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OF 2013 and 2014
Lynn Garfunkel, Rochester, NY Thomas L. Sato, Milwaukee, WI Energy Drinks: What Teenagers (and Their Doctors)
Rani Gereige, Miami, FL
Lindsey Grossman, Springfield, MA
Jacob Hen, Bridgeport, CT
Jeffrey D. Hord, Akron, OH
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55 Should Know
Kwabena L. Blankson, Amy M. Thompson, Dale M. Ahrendt,
PEDIATRICS IN REVIEW
Michael Macknin, Cleveland, OH
Vijayalakshmy Patrick
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Article substance abuse

Energy Drinks: What Teenagers (and Their Doctors)


Should Know
Kwabena L. Blankson, MD,*
Educational Gap
Amy M. Thompson, DO,†
Dale M. Ahrendt, MD,‡ Hundreds of different energy drinks are available and are marketed to adolescents, car-
x rying the potential for substance abuse that involves caffeine and alcohol. Clinicians
Vijayalakshmy Patrick, MD
must be educated to deal with their patients’ use of these products.

Author Disclosure
Objectives After reading this article, readers should be able to:
Drs Blankson,
Thompson, Ahrendt, 1. Understand the size and scope of the energy drink market and recognize common
and Patrick have energy drink brands.
disclosed no financial 2. Know that adolescents are high consumers of energy drinks and use them as
relationships relevant performance enhancers.
to this article. This 3. Know the contents of energy drinks and their adverse effects and safety concerns.
commentary does not 4. Know that energy drinks can be a cause of tachycardia, hypertension, obesity, and
contain a discussion of other medical problems in adolescents.
an unapproved/ 5. Know the dangers of mixing energy drinks with alcohol.
investigative use of 6. Understand the relationship between caffeine tolerance/dependence and alcohol
a commercial product/ tolerance/dependence.
device. 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, enhanc-
ing 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, benefits, 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 stu-
dents in Washington State were hospitalized and one almost died; their illness was attributed
to a fruit-flavored, caffeinated alcoholic drink. A month earlier, on a college campus in New
Jersey, 23 students were hospitalized after becoming intoxicated, again reportedly after drink-
ing the same product. Both campuses have since banned this caffeinated alcoholic beverage.
Shortly thereafter, Washington State Attorney General Rob McKenna reflected, “It's
time to bring an end to the sale of alcoholic energy drinks. They're marketed to kids by
using fruit flavors 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 Administra-
tion (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 first step, but it may do little to curb the practice of mixing energy
drinks and alcohol, a fixture 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 riboflavin, pyridoxine). Caffeine rarely is listed as an official


Energy drinks were first introduced in the late 1980s. ingredient, although all of the top-selling energy drinks con-
Presently, the energy drink market brings in upward of tain caffeine. Many of them do not state the quantities of
$5 billion a year, with >200 new brands introduced into caffeineor other ingredients, shieldingthisinformation under
the United States market in 2006. The market's leading the tag “proprietary blend.” When caffeine content is stated,
drink accounted for almost 49% of the revenue. often the amount given is not accurate. The FDA regulates
The US energy drink market has grown to its current the amount of caffeine in cola beverages. Energy drinks
size by being focused predominantly on adolescents. One and cold coffee beverages do not fall under the same jurisdic-
leading market research company found that teens in- tion. One of the reasons is that caffeine is a substance generally
creased their energy drink consumption by 16% from recognized as safe by the FDA, even though the FDA does
2003 to 2008, with 35% of teenagers regularly consum- regulate the sale of over-the-counter caffeine-containing
ing energy drinks. In one study of energy drink consump- drugs, one of which contains 100 to 200 mg of caffeine.
tion among college students, 50% consumed at least one A 6.5-oz cup of coffee, depending on how it is brewed,
to four drinks per month. (1) Reasons for drinking in- contains 80 to 120 mg of caffeine. A cup of tea contains
cluded inadequate amount of sleep, need for energy, approximately 50 mg of caffeine. And a 12-oz cola bever-
and wanting to mix with alcohol. Although one drink age by law cannot contain more than 65 mg of caffeine.
was sufficient to meet most needs, those who mixed with Even the carbonated fountain sodas sold at fast-food estab-
alcohol often consumed three or more energy drinks. Al- lishments and gas stations contain less than 49 mg of caf-
most one in three reported weekly “jolt/crash” episodes, feine per 16-oz serving. (5)
including headaches and palpitations. (1) The Table names some top-selling energy drinks,
Energy drinks are marketed to adolescents, specifically pointing out the volume in each.
males. Energy drink manufacturers allocate a significant The caffeine in 16 oz of leading energy drink brands
amount of marketing resources to sports sponsorships, ranges from 154 to 280 mg (the equivalent of two to
which include soccer teams, automobile racing teams, three cups of coffee). Some energy drinks contain 500
and extreme sports athletes. In a survey of almost 800 col- mg or more in a single can. Some of the drinks contain
lege students, 39% drank energy drinks in the past month other stimulants, such as guarana, or additives that can
(males more than females), and “jock identity” was asso- enhance the effects of caffeine. Several Internet sites pro-
ciated positively with frequency of energy drink (and en- vide specific information about caffeine content.
ergy drink mixed with alcohol) consumption. (2)(3) There is not a recommended daily allowance for caf-
Over the 3-year period spanning 2007–2009, although feine, but the American Dietetic Association posits that
Americans were huge consumers of energy drinks, the en- women of reproductive age and children should consume
ergy drink market penetration held flat at 15% of all adults no more than 300 mg of caffeine per day (two to three
aged 18 and older. Energy drink nonusers cited high prices cups of coffee). (5) Caffeine use and withdrawal have
(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.
Table. Some Popular Energy Drinks
This attitude is forcing the energy drink manufacturers Caffeine*
to come up with new strategies, such as targeting women, Energy Drink Brand Oz per Can (total mg)
herb and vitamin enthusiasts, the affluent, and youth. (4)
Red BullÔ 16 154
Energy drinks showing a “low, no, or reduced” calorie Monster Energy AssaultÔ 16 160
claim have increased from 6% to 11% between 2004 Monster Energy XXLÔ 24 240
and 2008. Major soft drink manufacturers have begun in- RockstarÔ 16 160
jecting their own “energy drinks” into the market or are Amp Energy-LightningÔ 16 160
Full ThrottleÔ 16 144
becoming distributors, further blurring the lines between
Wired X505Ô 24 505
regular carbonated soda and caffeinated energy drinks. CocaineÔa 8.4 280
*Does not include amounts of other stimulants such as guarana or
additives that can enhance the effects of caffeine. Note the variability in
What Is in an Energy Drink? how many mg of caffeine are present in 1 oz or 1 can.
Caffeine Visit http://www.energyfiend.com/the-caffeine-database for others.
a
Briefly banned in 2007, renamed “No-name,” now available again in
Most energy drinks contain the same basic ingredients: United States except in Texas under original name.
guarana, taurine, ginseng, sugars, and B vitamins (ie,

