as pancreas divisum
(Fig 2), abnormal junction of the common bile duct
and main pancreatic duct (common channel syndrome),
choledochal cysts, and annular pancreas increase the risk
for acute pancreatitis. Pancreas divisum is present in up to
15% of the population. This anatomic abnormality occurs
when the dorsal and ventral anlage of the pancreas fuse
incompletely, leading to lack of communication between
the dorsal (Santorini) and ventral (Wirsung) pancreatic
ducts. Despite its proposed obstructive mechanism leading to acute pancreatitis, clinical causality is still controversial. Recent studies suggest that the presence of a
SPINK-1 (serine protease inhibitor Kazal type 1) or
CFTR (cystic brosis transmembrane conductance receptor) mutation along with pancreas divisum increases
the risk of acute pancreatitis and accounts for the observation that only a fraction of people who have pancreas
divisum develop acute pancreatitis. (7)
IDIOPATHIC. Despite improvements in diagnostic testing, the rate of idiopathic pancreatitis continues to be signicant and unchanged. (3)(4)
METABOLIC. Although metabolic diseases are uncommon causes of acute pancreatitis, it is important to recognize them because treatment can prevent recurrent
episodes. Disorders that cause hypercalcemia, hypertriglyceridemia, and inborn errors of metabolism have all
been associated with acute pancreatitis.
GENETIC/HEREDITARY. The common genetic mutations associated with pancreatitis generally cause ARP
or CP and are discussed in the following text.
AUTOIMMUNE PANCREATITIS. Autoimmune pancreatitis has become increasingly recognized in childhood.
Autoimmune pancreatitis occurs in two forms (types 1
and 2). Type 2 seems to be more common in children
and has an association with inammatory bowel disease
and other autoimmune diseases. In adults, the diagnosis
of type 1 autoimmune pancreatitis relies on elevated levels of immunoglobulin G4 (IgG4), diffuse or segmental
enlargement of the pancreas, strictures of the pancreatic
Figure 2. Magnetic resonance cholangiopancreatography show-
ing pancreas divisum. Dorsal (yellow arrow) and ventral (red

arrow) pancreatic ducts with separate insertion of dorsal
pancreatic duct into minor papillae. The rest of the biliary tree
is delineated: common bile duct (blue arrow), common hepatic
duct (green arrow), right hepatic duct (white arrow), and left
hepatic duct (orange arrow). Courtesy: William M. Peterson II,
MD, and Sameh Tadros, MD, MSc, Department of Radiology;
Childrens Hospital of Pittsburgh of UPMC.
pancreatitis
Diagnosis
Acute pancreatitis can occur in mild and severe forms. Although the denition of the two forms can vary depending on the author, in general, mild pancreatitis is limited
to the pancreas and the peripancreatic fat, whereas severe
disease includes pancreatic necrosis, involvement of other
organs, cardiovascular collapse, infection, or uid collections. Most children (90%) have mild disease. (5)
Acute pancreatitis in pediatric patients requires at least
two of three criteria: (1) abdominal pain suggestive of or
compatible with acute pancreatitis (ie, abdominal pain of
acute onset, especially in the epigastric region); (2) serum
amylase or lipase activity at least three times greater than
the upper limit of normal; and (3) imaging ndings compatible with acute pancreatitis.
ABDOMINAL PAIN SUGGESTIVE OF OR COMPATIBLE
WITH ACUTE PANCREATITIS. Abdominal pain has a frequency of 80% to 95% in pediatric patients who have acute
pancreatitis. Specically, pancreatitis has been shown to present with epigastric pain in 62% to 89% of patients and diffusely in 12% to 20% of patients. The classic presentation
of epigastric pain radiating to the back occurs in only 1.6%
to 5.6% of patients. Epigastric pain plus back pain is present
in fewer than 10% of patients. (3) Assessing pain in children
who are nonverbal, have static encephalopathy, or are developmentally delayed can be challenging. Parental report of irritability is a common presenting sign in nonverbal children.
In infants and toddlers, abdominal distension, vomiting, and
fever were common presenting complaints. (8)
SERUM AMYLASE OR LIPASE ACTIVITY AT LEAST
THREE TIMES GREATER THAN THE UPPER LIMIT OF
NORMAL. Amylase and lipase values rise 2 to 12 hours
and 4 to 8 hours, respectively, after the onset of pancreatic inammation. It is important to note that the upper
reference values of serum amylase and lipase vary among
different laboratories; hence, reference values should always be given when considering levels. At present, both
amylase and lipase should be measured because only one
or the other may be elevated in individual patients, even
in the presence of radiographic evidence for pancreatitis.
It is important to note that other diseases can cause elevations of amylase and lipase (Table 2).
IMAGING FINDINGS COMPATIBLE WITH ACUTE
PANCREATITIS. The utility and timing of radiographic
studies in children who have suspected acute pancreatitis
remain controversial (Table 3). The frequency of gallstone
pancreatitis in children provides the most compelling
argument for early imaging. Endoscopic ultrasonography

(EUS) and magnetic resonance cholangiopancreatography
(MRCP) identify cholelithiasis best. (9)(10) MRCP is
magnetic resonance imaging of the biliary tree and surrounding structures (pancreas and liver). Because uid
in the pancreaticobiliary ducts appears bright, they can
be visualized easily. Although MRCP is expensive and requires general anesthesia in younger children, it has largely
supplanted endoscopic retrograde cholangiopancreatography (ERCP) as the preferred diagnostic study for biliary
and pancreatic ductal disease because it is less invasive and
does not cause pancreatitis, which can occur after ERCP.
EUS is not widely available in pediatric centers. Transabdominal ultrasonography represents a reasonable compromise for evaluating patients who have suspected
gallstone disease. Ultrasonography also may provide corroboration of acute pancreatitis and assist in identifying
causes. Findings can include pancreatic edema, dilated
main pancreatic duct, pancreatic calcications, and uid
collections.
Contrast-enhanced computed tomography (CT) of
the abdomen is a second option for imaging the pancreas.
A CT scan can show the same ndings as ultrasonography
and also may provide information about the presence or
absence of pancreatic necrosis. In general, CT scans are
most useful several days into the course of acute pancreatitis if the patient fails to improve or if the pancreas is
inadequately visualized on ultrasonography.
Management
The management of acute pancreatitis traditionally has consisted of pancreatic rest (no enteral feeding), antiemetics,
analgesia, uid support, and monitoring for complications. These treatments remain the mainstay of therapy,
but the approach to pancreatic rest and uid management has changed.
The initial treatment is directed at stabilizing the patients condition. Limited adult data suggest that aggressive hydration in the rst 24 hours decreases the risk of
multiorgan system failure. (11) Thus, intravenous uid
boluses to rehydrate the patient and subsequent uid administration at 1.5 times maintenance rates are recommended.
Antiemetics and analgesia are necessary to provide
comfort and to avoid increased energy expenditure. Opioid analgesics in oral or parenteral forms usually are required for pain control in acute pancreatitis. There is
no evidence to support the advantage of any particular
medication. Despite the long-time teaching that morphine
should be avoided because it may cause paradoxical
contraction of the sphincter of Oddi, this effect has
pancreatitis
Pediatric Conditions Associated With Elevation of Amylase or

Lipase Levels
Table 2.
Condition
Amylase
Lipase
Abdominal
Salivary gland
Thoracic
Infectious
Metabolic
Neoplastic
Drugs
Trauma
Renal
Inflammatory
Miscellaneous
Acute pancreatitis
Biliary tract disease
Intestinal obstruction/ischemia
Mesenteric infarction
Peptic ulcer
Appendicitis
Ruptured ectopic pregnancy
Ovarian neoplasm
Trauma
Infection (ie, mumps)
Sialolithiasis
Irradiation
Pneumonia
Pulmonary embolism
Myocardial infarction
Cardiopulmonary bypass
Viral gastroenteritis
Pelvic inflammatory disease
Diabetic ketoacidosis
Pheochromocytoma
Ovarian, lung, esophageal, or thymic tumors
Opiates
Cerebral trauma
Burns
Renal insufficiency
Renal transplantation
Macroamylasemia
Celiac disease
Cystic fibrosis
Acute liver failure
Viral gastroenteritis
Pregnancy
Eating disorders: anorexia, bulimia
not been demonstrated in clinical practice, and morphine

can be used safely in patients who have acute pancreatitis.
(12)
A careful directed investigation for treatable causes of
acute pancreatitis should be conducted (Table 1). The routine use of antibiotics is not recommended; they should be
reserved for patients who have evidence of infected necrosis.
Perhaps the greatest change in the management of
acute pancreatitis is the early institution of nutrition. In
patients who have mild acute pancreatitis, oral feedings
can be started within 24 to 48 hours after admission.
In the past, clear liquids were started, but recent studies
in adults show that regular meals can be given. (13) Limited data suggest that the practice of prescribing a low-fat
diet is not necessary. About 10% of patients will have abdominal pain after starting oral intake. Usually, feedings
Nonpancreatic abdominal pain

Acute cholecystitis
Esophagitis
Intestinal obstruction/ischemia
Peptic ulcer
Human immunodeficiency virus infection

Diabetic ketoacidosis
Hypertriglyceridemia
Renal insufficiency
Macrolipasemia
Celiac disease
can be resumed in the patients in another 24 hours. (5)

(14) An increase in serum levels of pancreatic enzymes is
not an indication to stop feedings.
Patients who have severe pancreatitis also can be successfully fed early in the treatment course. Typically, these
patients are fed through enteral tubes or by using total
parenteral nutrition (TPN). Enteral feeding is preferred
over TPN because of the complications associated with
the intravenous catheter and the expense of TPN. The
only clear indications for TPN include inability to tolerate
enteral nutrition due to prolonged ileus, pancreatic stulae, or complicating abdominal compartment syndrome.
The choice of enteral route, gastric or jejunal (which
bypasses the ampulla of Vater), is controversial and generally depends on the custom at individual institutions.
Both routes have been used successfully in adults who
pancreatitis
Utility of Radiographic Imaging for

Diagnosing Acute Pancreatitis
Table 3.
Imaging
Comments
Abdominal ultrasonography
Advantages
Reasonable test to assess for gallstones
Short duration
No radiation exposure
Usually available any time of day
Disadvantages
Operator dependence
Potential for bowel gas to obscure
pancreas
Advantages
Better than ultrasonography for
detecting changes associated with
pancreatitis
Short duration
Usually available any time of day
Utility lies in detecting pancreatic
necrosis if suspected
Disadvantages
Rather low sensitivity for detecting
changes associated with acute
pancreatitis
Radiation exposure
Cannot visualize gallstones
Advantages
Good assessment of pancreatic
parenchyma, ducts, and gallstones
Disadvantages
May not be available 24 hours a day
Limited in acutely ill patients due to
procedure time
Duration of test may necessitate
sedation in younger children
Abdominal computed tomography
Magnetic resonance
cholangiopancreatography
have severe acute pancreatitis. The choice of formula, elemental or polymeric, is also a matter of local practice.
Direct comparisons of elemental and polymeric formulas
have failed to demonstrate differences in feeding tolerance, morbidity, or mortality between the formulas.
(15)
to develop, although any uid collection is called a pseudocyst. Pseudocysts and other uid collections
typically resolve despite the initial
size but occasionally may require
drainage, which can be conducted
by using interventional radiology,
endoscopy, or surgery. Death is
uncommon in pediatric patients
who have pancreatitis, and most reported deaths occur in patients who
have other signicant disease, such
as trauma or sepsis. (3)(5)
Outcomes in acute pancreatitis
are similar among pediatric age
groups, are better than in adults,
and are not correlated with initial
amylase and lipase levels. There are
no existing scoring systems similar
to the APACHE (Acute Physiology
and Chronic Health Evaluation) or
the Ranson system used in adults
that can accurately predict outcome
in pediatrics. (4)
Acute Recurrent Pancreatitis
ARP is dened as at least two episodes of acute pancreatitis per year,

or more than three episodes over
a lifetime, in a patient without CP
or a pancreatic pseudocyst. Reliable
estimates of the risk of recurrence
are not available in pediatric patients.
Case series report that 10% to 35% of patients will have recurrence. (3) The pathophysiology of recurrent episodes
likely parallels the same pathways that are present in patients who experience a single episode, although these patients may have additional genetic modiers that increase
the likelihood of developing acute pancreatitis, given a particular trigger.
Complications
Table 4 details the potential local and systemic complications of acute pancreatitis in pediatric patients. These
complications also can be classied by early versus late onset. Pancreatic uid collections are the most common
complication of acute pancreatitis in pediatrics and usually
are caused by necrosis or trauma. Pseudocysts (Fig 3)
are dened as a homogeneous collection of pancreatic
uid encased by a membrane of granulation tissue. It
takes approximately 30 days for the granulation tissue
Etiology
As in patients who experience a single episode of pancreatitis, many patients who have ARP have no identiable
cause for their illness. Table 5 lists common etiologies associated with ARP. Many of the causes discussed here can
lead to recurrent episodes of pancreatitis, including biliary disease, anatomic pancreaticobiliary abnormalities, inammatory bowel disease, and autoimmune pancreatitis.
Complications of Acute
Pancreatitis
Table 4.
Local
Inflammation
Localized to pancreas
Systemic extension
Ileus
Pancreatic edema
Pancreatic necrosis
Pancreatic abscess
Fat necrosis pancreatic hemorrhage
Pancreatic pseudocyst
Pancreatic duct rupture
Pancreatic duct stricture
Thrombosis of adjacent blood vessels
Systemic
Shock
Sepsis
Hypermetabolic state
Hypocalcemia
Hyperglycemia
Vascular leak syndrome
Multiorgan system failure
Disseminated intravascular coagulation
Pleural effusions
Acute renal failure
Splenic artery pseudoaneurysm
Other causes to consider after a second, distinct episode

of pancreatitis are discussed in the following text.
GENETIC MUTATIONS ASSOCIATED WITH PANCREATITIS.
In the last 15 years, mutations in several genes have
pancreatitis
been associated with increased risk for pancreatitis.

(16)(17)
PRSS-1. Several mutations in the PRSS-1 gene that
encodes cationic trypsinogen cause hereditary pancreatitis. Inheritance is autosomal dominant with an 80% penetrance. The mechanism by which mutations in PRSS-1
lead to pancreatitis remains under investigation. Prevailing theories are increased autoactivation of trypsinogen
(an inactive form stored in the acinar cell) to trypsin or
increased resistance to inactivation of trypsin within the
acinar cell. Patients present in childhood with ARP and
later progress to CP with a high likelihood of exocrine
and endocrine deciency. The lifetime risk of pancreatic
cancer is 40% or greater in these patients. (16)(17)
SPINK-1. The gene product of SPINK-1 is produced in
acinar cells and acts as a defense for premature tryspinogen
activation. Several mutations in SPINK-1 increase susceptibility to ARP and CP. Patients who have homozygous or
compound heterozygous mutations have a higher risk than
patients who have heterozygous mutations. SPINK-1 mutations are considered disease modiers because most people who have these mutations, even when homozygous, do
not develop acute pancreatitis, ARP, or CP. The mechanism of increased risk associated with SPINK-1 mutations
is thought to be related to decreased ability to inactivate
trypsin. Denitive evidence for this mechanism is not available and other mechanisms, such as toxicity from misfolded
protein, remain possible. (16)(17)
CFTR. As with SPINK-1 mutations, CFTR mutations
are considered disease modiers. Heterozygous, compound heterozygous, and homozygous mutations increase
the risk for ARP and CP. The increased risk is less for
Figure 3. Scans of pancreatic pseudocyst (arrow). A. Computed tomography. B. Ultrasonography. Courtesy: William M. Peterson II,
MD, and Sameh Tadros, MD, MSc, Department of Radiology; Childrens Hospital of Pittsburgh of UPMC.
pancreatitis
Causes of Acute
Recurrent and Chronic
Pancreatitis
Table 5.
Biliary calculi
Macrolithiasis
Microlithiasis (<2 mm)a
Sludgea
Congenital pancreaticobiliary abnormalities
Anomalous pancreaticobiliary junction
Choledochal cyst
Annular pancreas
Pancreas divisumb
Geneticc
Hereditary pancreatitis, PRSS-1 mutation
SPINK-1 mutationb
CFTR mutation
Duodenal inflammation
Crohn disease
Celiac disease
Infection
Medications
Sphincter of Oddi dysfunction
Metabolic
Hypercalcemia
Hypertriglyceridemia
Intestinal duplication cyst
Gastric
Duodenal
Autoimmune
Localized to pancreas
Systemic disorder
Idiopathicc
CFTRcystic brosis transmembrane conductance regulator; PRSS1cationic trypsinogen; SPINK-1serine protease inhibitor Kazal type
1.
a
Controversial associations.
b
Only causative if present with another predisposing factor (eg, CFTR
heterozygote mutation).
c
Most common causes of chronic pancreatitis in pediatric patients.
patients who have heterozygous mutations than it is for

patients with two affected alleles. In general, one or both
affected alleles results in a CFTR protein with some function. These patients lack other clinical features of cystic
brosis or have mild disease in other organs and are
pancreatic-sufcient at presentation, although some will
develop pancreatic insufciency over time. When interpreting results of a genetic screen of the CFTR gene, it is
important to remember that the effect of many changes
in the gene sequence on protein function is unknown.
(16)(17)
CTRC. The chymotrypsin C gene (CTRC) encodes
for the digestive enzyme chymotrypsin C. There are
increased rates of CTRC mutations in patients who have