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


substance abuse energy drinks

been linked to a variety of health effects, including irrita- caffeine despite physical or psychological problems asso-
bility, anxiety, mental confusion, hand and limb tremor, ciated with caffeine use. The caffeine intake in these daily
osteoporosis, digestive problems, nausea, insomnia and users was only two to three cups of coffee. (6)
sleepiness, urinary frequency, headache, palpitations, ar- In this same study, adolescents who met criteria for mar-
rhythmias, and elevated blood pressure. (6) ijuana dependence (or any other drug abuse or dependence)
Associations have been shown between caffeine con- consumed significantly more caffeine than those not depen-
sumption and premature birth, miscarriage, fetal growth dent on marijuana or other drugs. Young adolescents are at
retardation, and decreased birthweight. Withdrawal symp- risk; a survey of over 5,000 seventh graders showed that
toms have been reported in school-age children who drank those possessing high caffeine risk (ie, consuming more than
as little as 120 to 145 mg per day (one to two cups of cof- six cups of coffee in the previous month) were more likely to
fee or three to five sodas) over a 2-week period. (7) use tobacco or alcohol by 1-year follow-up. (6)
Cardiovascular effects as a result of heavy caffeine use With alcohol use, the intensity of response diminishes
can be a significant source of morbidity in athletes. Hyper- with repeated administration, leading to tolerance. Higher
tension and palpitations in the adolescent athlete often doses of alcohol may be needed to attain the initial effect,
lead to extensive medical evaluations. The diuretic effect planting the seeds of abuse and dependence. Caffeine may
of high levels of caffeine could lead to dehydration in ath- work in the same fashion, and there is evidence that
letes who do not drink enough fluids to compensate. combining alcohol and caffeine increases alcohol toler-
Although the World Anti-Doping Agency (WADA) re- ance in comparison with exposures to either drug
moved caffeine from its list of banned substances in 2004, alone, which is sobering evidence, given observations
it is reconsidering its ban on caffeine given a recent adverse of adolescents mixing energy drinks with alcohol. (11)
outcome in an Australian football league athlete. Athletes
in the league routinely take as many as six caffeine tablets as Guarana
a game-day stimulant, and then take a sleeping pill to Guarana, also known as Brazilian cocoa, is a South Amer-
“come down.” A star player in the league was rushed to ican plant that is commonly added to energy drinks. It con-
the hospital with complications following ingestion of this tains a substance called guaranine, which is caffeine, with 1
pill cocktail. Although WADA has not officially banned it g of guarana being equivalent to as much as 40 mg of caf-
for Olympic athletes, caffeine is well-recognized as an er- feine. (12) Of note, when an energy drink lists its caffeine
gogenic aid or a performance enhancer, (8) and it remains content, it is usually not taking into account the guarana,
on WADA’s closely monitored drug list. which has been reported to exert a more prolonged effect
The National Collegiate Athletic Association consid- than an equivalent amount of caffeine. In reality, when
ers caffeine illegal if found in quantities in the urine that a drink is said to contain caffeine plus guarana, it contains
approximate five to eight cups of coffee consumed in 1 caffeine plus more caffeine. Guarana has not been evalu-
hour. Depending on the brand, that is the equivalent ated by the FDA for safety, effectiveness, or purity. All po-
of as few as one to three energy drinks. tential risks and advantages of guarana may not be known.
Caffeine usage patterns have been studied not only in
adolescent athletes, but also in the general teenage pop- Sugars
ulation. One study of high school students revealed that Most energy drinks contain sugars in the form of sucrose,
95% consumed caffeine, most of it coming from sodas. glucose, or high fructose corn syrup, with the sugar content
Their first consumption of the day was in the evening. varying from 21 to 34 g per 8 oz. Some adult studies have
Those who drank more coffee expected dependence shown that glucose combined with caffeine can synergisti-
symptoms and energy enhancement from caffeine and cally enhance athletic and cognitive performance. (13)(14)
also reported more daytime sleepiness and use of caffeine One study showed that one specific drink improved perfor-
to get through the day. (9) mance in a range of mental and physical measures. (15)
Studies of depressed youth show that they use more The amount of glucose in energy drinks is similar to
caffeine than nondepressed youth, and caffeine likely that found in sodas and fruit drinks. Users who consume
exacerbates daily anxiety. (10) In another study, daily two to three energy drinks could be taking in 120 to 180
caffeine use was associated with dependence in some mg of sugar, which is 4 to 6 times the maximum recom-
adolescents. The teens actually met Diagnostic and Sta- mended daily intake, according to US Department of Ag-
tistical Manual – IV criteria for dependence because they riculture dietary guidelines. Adolescents who consume
experienced tolerance, withdrawal, persistent desire, or energy drinks in abundance may be at risk for obesity
unsuccessful efforts to control use, and reported drinking and dental health problems as a result of high sugar intake.