ARP and CP. The mutations are disease modiers. Because CTRC can inactivate trypsin in vitro, it has been
suggested that this gene acts to protect acinar cells from
inapproporiate trypsinogen activation. (16)(17)
DRUG-INDUCED PANCREATITIS. A careful review of any
medications and home remedies used by the patient
should be conducted, and any medications associated
with pancreatitis should be discontinued.
SPHINCTER OF ODDI DYSFUNCTION. The role of sphincter of Oddi dysfunction in causing ARP in children is unclear. No studies have suggested that sphincterotomy
(cutting the muscles around the sphincter) has any efcacy in treating children with ARP.
METABOLIC. The metabolic causes for ARP (hypercalcemia, hypertriglyceridemia, and inborn errors of metabolism) have not been studied extensively but may be rare
triggers for ARP.
DUPLICATION CYSTS. Duplication cysts of the duodenum or stomach should be considered; these lesions
may lead to ARP secondary to pancreaticobiliary obstruction, based on their location. They can be difcult to
detect and may be apparent only after multiple investigations with different imaging modalities. It is important to note that duodenal duplication cysts can
oppose the head of the pancreas closely and be interpreted as a pseudocyst.
Diagnosis and Management

The diagnostic criteria for each ARP episode and its treatment are the same as described earlier for acute pancreatitis. It is important to thoroughly explore all potential
causes and triggers because many are preventable and
knowledge of the cause can guide management and
prognosis.
In cases of ARP, genetic screening for PRSS-1 and
SPINK-1 mutations should be conducted. Although
complete gene sequencing of CFTR is available, this investigation is not necessary for all patients. A sweat test
should be performed. Patients who have mild/variable
CFTR mutations will have values in the indeterminate
or low positive zones. The presence of a CFTR mutation
can then be conrmed by using complete gene sequencing. Patients who have CFTR mutations should be referred to a CF center for additional evaluation.
The anatomy of the biliary and pancreatic ducts
should be determined by using MRCP. This study also
can identify annular pancreas or congenital pancreatic
cysts. Select patients may require ERCP to conrm and
possibly treat ductal anomalies. For instance, pancreas divisum is treated by using sphincterotomy and stenting
of the minor papilla. Additional evaluation for systemic
inammatory disease, especially for Crohn disease,
should be considered. Upper endoscopy can identify inammatory or mass lesions that may partially obstruct the
ampulla. Autoimmune pancreatitis may be suggested by
results of the MRCP. IgG4 should be measured although
its utility in identifying children who have autoimmune
pancreatitis has been questioned. Imaging studies, usually ultrasonography or CT scan, will identify duplication
cysts. Because current opinion holds that ARP progresses
to CP, effective management has the potential to stop
this progression.
Chronic Pancreatitis
Definition
CP is dened as a process leading to irreversible destruction of the pancreatic parenchyma and ducts and loss of
exocrine function. Many of these patients have a history
of ARP before the irreversible changes in pancreatic anatomy and function become apparent. (18)
Epidemiology
CP can present at all ages in children. Classic cystic brosis is the most common cause in children and will not be
discussed further in this review. The incidence and prevalence of CP in childhood are not known.
Etiology
The causes of CP are the same as those of ARP (Table 5).
In children, CP is usually idiopathic or associated with
mutations in PRSS-1, SPINK-1, CFTR, or CTRC genes,
alone or in combination.
Pathophysiology
CP results from the sequelae of long-standing destructive
inammation. Current theory suggests that CP begins
with acute pancreatitis and progresses to brosis. Instead
of resolution, as in acute pancreatitis, the destructive process continues in susceptible individuals. Susceptibility
and rate of progression are likely inuenced by genetic
and environmental modiers. (18)
Diagnosis
The diagnosis of CP is clinical and based on a combination of symptoms, imaging studies, and functional insufciency. It is important to consider all of these parameters
when CP is suspected in a patient, because diagnosis often is delayed. With advanced disease, amylase and lipase
levels will not be elevated, even in the presence of disabling pain.
pancreatitis
CLINICAL FEATURES. For many patients, recurrent episodes of pancreatitis will raise concerns about CP. Patients present with mild to intense abdominal pain,
usually epigastric. The pain can be constant or intermittent and often is described as deep and penetrating, with
radiation to the back. Many times the pain is episodic, as
in ARP. There are numerous causes of this pain. The pain
can result from obstruction of pancreatic ducts by brosis or stones, inammation of the parenchyma (acuteon-CP), perineural inammation, or pain imprinting in
the peripheral or central nervous system. Rarely, patients
present with symptoms of malabsorption, such as weight
loss, fatty stools, or diarrhea. Even rarer are patients who
present with jaundice from extrahepatic biliary obstruction caused by pancreatic brosis or a pseudocyst. An occasional patient will have an upper gastrointestinal
hemorrhage from venous thrombosis as the presenting
sign. Diabetes develops late in the course of CP, and children seldom, if ever, present with symptoms of diabetes.
IMAGING. Imaging studies provide evidence of morphologic change in the gland or ducts. Transabdominal
ultrasonography, CT, MRCP, ERCP, and EUS each
can provide evidence of chronic change in the pancreas.
Currently, MRCP is the imaging method of choice. This
modality has limitations in that the side branches of the
main pancreatic duct are not well dened. ERCP is better
at dening ductal anatomy but usually is not required.
CT can reliably detect calcication, gland atrophy, fat replacement, and ductal dilation but is not as sensitive for
duct changes as MRCP or ERCP. In adults, EUS has
gained acceptance for detecting changes in CP, although
there is disagreement about the standards for diagnosing
chronic changes by using this method.
PANCREATIC FUNCTION TESTING. Pancreatic function
testing can identify pancreatic insufciency and support
the diagnosis of CP. Duodenal intubation with secretincholecystokinin stimulation remains the reference standard for diagnostic testing, but this option is not widely
available. More commonly, pancreatic secretions are
collected at upper endoscopy. This approach likely
underestimates pancreatic secretion, leading to the incorrect diagnosis of pancreatic insufciency in some patients. In recent years, fecal elastase has been used to
screen for pancreatic insufciency. This test is widely
available, easy to conduct, and can be performed even
if patients are taking pancreatic enzyme supplements.
Like all indirect tests, fecal elastase has poor sensitivity
for detecting mild to moderate pancreatic insufciency.
Lastly, watery stools dilute the fecal elastase concentration, and false-positive ndings can occur. The 72-hour
pancreatitis
fecal fat collection remains the best test for steatorrhea.

As with other noninvasive tests, the 72-hour fecal fat collection result is abnormal only with advanced disease. Fat
testing should not be used alone for diagnosis because
disease of the intestinal mucosa can cause steatorrhea.
Management
The stage and etiology of CP determine its management.
When recurrent episodes of acute pancreatitis dominate
the clinical course, the management is identical to that
of acute pancreatitis. With disease progression, chronic
pain management and therapy for pancreatic insufciency
are required. In a few pediatric patients, diabetes will require treatment.
Because unrelenting pain affects many patients, most
of the therapeutic effort centers on pain control. At rst,
acetaminophen may be effective, but therapy generally
advances to narcotics. Other approaches to pain control
are used, but none has clear efcacy. Pancreatic enzyme
supplements and antioxidant therapy (selenium, ascorbic
acid, b-carotene, a-tocopherol, and methionine) are prescribed frequently as therapeutic trials.
Endoscopic treatment for CP should be considered only
when ductal strictures or pancreatic duct stones are present
or for symptomatic pseudocysts. The role of endoscopic
sphincterotomy and stent placement remains controversial. Surgical approaches are still used in select patients.
Localized disease can be treated with partial pancreatic
resection.
Total pancreatectomy with islet cell autotransplant is
currently offered to patients who have genetic causes of
pancreatitis and to those aficted with unrelenting pain.
Although many patients have pain relief, a number of patients continue to have pain. In up to 20% of adults, the
pain is as intense as it was before the resection. One third
of these patients have no insulin requirement; another one
third will require low doses of insulin; and the remaining
one third will develop brittle diabetes. Preadolescents are
more likely to be insulin-independent than are older children and adults. Because islet cell yield is the best predictor
of diabetes outcome and the yield decreases in more severe
disease, timing of the operation is important. Unfortunately, no guidelines exist to direct decision-making.
(19)(20)
Pancreatic insufciency is treated with pancreatic enzyme replacement therapy. The goal is to restore digestive function and maintain weight gain and growth.
Because no studies of the effective dose range exist for
patients who have pancreatitis, the recommendations
for treating patients who have cystic brosis are used
for enzyme dosing in patients who have CP.
Complications
Long-term natural history studies are beginning to delineate the prognosis of CP. Contrary to previous teaching,
the pain of CP does not burn out. The pain may vacillate
in intensity and frequency, but it will not resolve with time.
Both pancreatic insufciency and diabetes appear later in
the course. Diabetes may take 2 or 3 decades to become
clinically signicant. Even so, pediatric patients will likely
develop diabetes in their lifetime. Pancreatic cancer is
a long-term risk for all pediatric patients who have CP.
In hereditary pancreatitis, pancreatic cancer appears rst
in the fourth decade (incidence of 0.5%), and the incidence
increases with age. (21) The high probability of pancreatic
cancer is a factor in deciding whether to proceed with total
pancreatectomy and islet cell autotransplant.
Summary
The prevalence of acute pancreatitis is increasing in
pediatrics (based on strong research evidence). (1)
There are etiologic differences between pediatric and
adult patients who develop acute pancreatitis, with
a notable rate of idiopathic cases (based on strong
research evidence). (3)(4)
An elevated amylase or lipase level in the absence of
clinical symptoms or radiologic findings is not
diagnostic of pancreatitis, although pediatric patients
who have pancreatitis may have a wide variety of
presenting clinical symptoms (based on strong
research evidence). (3)(8)
Normal values of amylase and lipase differ among
laboratories.
Successful early feeding is possible in treating acute
pancreatitis and may not necessitate a low-fat diet or
bypass of the ampulla of Vater (based on some
research evidence as well as consensus). (5)(15)
Chronic pancreatitis is a specific diagnosis
characterized by irreversible pancreatic changes and
can be diagnosed only via radiologic and biochemical
evidence, in addition to clinical symptoms (based on
strong research evidence). (16)
References
1. Morinville VD, Barmada MM, Lowe ME. Increasing incidence
of acute pancreatitis at an American pediatric tertiary care center: is
greater awareness among physicians responsible? Pancreas. 2010;39
(1):58
2. Kubisch CH, Logsdon CD. Endoplasmic reticulum stress and
the pancreatic acinar cell. Expert Rev Gastroenterol Hepatol. 2008;2
(2):249260
3. Bai HX, Lowe ME, Husain SZ. What have we learned about
acute pancreatitis in children? J Pediatr Gastroenterol Nutr. 2011;
52(3):262270
4. Lautz TB, Chin AC, Radhakrishnan J. Acute pancreatitis in