Pediatrics in Review Vol.34 No.2 February 2013 57


substance abuse energy drinks

Taurine engaged in athletics, or members of fraternities or soror-


Taurine is one of the most abundant amino acids in ities. Those who consumed alcohol mixed with energy
the human body, and it is one of the most common ingre- drinks (in comparison with those who consumed alcohol
dients in energy drinks. The human body can manufacture alone) had a significantly higher prevalence of alcohol-
taurine on its own from other amino acids, although in- related consequences including:
fants and sick adults must get it from their diet or supple-
• Being taken advantage of sexually
ments. Taurine is present in meat, seafood, and milk, and is
• Taking advantage of another sexually
purported to have beneficial physiologic effects. Most of
• Riding in a car with a driver under the influence of alcohol
these effects cannot be attributed to taurine alone, because
• Being hurt or injured
it was mixed with caffeine and other substances.
• Requiring medical treatment
The amount of taurine consumed by regular intake
of energy drinks far exceeds the amount in a normal diet Another study of college students showed that energy
(40–400 mg/day), although there is limited evidence of drink users (in comparison with nonusers) had heavier al-
adverse events from taurine use. (12) Some data from an- cohol consumption patterns and were more likely to have
imal models suggest that taurine might minimize some of used other drugs (such as marijuana and prescription
the adverse effects of alcohol consumption and could, by drugs), both concurrently and in the year preceding as-
extension, encourage greater alcohol consumption. (16) sessment. (18)
From the bold, colorful cans, to the edgy names, en-
Ginseng ergy drinks are marketed in a language teenagers know
Ginseng is a root most commonly found in East Asia. It well. Sales messaging for a popular energy drink includes
has been claimed that ginseng improves athletic perfor- references to “house parties” and “jungle juice,” the latter
mance, stimulates the immune system, and improves being a term for various improvised alcoholic beverages;
mood. Ginseng has been linked to adverse events such both allusions have strong associations with underage
as insomnia, palpitations, tachycardia, hypertension, binge drinking.
edema, headache, vertigo, mania, and estrogen-like ef- Some of the most popular energy drinks are manufac-
fects, such as breast tenderness and amenorrhea. Many tured already mixed with alcohol. These alcohol-containing
energy drinks do not contain therapeutic doses of gin- energy drinks share close resemblance to their non–
seng (100–200 mg/day), with a user needing to drink alcohol-containing counterparts. And, in most cases,
two to four cans of an energy drink to get even the lowest the alcohol-containing spinoff is less expensive. Energy
therapeutic dose. (17) There is little scientific evidence drink manufacturers may be blurring the lines between
that ginseng improves physical performance significantly. their drinks and alcoholic beverages, and the teenage con-
sumer might experience brand confusion.
Other Additives How much alcohol is in an alcohol-containing energy
A host of other additives (eg, B vitamins, glucuronolac- drink? The alcohol by volume (ABV) determination is
tone, Yohimbe, carnitine, and bitter orange) purport to one measure of the amount of alcohol in a beverage. The
have a bevy of positive effects on consumers. Most of the ABV content of one 23.5-oz can of a popular alcohol-
claims about these ingredients, such as that they reduce containing energy drink is 12%. The ABV content of a
cancer risk, improve sexual performance, and prevent di- domestic 12-oz beer ranges from 4.2% to 5%. The ABV
abetes, lack sufficient scientific evidence. The quantities of a standard wine bottle is approximately 12%.
of these ingredients found in energy drinks often are The strength of an alcoholic beverage is best under-
sub- or supratherapeutic, with doses so low or so high stood in terms of units of alcohol, when ABV and the vol-
that no one knows what effect they have on the human ume of the drink are known. One unit of alcohol is the
body. Even taking into account some of the known phys- amount of alcohol that an average healthy adult can me-
iologic benefits, little is known about the effects of daily tabolize in 1 hour. A unit of alcohol can be calculated
consumption of energy drinks on long-term health. with a simple formula:

Alcohol ðABV=1; 000Þ   amount  ðmillilitersÞ 


In a recent survey of ten universities in North Carolina, ¼  strength  of   drink  ðin  units  of   alcoholÞ
one-fourth of college students had consumed energy
drinks mixed with alcohol in the past month. (4) These The number of units of alcohol in different alcoholic
students were more likely to be younger, white, male, beverages is as follows:

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


substance abuse energy drinks

Large glass of wine: 3 units do you?” may not facilitate open discussion with the teen-
12-oz can of beer: 1.75 units age patient.
Single shot of liquor (whisky, rum, vodka): approxi- The HEEADSSS interview (Home, Education, Eat-
mately 1 unit ing, Activities, Drugs/Alcohol abuse, Sexual activity,
Safety, Suicide/Depression) provides an easy method
In the case of one popular alcohol-containing energy
and effective tool for examining the important spheres
drink, the determination of units of alcohol is as follows:
of adolescence that affect health and well-being. (21) Un-
(12% ABV/1,000) × 695 mL (w23.5 oz) = 8.3 units.
der the E, many clinicians address education, eating, and
Thus, a can of this drink has essentially the same strength
exercise, with sleep going hand-in-hand with these issues.
as an entire bottle of wine (9 units); with its estimated
During this interview would also be a perfect time to
500 mg of caffeine, consuming it is comparable to drink-
ask about energy drink use, either to stay up late to study,
ing almost a 6-pack of beer plus five cups of coffee. Other
to get going in the morning, or to enhance athletic per-
23.5-oz caffeinated alcoholic beverages range between
formance. Under the D, providers should ask about drug
6.5% ABV and 12% ABV. Thus, drinking two to three
use, caffeine intake, and energy drinks, because studies
of these drinks at a party could amount to drinking
have shown a connection between heavy caffeine use
two to three bottles of wine/6 packs of beer, and 10
and illicit substance use. The interviewer also can ask
to 15 cups of coffee.
about alcohol use, segueing into specific questions on al-
Mixing these caffeinated alcoholic beverages with ad-
cohol mixed with energy drinks, based on a positive re-
ditional alcohol, as was done by the nine college students
sponse. An opportunity for education might present
in Washington State, could be especially dangerous,
itself; we suspect many teens will have no idea how much
given their already high alcohol content. This practice
alcohol and caffeine they are consuming when they ingest
demonstrates either a poor understanding of the amount
these energy drinks.
of alcohol in the mixed beverage or a disregard of the
The CRAFFT pneumonic has been validated as an ap-
danger altogether.
propriate screening tool for substance abuse in adoles-
Adolescents who combine energy drinks with alcohol
cents. (22) It is a series of six questions developed to
perceive less of an effect from alcohol. (19)(20) For ex-
screen adolescents for high-risk alcohol and other drug
ample, one study noted that young adults who consumed
use disorders. Have you ever ridden in a CAR driven
energy drinks with alcohol felt fewer symptoms such as
by yourself or someone who had been using alcohol or
headache, weakness, and impaired muscular coordina-
drugs? Do you ever use alcohol/drugs to RELAX, feel
tion. (19) But these participants still were impaired in
better about yourself, or fit in? Do you ever use alco-
terms of motor coordination and visual reaction time.
hol/drugs while you are ALONE? Do you ever FORGET
The study by O’Brien reported that 15% of adolescents
things you did while using alcohol/drugs? Do your fam-
mixed energy drinks with alcohol “to drink more and
ily or FRIENDS ever tell you that you should cut down
not feel as drunk,” and 5% of teens “did not want to look
on your drinking/drug use? Have you gotten into
as drunk.” (4)
TROUBLE while you were using alcohol/drugs? Add-
Thus, there is the grave danger that adolescents may
ing energy drinks mixed with alcohol to the questioning
feel unimpaired, when they are just as impaired as a person
could be useful.
with the same blood alcohol level, and subsequently may
College student drinkers who report mixing alcohol
drink much more than they intended to and attempt to
with energy drinks are at increased risk for alcohol-related
drive themselves and others home. One high-potency
consequences. Of great concern, students who report con-
drink might provide the rush of five cups of coffee; but
suming energy drinks mixed with alcohol were more than
the sobering reality is that the adolescent is now, as
twice as likely to ride in a car with an intoxicated driver. (4)
one school official stated, “a wide-awake drunk.”
Because teenagers who consume alcohol mixed with en-
ergy drinks underestimate their degree of intoxication, it
Discussion is critical to educate all teens properly, as both drivers
Clinician Intervention and passengers. If the person driving a teenager home says
What can the medical provider do? First and foremost, as he is sober but has been drinking alcohol mixed with en-
with any other sensitive issue in the adolescent patient, ergy drinks, the teen passenger can assume the driver may
the clinician must ask in the first place whether energy be gauging his level of sobriety inaccurately.
drinks are being consumed. How the question is asked Clinicians should not be shy about bringing up this
is equally important. “You don’t drink energy drinks, issue with their teenage patients. As with discussing