children: spectrum of disease and predictors of severity. J Pediatr
Surg. 2011;46(6):11441149
5. Lowe ME, Greer JB. Pancreatitis in children and adolescents.
Curr Gastroenterol Rep. 2008;10(2):128135
6. Sugumar A, Chari ST. Autoimmune pancreatitis. J Gastroenterol
Hepatol. 2011;26(9):13681373
7. Bertin C, Pelletier AL, Vullierme MP, et al. Pancreas divisum is
not a cause of pancreatitis by itself but acts as a partner of genetic
mutations. Am J Gastroenterol. 2012;107(2):311317
8. Kandula L, Lowe ME. Etiology and outcome of acute pancreatitis in infants and toddlers. J Pediatr. 2008;152(1):106110, 110.e1
9. ONeill DE, Saunders MD. Endoscopic ultrasonography in
diseases of the gallbladder. Gastroenterol Clin North Am. 2010
Jun;39(2):289305
10. Yeh BM, Liu PS, Soto JA, Corvera CA, Hussain HK. MR imaging
and CT of the biliary tract. Radiographics. 2009;29(6):16691688
11. Nasr JY, Papachristou GI. Early uid resuscitation in acute
pancreatitis: a lot more than just uids. Clin Gastroenterol Hepatol.
2011;9(8):633634
12. Thompson DR. Narcotic analgesic effects on the sphincter of
Oddi: a review of the data and therapeutic implications in treating
pancreatitis. Am J Gastroenterol. 2001;96(4):12661272
13. Moraes JM, Felga GE, Chebli LA, et al. A full solid diet as the
initial meal in mild acute pancreatitis is safe and result in a shorter
length of hospitalization: results from a prospective, randomized,
controlled, double-blind clinical trial. J Clin Gastroenterol. 2010;44
(7):517522
pancreatitis
14. Jacobson BC, Vander Vliet MB, Hughes MD, Maurer R,

McManus K, Banks PA. A prospective, randomized trial of clear
liquids versus low-fat solid diet as the initial meal in mild acute
pancreatitis. Clin Gastroenterol Hepatol. 2007;5(8):946951,
quiz 886
15. Petrov MS, van Santvoort HC, Besselink MG, Cirkel GA,
Brink MA, Gooszen HG. Oral refeeding after onset of acute
pancreatitis: a review of literature. Am J Gastroenterol. 2007;102
(9):20792084, quiz 2085
16. LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin
Gastroenterol. 2011;27(5):467474
17. Rosendahl J, Landt O, Bernadova J, et al. CFTR, SPINK1,
CTRC and PRSS1 variants in chronic pancreatitis: is the role of
mutated CFTR overestimated [published online ahead of print
March 17, 2012]? Gut.
18. Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic
pancreatitis. Lancet. 2011;377(9772):11841197
19. Schmulewitz N. Total pancreatectomy with autologous islet
cell transplantation in children: making a difference. Clin Gastroenterol Hepatol. 2011;9(9):725726
20. Rodriguez Rilo HL, Ahmad SA, DAlessio D, et al. Total
pancreatectomy and autologous islet cell transplantation as a means
to treat severe chronic pancreatitis. J Gastrointest Surg. 2003;7(8):
978989
21. Howes N, Lerch MM, Greenhalf W, et al. European Registry
of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC).
Clinical and genetic characteristics of hereditary pancreatitis in
Europe. Clin Gastroenterol Hepatol. 2004;2(3):25261
PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. Note: Learners can take Pediatrics in Review quizzes and claim credit

level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. To successfully
complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or
higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.
1. Which of the following scenarios clearly defines a patient with acute pancreatitis?
A. Amylase level two times the upper limit of normal, lipase level two times the upper limit of normal, midepigastric pain, and normal pancreas on abdominal ultrasonography.
B. Elevated lipase level, no symptoms, and pancreatic inflammation on abdominal computed tomography (CT).
C. Amylase level four times the upper limit of normal, lipase level two times the upper limit of normal, midepigastric pain, and normal pancreas on abdominal ultrasonography.
D. Amylase level two times the upper limit of normal, lipase level 1.5 times the upper limit of normal, no
symptoms, and normal pancreas on abdominal CT.
E. Amylase level 1.5 times the upper limit of normal, lipase level two times the upper limit of normal, no
symptoms, and normal pancreas on abdominal CT.
pancreatitis
2. A 10-year-old girl has acute pancreatitis. She was hospitalized yesterday and has been given intravenous fluids
for 24 hours. The girl is feeling better, and her mother would like to know when the girl can begin eating again.
You are most likely to respond that:
A. She can begin eating after 24 hours with no pain.
B. She can eat when her lipase levels have normalized.
C. She should be able to start eating within the next 24 hours.
D. You will order parenteral nutrition before she eats by mouth.
E. You will request nasojejunal tube feedings today.
3. A 16-year-old girl has chronic pancreatitis associated with the cationic trypsinogen (PRSS-1) gene mutation.
She takes narcotic medications to control her abdominal pain and supplements, including pancreatic enzyme
supplements, selenium, and ascorbic acid. Her blood glucose and hemoglobin A1c levels are normal. She has
read that she is at increased risk for pancreatic cancer. You are most likely to respond that she:
A.
B.
C.
D.
E.
Has a small (<10%) lifetime risk of developing pancreatic cancer.

Has decreased risk related because of her adequate insulin production.
Is at small risk for developing pancreatic cancer in her 30s.
Is at the same risk as the general population.
Is only at risk if she has a homozygous gene mutation.
4. A 7-year-old boy has had three episodes of acute pancreatitis. This boys father and paternal grandmother also
have a history of recurrent pancreatitis. The boys grandmother had pancreatic cancer and is deceased. The
boys father takes pain medication daily for chronic pancreatitis. On further testing, the most likely study to
elucidate the etiology of this boys pancreatitis is:
A. Cystic fibrosis transmembrane conductance regulator mutation testing.
B. Endoscopic retrograde cholangiopancreatography.
C. Magnetic resonance cholangiopancreatography.
D. PRSS-1 mutation testing.
E. Serine protease inhibitor Kazal type 1 mutation testing.
5. A 21-year-old man with chronic pancreatitis is in severe pain. He has a PRSS-1 mutation, and his father has
pancreatic cancer. He would like information about surgical treatment. You are most like to tell him that:
A.
B.
C.
D.
E.
He should undergo endoscopic sphincterotomy before considering pancreatectomy.

His life-time risk for diabetes is much higher with the surgery.
His risk for diabetes after pancreatectomy is related to islet cell yield with the procedure.
Pancreatic enzyme function is preserved after pancreatectomy.
The pain from his pancreatitis will resolve after pancreatectomy.
Article
complementary medicine
Complementary, Holistic, and Integrative