Pediatrics in Review Vol.34 No.2 February 2013 59


substance abuse energy drinks

sexuality, there is little proof that talking about the issue of energy drink consumption. By educating themselves,
will encourage dangerous activity or behavior. Rather, adolescents, and parents about the potentially dangerous
education should be protective. Teenagers already know consequences of energy drink consumption, pediatri-
about mixing energy drinks with alcohol; adults (and spe- cians may prevent unnecessary evaluation of symptoms
cifically primary care providers) need more education. due to energy drink effects and halt the needless hospi-
Some college students, in the wake of the ban of a popular talization of young adults who mix energy drinks with
alcohol-mixed energy drink, proceeded to stock up, while alcohol.
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 pop-
ular website describing over 200 alcoholic beverages that Summary
call for energy drinks as an ingredient.
Clinicians can apply the concepts of motivational in- • The energy drink industry has successfully marketed
their products to adolescents.
terviewing in their discussions of energy drink consump-
• There is great concern over the safety and negative
tion. A discussion of motivational interviewing with video health effects of energy drinks, given their high
can be found in Pediatrics in Review (Barnes AJ, Gold caffeine content and the common practice
MA. Promoting Healthy Behaviors in Pediatrics: Motiva- on college campuses of mixing energy drinks with
tional Interviewing. Pediatr Rev. 2012;33(9):e57–e68). alcohol.
• Knowledge about the safety of energy drinks in the
[www.pedsinreview.org/content/33/9/e57.full].
adolescent population is lacking.
• Caffeine use is associated with a variety of health
Education effects, such as palpitations, anxiety, insomnia,
Pediatricians should discuss energy drink consumption digestive problems, elevated blood pressure,
with their adolescent patients. (23) Evidence suggests that dehydration, and more. Caffeine is the major ingredient
in most energy drinks, but none of the drinks
energy drinks may provide some therapeutic benefit (in-
state its exact caffeine content and these products
creased wakefulness, focus, performance-enhanced exer- are not FDA-regulated. Top-selling energy drinks
cise). But given the unknown levels of caffeine and may contain the equivalent of two or three cups of
other poorly studied additives, there is significant risk as- coffee and more caffeine than FDA-regulated alertness
sociated with energy drink consumption that may out- pills.
• Heavy energy drink consumption can cause significant
weigh the benefits in the adolescent consumer.
morbidity in adolescents that often leads to extensive
Energy drinks contain high, unregulated amounts of medical evaluations.
caffeine that may lead to significant morbidity in adoles- • Recent news reports about events on college campuses
cents (cardiovascular effects, withdrawal symptoms, mixing remind us that adolescents frequently combine energy
with alcohol, association with substance dependence). drinks and alcohol, but many young people fail to
appreciate the strength of an alcohol-mixed energy
Additives such as guarana, ginseng, taurine, carnitine,
drink. A can of a caffeinated alcoholic beverage may be
and bitter orange are not regulated by the FDA, and equivalent to drinking a bottle of wine and a few cups of
their short- and long-term side effects are incompletely coffee. Consuming more than one of these drinks (or
understood. mixing them with additional alcohol) can be very
Little is known about potential negative interactions dangerous.
• One-quarter of college student drinkers report
between energy drinks and common medications taken
mixing energy drinks with alcohol and are at increased
by adolescents, such as stimulants, antidepressants, and risk for alcohol-related consequences. As clinicians, we
atypical antipsychotics, and there are case reports of en- must be aware of this behavior and educate teens
ergy drink consumption associated with new-onset seiz- properly.
ures and manic episodes. (17) When mixed with alcohol, • The HEADSSS interview provides an easy method for
examining the spheres of adolescence that affect
energy drinks present serious potential for harm and
overall health. This interview is a perfect avenue for
abuse. In-office counseling on daily exercise, early bed- asking about energy drinks and alcohol-mixed energy
time, and healthy dieting appropriately addresses some drinks, assessing risk-taking behaviors, and providing
of the goals that underlie the reasons why adolescents counseling.
choose to consume energy drinks. • CRAFFT is an excellent screening tool for substance
use and abuse and another avenue for assessing
Primary care clinicians should be aware that abnormal
energy drink abuse (mixing energy drinks with
vital signs (tachycardia, hypertension), insomnia, anx- alcohol).
iety, palpitations, and headache are all potential effects

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


substance abuse energy drinks

References glucose, caffeine and herbal flavouring fractions. Psychopharmacol-


1. Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, ogy (Berl). 2004;176(3-4):320–330
Barber-Heidal K. A survey of energy drink consumption patterns 14. Rao A, Hu H, Nobre AC. The effects of combined caffeine and
among college students. Nutr J. 2007;6(6):35 glucose drinks on attention in the human brain. Nutr Neurosci.
2. Miller KE. Wired: energy drinks, jock identity, masculine norms, 2005;8(3):141–153
and risk taking. J Am Coll Health. 2008;56(5):481–489 15. Alford C, Cox H, Wescott R. The effects of red bull energy
3. Miller KE. Energy drinks, race, and problem behaviors among drink on human performance and mood. Amino Acids. 2001;21(2):
college students. J Adolesc Health. 2008;43(5):490–497 139–150
4. O’Brien MC, McCoy TP, Rhodes SD, Wagoner A, Wolfson M. 16. Quertemont E, Lallemand F, Colombo G, De Witte P. Taurine
Caffeinated cocktails: energy drink consumption, high-risk drink- and ethanol preference: a microdialysis study using Sardinian
ing, and alcohol-related consequences among college students. alcohol-preferring and non-preferring rats. Eur Neuropsychophar-
Acad Emerg Med. 2008;15(5):453–460 macol. 2000;10(5):377–383
5. McCusker RR, Goldberger BA, Cone EJ. Caffeine content of 17. Clauson KA, Shields KM, McQueen CE, Persad N. Safety
energy drinks, carbonated sodas, and other beverages. J Anal issues associated with commercially available energy drinks. J Am
Toxicol. 2006;30(2):112–114 Pharm Assoc (2003). 2008;48(3):e55–e63, quiz e64–e67
6. Bernstein GA, Carroll ME, Thuras PD, Cosgrove KP, Roth ME. 18. Arria AM, Caldeira KM, Kasperski SJ, et al. Increased alcohol
Caffeine dependence in teenagers. Drug Alcohol Depend. 2002;66(1): consumption, nonmedical prescription drug use, and illicit drug use
1–6 are associated with energy drink consumption among college
7. Bernstein GA, Carroll ME, Dean NW, Crosby RD, Perwien AR, students. J Addict Med. 2010;4(2):74–80
Benowitz NL. Caffeine withdrawal in normal school-age children. 19. Ferreira SE, de Mello MT, Pompéia S, de Souza-Formigoni
J Am Acad Child Adolesc Psychiatry. 1998;37(8):858–865 ML. Effects of energy drink ingestion on alcohol intoxication.
8. Ahrendt DM. Ergogenic aids: counseling the athlete. Am Fam Alcohol Clin Exp Res. 2006;30(4):598–605
Physician. 2001;63(5):913–922 20. Marczinski CA, Fillmore MT. Clubgoers and their trendy
9. Bryant Ludden A, Wolfson AR. Understanding adolescent cocktails: implications of mixing caffeine into alcohol on informa-
caffeine use: connecting use patterns with expectancies, reasons, tion processing and subjective reports of intoxication. Exp Clin
and sleep. Health Educ Behav. 2010;37(3):330–342 Psychopharmacol. 2006;14(4):450–458
10. Whalen DJ, Silk JS, Semel M, et al. Caffeine consumption, 21. Goldenring J, Rosen D. Getting into adolescent heads: an
sleep, and affect in the natural environments of depressed youth and essential update. Contemp Pediatr. 2004;21(1):64–90
healthy controls. J Pediatr Psychol. 2008;33(4):358–367 22. Knight JR, Sherritt L, Shrier LA, Harris SK, Chang G.
11. Fillmore MT. Alcohol tolerance in humans is enhanced by Validity of the CRAFFT substance abuse screening test among
prior caffeine antagonism of alcohol-induced impairment. Exp Clin adolescent clinic patients. Arch Pediatr Adolesc Med. 2002;156
Psychopharmacol. 2003;11(1):9–17 (6):607–614
12. Finnegan D. The health effects of stimulant drinks. Nutr Bull. 23. Committee on Nutrition and the Council on Sports Medicine
2003;28:147–155 and Fitness. Sports drinks and energy drinks for children and
13. Scholey AB, Kennedy DO. Cognitive and physiological effects adolescents: are they appropriate? Pediatrics. 2011;127(6):1182–
of an “energy drink”: an evaluation of the whole drink and of 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 boy’s
symptoms are most likely related to ingestion of:
A. Alcohol.
B. Caffeine.

Pediatrics in Review Vol.34 No.2 February 2013 61


substance abuse energy drinks

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 boy’s 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 performance-
enhancing 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 nephew’s 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. Caffeine in the drinks adversely affects cognition.
B. Ingestion of the drinks is associated with hypertension in athletes.
C. Only benefit to the drinks is improved hydration.
D. Team’s performance will likely be impaired by the energy drinks.
E. 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.