Medicine: Acne
Anju Sawni, MD,*
Introduction
Amritpal Singh, MD
Acne vulgaris is a common skin disorder that affects w70% to 87% of adolescents and
young adults. (1) The pathogenesis of acne is multifactorial and complex, and is thought
to be due to androgen-stimulated sebum production. This production leads to follicular
occlusion and hyperkeratinization, with comedo formation, as well as microbial colonization of pilosebaceous follicles by Propionibacterium acnes, leading to inammatory papules
and pustules. Conventional treatments for acne include salicylic acid, benzoyl peroxide, retinoids, and antibiotics (topical and systemic). However, symptoms may not always improve, and patients may have adverse reactions to conventional treatments and thus
seek alternative treatments. Antibiotic resistance in P acnes also has been rising, thus promoting the need to look at alternative therapies. (2)
Author Disclosure
Drs Sawni and Singh
have disclosed no
financial relationships
relevant to this article.
This commentary does
an unapproved/
Dietary and Lifestyle Factors
The inuence of diet on acne has been debated for decades. One review of the literature
looking at the evidence for diet, face washing, and sunlight exposure in acne management
concluded that the evidence is incomplete at best. (3) Another review did not support any
link between acne and foods such as dairy products, chocolate, and fatty foods. (4) However, with more recent focus on diet and nutritional supplements, emerging research suggests that diet may be a factor, particularly in mediating the inammation and oxidative
stress of the acne process. (5)(6)(7)
Western diets, with characteristically high glycemic indices, can elevate insulin and
insulin-like growth factor 1 levels acutely and chronically. (5) These hormones stimulate adrenal and gonadal androgen production, leading to increased sebum production
and acne. Frequent consumption of high-glycemic-index carbohydrates may repeatedly
expose adolescents to acute hyperinsulinemia. Therefore, a low-glycemic-load diet may
have a benecial effect on acne. (6)
A review article by Berra and Rizzo (7) also supported a possible correlation between a high
glycemic diet and acne, and suggested an improvement in acne after glycemic index and glycemic load were reduced. A randomized controlled trial of 43 male patients age 15 to 25 years
found that a low-glycemic-load diet improved acne lesions and reduced weight and BMI. (8)
Weight loss is known to decrease circulating androgen and insulin levels; thus, it was unclear if
improvement in acne was due to the dietary differences, the weight reduction, or both.
A cross-sectional, self-report study of 47,355 nurses revealed that intake of milk during
adolescence was associated with history of teenage acne. (9) The authors also prospectively
examined the effects of milk intake and acne in the children of these nurses and found that
higher milk consumption, regardless of fat content, was associated with acne. (10)(11) The
authors speculated that milk (whole or nonfat) contains hormones and bioactive molecules,
such as androgens, progesterone, and insulin-like growth factor 1, that can have an acnestimulating effect. (12)
These cohort studies, however, can only suggest correlation, not causation. Stress also
has been blamed as a trigger for acne ares. Two independent groups of researchers studied
high school and university students and found that increased
stress levels during examination periods correlated with increased acne severity. (13)(14) The mechanism by which
stress negatively affects acne is unclear, but practicing
mindbody therapies, such as yoga, to reduce stress
may be benecial for patients who have acne as well.
device.
Abbreviations
EFAs: essential fatty acid
LTB4: leukotriene B4
*Pediatric Education, Hurley Childrens Hospital/Hurley Medical Center, Flint, MI.
Department of Dravyaguna (Medicinal Plants), Sri Dhanwantry Ayurvedic College, Chandigarh, India.
Nutritional Supplements and Phytochemicals

Arachidonic acid (omega-6 fatty acid, which is a major
part of a Western diet) is a precursor to the manufacture
of proinammatory leukotriene B4 (LTB4). The involvement of LTB4 in the pathogenesis of acne has been described; a study looking at the administration of a novel
LTB4 blocker found a 70% reduction in inammatory
acne lesions. (15)
The anti-inammatory properties of omega-3 essential
fatty acids (EFAs), including LTB4 inhibition, are well
known. (16) To the best of our knowledge, there are no
studies that have looked at the direct effect of supplementation with omega-3 EFAs on acne, although a diet high
in omega-3 EFAs may have a synergistic effect with a lowglycemic-load diet on improving acne. (6)(17)
Lactoferrin (a whey milk protein/iron-binding protein)
as a dietary supplement also has been shown to decrease
skin inammation due to its broad antibacterial and antiinammatory activities. (18) Two trials, one an open-label,
single-arm study and the other a double-blind, placebocontrolled study, looked at the efcacy and tolerability
of lactoferrin in adolescents and young adults who
had mild to moderate facial acne vulgaris. (19)(20) They
found a signicant reduction in the inammatory acne lesion count in the lactoferrin group. The results suggest
that dietary supplementation with bovine lactoferrin in
mild to moderate acne vulgaris can decrease acne lesions.
Another nutritional supplement called APC (methionine-based zinc complex, chromium, and vitamins with
antioxidants) was studied in an observational pilot study
of 48 patients (age 1535 years) who have acne. The oral
form of this supplement was given thrice daily for 3
months. At the end of treatment (week 12), there was a statistically signicant improvement in the global acne count,
with a decrease in pustules and papules (P < .001). (21)
Resveratrol is a natural compound produced by some
spermatophytes, such as grapes and other plants, that has
been shown to be anti-inammatory and active against
several bacteria, including P acnes. (22) A single-blind pilot study of 20 patients assessed the therapeutic effects of
resveratrol on acne vulgaris. (23) Resveratrol gel was applied daily on the right side of the face for 60 days, compared with a control hydrogel on the left side of the face.
There was a 53.75% mean reduction in the global acne
grading system score on the resveratrol-treated sides of
the face compared with 6.10% on the control sides.
Biochemical Therapies
Few herbal medicines have been evaluated systematically
in clinical trials. Witch hazel (Hamamelis virginiana)
bark has been used to treat acne because of its naturally

astringent properties. (24) To date, no randomized trials
have been conducted to substantiate the use of this agent,
but it is used often in acne products.
Tea Tree Oil

Green tea extract and tea tree oil have been investigated in
the treatment of acne. Tea tree oil is an essential oil of the
native Australian tree Melaleuca alternifolia and has been
shown to have antibacterial and antifungal properties. (25)
A randomized, double-blind, placebo-controlled study investigated the efcacy of 5% topical tea tree oil gel in 60
patients (age 1525 years) who had mild to moderate
acne vulgaris. Total lesion count (TLC) and acne severity
index (ASI) scores were used to determine efcacy of the
treatment. (26) Tea tree oil gel was 3.55 times (for TLC
score) and 5.75 times (for ASI score) more effective than
placebo.
A single-blind, randomized clinical trial of 124 patients
who had mild to moderate acne was conducted to evaluate
the efcacy and skin tolerance of 5% tea tree oil with 5%
benzoyl peroxide lotion. (27) After 3 months of treatment,
both 5% tea tree oil and 5% benzoyl peroxide reduced acne
signicantly, but fewer adverse effects were reported with
the use of tea tree oil (44% vs 79%). The onset of action
was slower, however, in the tree tea oil therapy group.
Green tea has catechins, which are phytochemical phenolic compounds that have anti-inammatory effects. Two
studies assessed the efcacy of topical 2% green tea lotion
(natural plant extract) in the treatment of mild to moderate
acne vulgaris in adolescents and young adults. Topical 2%
green tea lotion was found to be signicantly effective
for mild to moderate acne vulgaris. (26)(28)(29) Several
other natural ingredients, such as colloidal oatmeal, feverfew,
licorice, aloe vera, chamomile, curcumin, soy, coffeeberry,
mushroom extracts, pine bark extract, vitamin E, vitamin
C, and niacinamide, have antioxidant, anti-inammatory,
or moisturizing properties; thus, these ingredients may be
effective adjuncts with other acne therapies to decrease
the erythema associated with inammatory acne. (30)
Ayurvedic Herbs
Two randomized, double-blind, placebo-controlled clinical studies exploring the efcacy of ayurvedic treatment
(a Hindu system of traditional medicine) in acne have
been published. These studies indicate that some ayurvedic remedies might be effective for acne. One study demonstrated that the combination of an oral ayurvedic
preparation and a topical ayurvedic, multicomponent
preparation (cream or gel) was more efcacious in treating acne than oral therapy alone. (31) Another study
found that treatment with an oral preparation of sunder

vati resulted in a signicant reduction in acne lesion count
and was well tolerated. Treatment with three other oral
formulations that were studied failed to show any improvement. (32)
Traditional Chinese Medicine/Acupuncture

A few small studies in adults have looked at the effectiveness of traditional Chinese herbs and acupuncture for the
treatment of acne and found them to be promising.
A double-blind, controlled trial evaluated the efcacy of
ah shi point and general acupuncture point treatment of
acne vulgaris in 36 adults. (33) Ah shi point acupuncture
involves inserting a needle at painful or pathologic sites
(papules and nodules of acne) to directly reduce inammation of the acne site. After 12 treatment sessions, there was
a signicant reduction in the inammatory acne lesion
counts, the scores on a quality of life scale (Skindex-29,
a self-administered questionnaire designed to measure the
effects of skin diseases on patients quality of life), and the
subjective symptom scores from baseline in both groups.
A Chinese herbal compound, compound oldenlandis
mixture, was compared with angelica and sophora root
pills in 120 patients who had acne, and the patients were
found to have 73% improvement in acne lesions. (34) A
meta-analysis evaluated the therapeutic effect and safety
of acne treatment with acupuncture and moxibustion
compared with routine Western medicine. It was concluded that comprehensive acupuncture/moxibustion
was safe and effective, and possibly better than routine
Western medicine, for the treatment of acne. (35)
Light Therapy
Acne therapy using various light sources that target Propionibacterium species seems promising. The development
of infrared nonablative lasers to target sebaceous glands

has resulted in the creation of a number of laser, light,
and radiofrequency devices for acne. The main light
and laser therapies used to treat acne include intense
pulsed light; pulsed dye lasers; and broad-spectrum,
continuous-wave, blue and red visible light. A few studies
have shown some positive results, and light and laser
treatments may be effective and safe for acne, although
more studies are needed. (36)(37)
Summary
Preliminary evidence and small pilot studies, mostly in
young adults, suggest that complementary and
alternative therapies may have some value in the
treatment of acne.
Some emerging data suggest that dietary modification
(in particular, decreasing the glycemic index and
glycemic load), as well as supplementation with
omega-3 essential fatty acids, may be beneficial in
acne management.
A few small pilot studies have reported efficacy of
some herbs and nutritional supplements, traditional
Chinese medicine, ayurvedic herbs, and phototherapy
in the treatment of acne.
More research and larger clinical trials are warranted
in the evaluation of the effectiveness of
complementary therapies in treating acne.
Note: To view the references for this article, visit the February issue at http://pedsinreview.aappublications.org
and click on the Complementary, Holistic, and Integrative Medicine article.
index of suspicion
Case 1: Intermittent Swelling and Arm Pain for 2 Years

in an Adolescent Girl
Case 2: Tender Nodule in Left Mastoid Area of a
7-year-old Girl
Case 1
The reader is encouraged to write
possible diagnoses for each case before
turning to the discussion.
The editors and staff of Pediatrics in

Review find themselves in the
fortunate position of having too many
submissions for the Index of Suspicion
column. Our publication slots for Index
of Suspicion are filled through 2013.
Because we do not think it is fair to
delay publication longer than that, we
have decided not to accept new cases
for the present. We will make an
announcement in Pediatrics in Review
when we resume accepting new cases.
We apologize for having to take this
step, but we wish to be fair to all
authors. We are grateful for your
interest in the journal.
Author Disclosure
Drs Castillo, Flores, Nunez, and
Torralbas have disclosed no financial
relationships relevant to this article.
This commentary does not contain
discussion of unapproved/
investigative use of a commercial
product/device.
Presentation
A 17-year-old girl presents with intermittent right upper extremity swelling and pain over the past 2 years.
Her symptoms began after an episode
of Bells palsy. She describes swelling
and an electrical shooting pain in
the right shoulder that radiates toward her hand, followed by a cool feeling of the hand and decreased range
of motion of the arm. The episodes
occur during both summer and winter
and can last anywhere from 2 to 30
days. Initially, between these episodes,
she regained normal function, but recently has noted residual weakness.
She denies any history of trauma, fever, rash, or muscle weakness.
On examination, there is swelling
of the entire right arm. The nails are
normal. The right arm is colder in
comparison with the left and has decreased hair growth. Peripheral pulses
and capillary rell were normal. Pinprick and temperature sensations are
intact, without hyperesthesia. Range
of motion of the right arm, forearm,
and hand is compromised because of
pain. Except for her right arm, she is
warm, well perfused, and free of joint
swelling. The muscle tone is normal,
and strength in the other muscle
groups is 5/5.
Laboratory studies reveal an erythrocyte sedimentation rate of 15 mm/h,
C-reactive protein <0.5 mg/dL, white
blood cell count of 6.3 to 103/mL, and
creatine phosphokinase level of 100
U/L. The results of additional laboratory studies, including antinuclear
antibody, rheumatoid factor, antibody test for Borrelia burgdorferi,
rapid plasma regain test for syphilis, urine-amplied DNA assay for
Chlamydia and gonorrhea, hemoglobin electrophoresis, serum lactic acid

dehydrogenase level, and uric acid
level, are normal or negative.
Radiographs of cervical spine, chest,
right elbow, forearm, and hand as well
as magnetic resonance imaging (MRI)
of the brain, cervical spine, and entire
arm are normal. Right upper extremity vascular duplex ultrasonography
shows normal ow without evidence
of a deep venous thrombosis.
Case 2
Presentation
A previously healthy 7-year-old Hispanic girl presents with pain behind

the left ear. The mother reports that
3 days ago, while she was combing
her daughters hair, the patient complained of pain, and the mother noticed a red and irritated area behind
the left ear. There has been no fever,
loss of appetite or weight, sick contacts, recent travel, trauma, or animal
contacts. Her family history is noncontributory. Her immunizations are
up to date, and a recent tuberculin test
result was negative.
On physical examination, the girl
is not in acute distress. Her vital signs
are within normal limits. Her weight
and height are both at the 75th percentile for age. In the left mastoid
area there is a 2-cm yellowish-brown
nodule and numerous satellite papules around the primary lesion. The
nodule is tender to palpation. A number of rm and nontender posterior
cervical nodes are palpable bilaterally.
Findings on the rest of the examination are normal.
Laboratory tests, including complete blood count, erythrocyte
index of suspicion
sedimentation rate, and urinalysis, as

well as levels of serum electrolytes,
blood urea nitrogen, creatinine, liver
enzymes, and C-reactive protein are
normal. An imaging study explains
the lesion behind her left ear, and
the histologic ndings of skin, bone,
and lymph node biopsies conrm the
diagnosis.
Case 1
Discussion
This patient was evaluated thoroughly

by consultants from anesthesiology,
neurology, and rheumatology. Her
pain was poorly controlled with morphine. During her hospitalization,
the skin temperature along her right
arm became normal, but she developed hyperesthesia and allodynia
(perception of pain from a nonpainful
stimulus) of her right arm. She also
developed tenderness of the right trapezius muscle. She was unable to
move her ngers because of weakness. Temperature sensation was decreased over the entire surface of the
arm.
After ruling out other possible
causes, such as malignancy, postinfectious reaction, and rheumatologic diseases, it was felt that she
met criteria for complex regional
pain syndrome (CRPS). A trial of
gabapentin and amitriptyline was
begun and her symptoms improved.
Subsequently, she had a nerve block
placed, following which she regained
use of her arm. She has had some
residual weakness, for which she is
receiving physical and occupational
therapy.
The Condition
CRPS type 1, formerly known as reex sympathetic dystrophy syndrome,
is a chronic progressive disease characterized by severe pain, swelling,
and changes in the skin. Current understanding of this condition is that it
is caused by a disruption of the autonomic nervous system. The International Association for the Study of
Pain (IASP) has divided CRPS into
two types based on the detection of
a nerve lesion. Type 1 is not associated with an identiable nerve lesion,
whereas type 2, previously known as
causalgia, presents evidence of obvious nerve damage. It is unclear what
causes the abnormal pain sensations
that typify CRPS, but injury of the
affected body part and stress seem
to play a role.
Most cases of CRPS occur in the
fourth decade after birth. However,
the incidence of CRPS among children is increasing.
Diagnosis
The most widely accepted criteria for
the diagnosis have been published by
IASP (1) and are as follows:
1. The presence of an initiating noxious
event or a cause for immobilization
2. Continuing pain, allodynia, or
hyperalgesia disproportionate to
the inciting event
3. Evidence at some time of edema,
changes in skin blood ow, or abnormal motor activity in the area
of pain
4. Exclusion of the diagnosis by the
existence of any condition that
would otherwise account for the
degree of pain and dysfunction.
Criteria 2 through 4 must be present for the diagnosis.
According to the IASP, the diagnostic criteria for CRPS II (also
known as causalgia) are as follows:
1. The presence of continuing pain,
allodynia, or hyperalgesia after
a nerve injury, not necessarily limited to the distribution of the injured nerve
2. Evidence at some time of edema,
changes in skin blood ow, or
abnormal motor activity in the region of pain

3. Exclusion of the diagnosis by
the existence of any condition that
would otherwise account for the
degree of pain and dysfunction.
All three criteria must be present
to make the diagnosis.
No specic laboratory or imaging
studies are available to establish the
diagnosis of CRPS, and most experts
agree that diagnostic studies are not
necessary to make the diagnosis.
However, the following tests have
been found useful in conrming the
diagnosis:
Three-phase bone scan and gadolinium MRI have been used to diagnose and stage the disease. Although
radiographs can be normal in as
many as 30% of patients, osteoporosis may be demonstrated as early as
3 to 5 weeks after the onset of the
symptoms. Laser Doppler ow studies have been used to monitor background vasomotor control. A cold
pressor test performed in conjunction with thermographic imaging
may demonstrate a vasoconstrictor
response.
Treatment
A number of different treatment modalities are available, including nerve
blockades; medications such as topical analgesics, gabapentin, tricyclic
antidepressants, and corticosteroids;
and psychotherapy. Physical therapy
is an essential and nonnegotiable part
of treatment. It is extremely important to restore normal function of
the affected body part through vigorous and intense physical therapy.
Additionally, tactile stimulation can
reduce the associated pain and swelling signicantly.
Prognosis
The prognosis is good if the condition
is treated early, ideally within the rst 3
index of suspicion
months of onset. Patients may develop

permanent muscle, nerve, and skin
damage if CRPS is not diagnosed
and treated in a timely fashion.
Lessons for the Clinician