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


Article central nervous system

Childhood Brain Tumors


John Crawford, MD, MS*
Educational Gap
Brain tumors are the most common solid tumor of childhood and the No. 1 cause of death
Author Disclosure among all childhood cancers. The pediatrician is pivotal in both the diagnosis and long-
Dr Crawford has term management of brain tumors. A lack of awareness of the clinical signs and symp-
disclosed no financial toms of brain tumors may delay diagnosis and worsen patient outcomes.
relationships relevant
to this article. This
Objectives After completing this article, readers should be able to:
commentary does
contain a discussion of 1. Recognize the presenting signs of brain tumor (eg, headache, deteriorating school
an unapproved/ performance, ataxia, emesis).
investigative use of 2. Recognize the signs and symptoms of craniopharyngioma.
a commercial product/
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 five 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 tu-
mors. This primary care–focused review will offer a practical overview of childhood brain tu-
mors, including diagnosis, classification, management, and both early and late effects. Potential
late effects of therapy include neurocognitive deficits, endocrinopathies, vasculopathies, and de-
velopment 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 classification of primary brain tumors is based on histologic criteria presented by
the World Health Organization (WHO). (3) Brain tumors are broadly classified according to
the cell of origin and most commonly are neuroepithelial de-
rived. WHO classification categories of primary brain tumors
include tumors of the neuroepithelium, cranial nerves, menin-
Abbreviations ges, and sella, as well as those of hematopoietic and germ cell
CNS: central nervous system origin.
CSF: cerebrospinal fluid Among the neuroepithelial tumors, gliomas are the most
CT: computed tomography common brain tumors of childhood, occurring at an incidence
MRI: magnetic resonance imaging of 1.16 per 100,000 person-years. (1) Gliomas are astrocyte-
NF-1: neurofibromatosis type 1 derived tumors and are graded 1 through 4, according to
NF-2: neurofibromatosis type 2 increasing degree of aggressiveness. Juvenile pilocytic astrocy-
WHO: World Health Organization toma and diffuse fibrillary astrocytoma represent the majority of
low-grade gliomas (WHO grades I and II), whereas anaplastic

*University of California San Diego and Rady Children’s Hospital, San Diego, CA.

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


central nervous system brain tumors

astrocytoma and glioblastoma multiforme represent the ma- Medulloblastoma is derived from tumor stem cells of
lignant variants (WHO grades III and IV). the external granular layer of the cerebellum and can be
Although there is no histologic distinction between categorized according to distinct histologic variants (clas-
adult and pediatric gliomas, there are striking differences sic, nodular desmoplastic, and anaplastic large-cell). Re-
in their epidemiology. Glioblastoma multiforme represents cent studies have divided medulloblastoma into distinct
the most common glioma of adulthood (3.19 per 100,000 molecular subgroups that can potentially be used to pre-
person-years), whereas juvenile pilocytic astrocytoma is the dict survival and provide risk-adapted therapies. (4)(5)
most common glioma of childhood (0.8 per 100,000 per- A histopathologic and neuroradiographic mimicker of
son-years). (1) medulloblastoma, the atypical teratoid rhabdoid tumor is
Three commonly encountered neurogenetic syndromes a highly malignant tumor related to the rhabdoid tumor
diagnosed in childhood (neurofibromatosis type 1 [NF-1], of the kidney that most often occurs in children age youn-
neurofibromatosis type 2 [NF-2], and tuberous sclerosis) ger than 2 years. (6) Atypical teratoid rhabdoid tumor is
have a predisposition for low-grade glioma formation categorized molecularly by a mutation/deletion of the
based on their respective genetic mutations. In the case hSNF5/INI-1 gene on chromosome 22q11.2 and can oc-
of NF-1, children may develop low-grade gliomas of the cur outside of the CNS in the kidney and soft tissues.
optic pathway, cerebrum, cerebellum, and spinal cord. Atypical teratoid rhabdoid tumors can occur in both infra-
Children who have NF-2 are also at risk for glioma forma- tentorial and supratentorial locations. The diagnosis is con-
tion but more commonly develop meningiomas, ependy- firmed by an immunohistochemical lack of INI-1 protein
momas, and acoustic schwannomas. Children who have expression that distinguishes it from the histologically
tuberous sclerosis may develop subependymal giant cell as- similar medulloblastoma. The distinction between medullo-
trocytomas (WHO grade I) that can obstruct the foramen blastoma and atypical teratoid tumor is critically important
of Monro, leading to obstructive hydrocephalus. because atypical teratoid rhabdoid tumors can be more ag-
Aside from a few genetic syndromes with a predisposi- gressive, may have poorer survival rates, and may require
tion for developing CNS tumors (ie, NF-1, NF-2, tuber- more aggressive therapy than classic medulloblastomas.
ous sclerosis, Li-Fraumeni syndrome, Gardner syndrome, Ependymomas are the second most common embryo-
Turcot syndrome, Gorlin syndrome), brain tumor patho- nal tumor of childhood (0.29 per 100,000 person-years)
genesis is largely unknown. Brain tumor genesis is most and are derived from ependymal cells within the CNS.
likely a consequence of inherited, acquired, and epigenetic Ependymoma can be of varying grades (WHO grades I
phenomena. and III) and locations. They are found more commonly
In general, patient characteristics such as age and gender in the posterior fossa; however, these tumors also can oc-
are not associated with a predisposition to a brain tumor, cur in the supratentorial region and in the spinal cord.
with a few exceptions. For instance, CNS germ cell tumors With more than 30 histopathologic classifications of
occur more commonly in boys (twofold), and pituitary tu- primary pediatric brain tumors, establishing a diagnosis
mors are more common in girls (threefold). Although en- can be challenging even for the most experienced pediatric
vironmental and other epigenetic causes are under intense neuropathologist. The current WHO classification system
investigation, there is no proven cause of childhood brain is helpful with regard to establishing a uniform guideline
tumors aside from the known associated genetic syndromes for brain tumor classification and grading, but it is by
mentioned earlier. no means complete. Advances in molecular genetics have
Tumors of young children (age 0–4 years) most com- improved our ability to classify brain tumors based on bi-
monly are of embryonal origin and often are located in ologic markers but likely will not replace our current his-
the posterior fossa. The differential diagnosis of posterior topathologic classification for many years. Unfortunately,
fossa tumors in this age group, listed by decreasing fre- not all brain tumors are “created equal,” making diagnos-
quency, include medulloblastoma, juvenile pilocytic astro- tic and management strategies nonuniform and highly in-
cytoma, ependymoma, and atypical teratoid rhabdoid dividualized at times.
tumor. In older children, juvenile pilocytic astrocytoma is The morbidity and mortality associated with child-
the most common posterior fossa tumor, followed by hood brain tumors are multifactorial and depend not only
medulloblastoma. on tumor pathology but also on location and treatment.
Across all ages, medulloblastoma (WHO grade IV) is Figure 1 lists some of the more common pediatric brain
the most common malignant brain tumor of childhood tumors according to neuroanatomic location. This list is
(0.51 per 100,000 person-years) and the most common far from exhaustive and is meant to demonstrate the di-
primary brain tumor in children age 0 to 4 years. versity of tumor types based on location. It is also meant