CRPS is a diagnosis that sometimes is overlooked but should
be considered if there is intense
and intractable pain, especially in
an isolated area
For most patients, the diagnosis
and treatment are delayed by
months and even years
Early diagnosis and treatment can
prevent long-term damage, such as
muscle atrophy, joint contractures,
and possible permanent loss of function of the affected extremity.
(Rhina Castillo, MD, Josue Flores,
MD, Randolf Nunez, MD, Department of Pediatrics, Lincoln Medical
& Mental Health Center, New York,
NY)
Case 2
Discussion
CT scan of the temporal bones revealed

a destructive soft tissue lesion. The differential diagnosis included a small
round cell tumor, such as neuroblastoma, rhabdomyosarcoma, and lymphoma or leukemia. Langerhans cell
histiocytosis was another consideration.
The patient was referred to the pediatric hematologist/oncologist, who
obtained an MRI of the brain that conrmed the ndings on CT scan. A skeletal survey showed an additional lytic
lesion of the right humeral epiphysis.
Her bone marrow examination yielded
normal results. Findings on biopsy conrmed the diagnosis of Langerhans cell
histiocytosis (LCH) of bone.
The Condition
LCH is a rare disorder that occurs at
any age but most frequently affects
young children. The incidence is
estimated to be 1/200,000 children

younger than 15 years of age. The
name of the disease is derived from
the type of cell involved, which is
the histiocyte. Normal histiocytes
originate from pluripotent stem cells,
which can be found in bone marrow.
Under the inuence of various cytokines, these precursor cells can be
committed to becoming specialized
cells, monocytes, which migrate from
the bloodstream to their various tissue sites and differentiate into macrophages and dendritic cells.
Macrophages are found in loose
connective tissues and some organs
(Kupffer cells of the liver), and
their main function is phagocytosis.
Dendritic cells, which are antigenpresenting cells to T and B lymphocytes, are known as Langerhans cells
in the skin. Histiocytosis, with accumulation and inltration in the affected tissues, is believed to be due
to dysfunction of lymphocytes and
cytokines. The Histiocytosis Society
classies the histiocytic syndromes into dendritic cell-related (Langerhans
cell histiocytosis and juvenile xanthogranuloma) and macrophage-related
(hemophagocytic lymphohistiocytosis,
familial, or primary and acquired)
disorders.
One century has passed since histiocytic disorders were recognized.
In 1987, the Histiocytosis Society
adopted the name LCH and dened
the criteria for diagnosis. Langerhans refers to Dr Paul Langerhans,
who rst described these cells in
the skin. In the past, the condition
was called histiocytosis X, encompassing three clinical conditions: eosinophilic granuloma (a disease that
affects a single part of the body,
eg, bones); Hand-Schuller-Christian
disease (involving bones, pituitary
gland causing diabetes insipidus,
and exophthalmos); and LettererSiwe disease (which affects mainly
newborns and has systemic involvement,
including skin, liver, spleen, lung,

and bone marrow).
Clinical Presentation
The clinical manifestations depend
on the site of the lesions and on the
organs involved. LCH can affect a single organ or multiple organs. Bone
involvement, which can be a single
lesion or multiple lesions, is observed
in 80% of patients. Skull bones are involved in 50% of cases. Symptoms
due to bone involvement are swelling
or lumps on the skull, which can be
painful. Long-bone involvement can
cause fractures.
Cutaneous disease occurs in 50%
of patients, usually during the rst
months after birth, presenting as
papulosquamous, erythematous, petechial patches suggestive of eczema or
seborrheic dermatitis. Lymph node
enlargement is observed in 30% of patient, whereas pulmonary involvement
occurs in 20% to 40% of patients. Respiratory symptoms include cough,
dyspnea, and chest pain due to pneumothorax. Other organs also may
be involved, with hepatic manifestations that include hepatomegaly with
hypoalbuminemia, increased liver enzymes levels, and clotting factor
deciency.
Patients also can present with diarrhea, gingival hypertrophy, ulcers of
the oral mucosa, and discharge from
the ear. Splenic involvement can lead
to hypersplenism. Both hypersplenism
and bone marrow involvement can
cause anemia and thrombocytopenia.
LCH can inltrate various areas of
the brain, resulting in cerebellar dysfunction, seizures, and disruption of
hypothalamic and pituitary function
that can cause diabetes insipidus.
Diagnosis
Laboratory evaluation depends on
the extent of the disease suspected
on the basis of the history and physical ndings. The diagnosis is always
index of suspicion
made on cytologic examination. Regardless of the clinical severity, the

histopathology of LCH generally is
uniform. An electron microscopic
nding of racquet-shaped bodies
(Birbeck granules) in the cells labeled
with anti-CD1a antibodies conrms
the pathologic diagnosis.
CT and MRI imaging are used to
determine the extent of organ system
involvement and can help in staging
the disease.
Treatment and Prognosis

Progress has been made in understanding the pathogenetic mechanisms of LCH, which has helped to
design effective therapy. The goal of
therapy is to relieve clinical symptoms
and prevent complications. Multidisciplinary care is essential for all patients.
For single-system disease, observation
or local therapy only is recommended,
including topical corticosteroids for
skin lesions and curettage if there is localized bone involvement. This recommendation is based on the fact
that 15% to 20% of patients achieve

spontaneous regression when they
have localized disease.
Chemotherapy is recommended for
multisystem disease. A number of combinations of chemotherapeutic agents, including vinblastine, vincristine,
and 6-mercaptopurine as well as corticosteroids, are used for treating
multisystem disease. Radiation therapy is effective for localized disease.
Myeloablative therapy followed by
bone marrow transplantation has been
tried in patients with refractory disease.
Long-term follow-up by a team of
individuals with experience in managing patients with LCH is critical,
because there is a signicant risk of
developing late complications of
the disease or adverse effects of treatment. The extent of organ involvement
and the rapidity of the response to
chemotherapy correlate with the
prognosis.
This patient received a chemotherapeutic regimen which included vinblastine and prednisone after
resection of her bony lesions. She

has responded well to therapy.
Lessons for the Clinician

Because of its diverse clinical presentations, the differential diagnosis of LCH can be extensive.
Timely intervention may decrease
morbidity and mortality and thus
improve prognosis.
(Alfredo Torralbas, MD, Doctors Medical
Center & Miami Children Hospital,
Miami, FL)
Reference
Merskey H, Bogduk N, eds. International
Association for the Study of Pain. Classication of Chronic Pain: Descriptions of
Chronic Pain Syndromes and Denitions
of Pain Terms. Seattle, WA: IASP Press;
1994
To view Suggested Reading lists

for these cases, visit http://pedsinreview.
aappublications.org and click on
the Index of Suspicion link.
Answer Key for February 2013 Issue:

Energy Drinks: 1. B; 2. A; 3. D; 4. B; 5. D
Childhood Brain Tumors: 1. D; 2. C; 3. E; 4. D; 5. D
Pediatric Pancreatitis: 1. C; 2. C; 3. C; 4. D; 5. C
visual diagnosis
A 3-year-old Boy With Sickle

b-Thalassemia and a Groin Mass
Aditi Bagchi, MD,* Ashraf Elnawawi, MD,
Swayam Sadanandan, MD
Presentation
Figure 1. Computed tomography scan reveals a well-circumscribed soft tissue mass in the left groin, w3 cm 3 4 cm in
cross-sectional dimension.
Author Disclosure
Drs Bagchi, Elnawawi, and Sadanandan have disclosed no
financial relationships relevant to this article. This
commentary does not contain discussion of unapproved/
investigative use of a commercial product/device.
A 3-year-old boy with a history of sickle b-thalassemia

presents to the hematology/oncology clinic for evaluation of a mass in his left groin. The childs mother had
noted a small lump in his left inguinal region 2 years
ago. At that time, the pediatrician recommended observing the lump and monitoring any progression. Subsequently, the family moved out of town and did not
seek further medical attention until now. Two weeks
ago, his mother thought the mass had grown in size
and brought him to a nearby hospital for evaluation.
He was prescribed a 5-day course of oral antibiotics
for a presumed local infection. However, there was
no signicant change in the size of the mass; so his
mother brought him to the hematology/oncology clinic.
There is no history of groin pain or erythema, abdominal
pain, fever, weight loss, or change in bowel or bladder
habits. There is no history of trauma.
The child was born at term after an uncomplicated
pregnancy and delivery, but newborn screening indicated
sickle cell disease. On further evaluation, his mother was
found to have b-thalassemia trait and his father had sickle
cell trait. The patient was diagnosed as having sickle
b-thalassemia and placed on penicillin prophylaxis and
folic acid supplementation. Since then, he has had four
hospitalizations for febrile illnesses but no history of documented bacteremia. He has not had any vaso-occlusive crises. His motor milestones are appropriate for age, with the
exception of speech delay.
On physical examination, the child is well nourished
and his vital signs are normal. He appears pale, but there
is no evidence of icterus. Examination of the head, ears,
eyes, and throat shows no abnormalities. He has an enlarged spleen palpable 5 cm below the left costal margin.
No lymph nodes are palpable in the neck, axillae, or right
inguinal region. Palpation of the left groin reveals an 8 cm
5 cm oblong, well-dened mass that extends inferiorly
into the superior aspect of the left scrotum. The left testis
*Resident (PGY-3), Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY.
Attending Physician, Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY.
Associate Chairperson, Department of Pediatrics, Chief, Division of Pediatric Hematology and Oncology, The Brooklyn Hospital Center, Brooklyn, NY.
Pediatrics in Review Vol.34 No.2 February 2013 e5
visual diagnosis
is not palpable; the right testis is palpable and appropriate

in size. The left groin mass is rm, mobile, and nontender
with an irregular contour; it feels like multiple lymph nodes
matted together. There is no overlying skin edema or
erythema. The rest of the physical ndings are normal.
Laboratory examination shows a hemoglobin level of
8.8 g/dL (11.015.6 g/dL), white blood cell count of
8.5 103/mL (4.012.0 103/mL), and platelet count
348 103/mL (130400 103/mL). Mean corpuscular
volume is 76 fL (78.095.0 fL), and reticulocyte count
is 4% (1%2%). Lactate dehydrogenase concentration
is 376 U/L (125243 U/L). Serum electrolyte levels
and liver function test results are normal. Epstein-Barr virus titers are negative. Hemoglobin electrophoresis
shows 4.1% (0%4.0%) hemoglobin A2, 34.3% hemoglobin F (0%5%), and 61.6% hemoglobin S (0%).
Based on physical and laboratory ndings, the patient
is suspected of having either a sclerotic lymph node mass,
a calcied hematoma, a myoma, a lymph node mass with
brotic changes, a benign testicular tumor, or a rare broid tumor such as a calcifying brosing pseudotumor
or spindle cell tumor.
To further distinguish the mass, a computed tomography scan is performed. A well-circumscribed soft tissue
mass, w3 cm 4 cm in cross-sectional dimension (Fig 1)
shows a few punctate calcications (Fig 2). The left testis
is normal. Based on the computed tomography scan ndings, the differential diagnosis is expanded to include
a rhabdomyosarcoma or testicular mass.
An excisional biopsy of the mass is performed (Fig 3).
At surgery, the mass is found to be lobular, rm, and adherent, but separable from the testicle and the scrotum.
The mass also adheres to the oor of the inguinal canal
and is attached medially to the pubic tubercle. The mass
does not appear to invade any surrounding tissue.
Histologic examination reveals the diagnosis.
Figure 2. Computed tomography scan reveals a few punctate
calcifications (arrow) within the mass.
staining with antibodies against factor XIIIa. CD34 antibody staining also showed endothelial cells and localized
broblasts. These ndings were consistent with a calcifying brous pseudotumor (CFP).
Diagnosis: Calcifying Fibrous Pseudotumor

Surgical exploration exposed a rubbery, tan-gray, solid,
well-circumscribed mass that measured 10.0 cm 3.5
cm along its largest diameters.
Microscopic examination revealed adipose tissue inltrated by spindle cells arranged in an irregular fascicular
pattern. Dense hyalinized collagen was marked by inammatory inltration, primarily by lymphocytes and
plasma cells (Fig 4). Eosinophils, neutrophils, and mast
cells were present in variable numbers. Calcications
were dystrophic, ossifying, or psammomatous (Fig 5).
No necrosis, atypia, or mitoses were noted. Immunohistochemically, the spindle cells showed diffuse cytoplasmic
e6 Pediatrics in Review Vol.34 No.2 February 2013
Figure 3. A biopsy is performed on the left-sided groin mass.
visual diagnosis
Figure 4. Microscopy reveals the presence of plasma cells

(arrows) within dense hyalinized matrix.
Discussion
CFP is a rare benign lesion, rst described in 1988 under
the name of childhood brous tumor with psammoma
bodies. (The descriptive term psammoma refers to
a round collection of calcium.) A series of ten cases
was reported in 1993, and the term calcifying brous
pseudotumor was used for the rst time. Initial reports
suggested that these lesions occurred mainly in young
children. However, CFP occurs in almost all age groups.
The reported mean age at presentation is 16.5 years, with
a slight predilection for females. CFP presents typically as
a mass in an otherwise healthy individual. There are rare
case reports of multiple tumors occurring at the same
time. CFP can appear in the soft tissues of the trunk,
limbs, peritoneum, epididymis, neck, pleura, chest wall,
and mediastinum.
The etiology and pathogenesis of this recently described distinctive lesion remain unclear. These lesions
are thought to be reactive, without evidence of any specic cytogenetic abnormality. A possible relationship with
other pseudotumors, such as nodular fasciitis or inammatory myobroblastic tumor (IMT), has been proposed.
IMT describes a spindle cell tumor with a variable inammatory component; its cause is unknown. In a recent publication, CFP was proposed to a burned out or late
sclerosing IMT. However, there are no convincing morphologic or immunophenotypic features that would support the classication of CFP as a burned out IMT.
On gross examination, CFP appears as a well-circumscribed,
tan-gray, solid mass that occasionally entraps neighboring
structures. Histologically, these lesions are characterized
by a proliferation of broblastic spindle cells embedded
in a dense stroma showing variable degrees of mineralization and inammation. Stromal calcication may be
psammomatous or dystrophic in appearance. The amount
of inammation is variable; but, in all cases, the inammatory cells are primarily plasma cells and, to a lesser extent,
lymphocytes. Occasionally, eosinophils and mast cells with
rare reactive giant cells appear. Identication of the spindle
cells in CFP is achieved by diffuse cytoplasmic staining by
antibodies against factor XIIIa and the protein vimentin;
there may be some focal staining for the glycoprotein
CD68.
Differential Diagnosis
CFP can present with inammatory or infectious clinical
features. CFP should be distinguished pathologically
from brous inammatory lesions, bromatosis, other
spindle cell neoplasms, and IMT. In general, IMT has
a higher incidence than CFP and tends to occur in the
retroperitoneal region. Histologically, IMT can vary from
hyalinized, hypocellular area to areas with orid broblastic proliferations that may suggest sarcomas. Calcications are rarely seen.
Management
Gross total surgical excision is the standard treatment
for CFP. Repeat surgical excision is indicated for tumor
recurrence.
Abbreviations:
Figure 5. Microscopy reveals dystrophic calcification (1),
CFP: calcifying brous pseudotumor

IMT: inammatory myobroblastic tumor
dense collagen matrix (2), and psammoma bodies (3).

Pediatrics in Review Vol.34 No.2 February 2013 e7
visual diagnosis
Prognosis
CFP has an excellent prognosis. Recurrence is rare and
usually displays the same morphology as the initial tumor.
has an excellent prognosis, surgical resection is the treatment, and further intervention is unnecessary.
Suggested Reading
Patient Course
The child was discharged from the hospital 3 days after
the surgical excision. He continues to go to the hematology/oncology clinic for his sickle cell disease and so far
has shown no evidence of tumor recurrence.
Summary
A benign, slowly progressive, nontender mass in children
should raise the possibility of CFP or IMT. Punctate calcications within the mass are a unique feature of CFP.
The diagnosis can be conrmed by histology that shows
a dense hyalinized matrix, spindle cells, psammoma bodies, and the absence of markers for smooth muscles. CFP
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Editor-in-Chief: Joseph A.

Zenel, Sioux Falls, SD

Susan Massengill, Charlotte, NC

Publisher: American Academy of Pediatrics

Pediatrics in Review Vol.34 No.2 February 2013

Energy Drinks: What Teenagers (and Their Doctors)

Childhood Brain Tumors

Complementary, Holistic, and Integrative

Case 1: Intermittent Swelling and Arm Pain for

ART CONTEST FOR COVERS

Your favorite thing to do

ENTRY INFORMATION (Please fill in ALL information):

Abstract appears on page 94.

Visual Diagnosis: A 3-year-old Boy With

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Sickle b-Thalassemia and a Groin Mass

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Pediatrics in Review is supported, in part, through an

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Answer key appears on page 98, the last page

Energy Drinks: What Teenagers (and Their Doctors)

After reading this article, readers should be able to:

Pediatrics in Review Vol.34 No.2 February 2013 55

substance abuse energy drinks

Marketing and Advertising

What Is in an Energy Drink?

riboavin, pyridoxine). Caffeine rarely is listed as an ofcial

Some Popular Energy Drinks

Energy Drink Brand

*Does not include amounts of other stimulants such as guarana or

substance abuse energy drinks

Being taken advantage of sexually

Another study of college students showed that energy

Large glass of wine: 3 units

substance abuse energy drinks

sexuality, there is little proof that talking about the issue

of energy drink consumption. By educating themselves,

glucose, caffeine and herbal avouring fractions. Psychopharmacology (Berl). 2004;176(3-4):320330

New Minimum Performance Level Requirements

substance abuse energy drinks

Caffeine in the drinks adversely affects cognition.

62 Pediatrics in Review Vol.34 No.2 February 2013

central nervous system

Childhood Brain Tumors

After completing this article, readers should be able to:

Brain Tumor Classification, Epidemiology, and Pathogenesis

Pediatrics in Review Vol.34 No.2 February 2013 63

central nervous system

Medulloblastoma is derived from tumor stem cells of

central nervous system

and symptoms, should alert the clinician

central nervous system

central nervous system

Signs and Symptoms Associated With

cranial neuropathies that would

Pediatrics in Review Vol.34 No.2 February 2013 67

central nervous system

Key Components of the Neurologic Examination in a Child Who

Pertinent Findings Suggestive of a Tumor

Mental status (level of alertness, speech and language)

Encephalopathy, progressive neurocognitive decline

Cranial nerve 8 (hearing, balance)