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


central nervous system brain tumors

and symptoms, should alert the clinician


to the likelihood of cerebrospinal fluid
(CSF) obstruction secondary to a brain tu-
mor. In 15% of children newly diagnosed
as having a brain tumor, papilledema also
may be present.
The triad of headache, nausea or vom-
iting, and gait imbalance is the most
common presentation of posterior fossa
tumors and is usually accompanied by
early morning vomiting as the defining
feature. The pathophysiology of early
morning vomiting is related to noctur-
nal hypoventilation, hypercarbia, vaso-
dilation 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, par-
ticularly when there is invasion of the
Figure 1. Common pediatric brain tumor subtypes according to anatomic location.
foramen of Luschka.
One of the most difficult presenting
to provide the primary care physician with a general dif- signs of pediatric brain tumors to detect clinically is a visual
ferential diagnosis in children suspected of having a brain field deficit. These defects can be associated with a variety
tumor in the context of abnormal results on neurologic of suprasellar and optic pathway tumors, including cranio-
examination. pharyngioma, optic glioma, and low-grade glioma, to
name a few. Often, the visual field deficits in children
are subacute or chronic and are not readily noticed by
Signs and Symptoms the child or caregiver, regardless of age, until progression
The presenting signs and symptoms of pediatric brain tu- to extreme papilledema and subsequent optic nerve pallor
mors can be incredibly diverse and elusive to the patient, or infarction develops.
parent, and clinician alike. In general, symptoms arise from Similar to visual field deficits, signs and symptoms re-
the neuroanatomic pathways that are disrupted by the tu- lated to endocrine dysfunction may be present several
mor, as illustrated in Fig 2. The most common symptom months before a diagnosis of a brain tumor is made.
reported by children with a newly diagnosed brain tumor is The more common signs of endocrine dysfunction associ-
headache. Headache occurs in approximately one third of ated with brain tumors include precocious or delayed pu-
pediatric patients newly diagnosed as having brain tumors. berty, anorexia, and excessive urination. These symptoms
(7) Headache in the absence of other symptoms associated localize to a tumor in the region of the hypothalamic-
with normal neurologic findings does not have reliable pituitary axis and include pituitary adenomas, germinomas,
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
a “red flag” for this diagnosis. onset, may be seen in up to 40% of children diagnosed with
Nausea and vomiting may occur in approximately one cortical-based tumors. (7) Although seizures are a common
third of children newly diagnosed as having a brain tumor. presenting feature of brain tumors, the vast majority of sei-
(7) However, children who have systemic illnesses such as zures are due to other systemic or genetic influences. Over-
gastroenteritis, viral meningitis, and childhood migraine all all, a new childhood brain tumor is associated with less than
can present with similar symptoms, and these are far more 4% of all new-onset seizure presentations.
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
nausea or vomiting, and gait imbalance that develops over confused with other postinfectious, demyelinating, or neu-
weeks to months. This triad, with progression of signs rodegenerative diseases. CNS germinomas or low-grade

Pediatrics in Review Vol.34 No.2 February 2013 65


central nervous system brain tumors

Neurologic Examination
A thorough neurologic examination is
of paramount significance in the assess-
ment of a child suspected of having a
brain tumor. The majority of children
diagnosed as having a brain tumor have
abnormal findings on neurologic ex-
amination 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 ex-
amination include evaluation of mental
status, cranial nerves, motor skills, sen-
sation, reflexes, coordination, and gait
(Table 2).
In terms of mental status, an in-
creased degree of encephalopathy will
most likely prompt emergent neuroim-
Figure 2. Common symptoms of pediatric brain tumors according to anatomic location. aging. However, in patients who have
chronic hydrocephalus secondary to
gliomas of the basal ganglia, midbrain, or deep white a midbrain tectum low-grade glioma, a history of slow
matter in particular are associated with atypical symptoms. but steady decline in school performance may be the only
Young children who have brain tumors often are the warning sign.
most challenging patients to diagnose. These children Examining extraocular movements can be a sensitive
will present with macrocephaly (40%), vomiting (30%), component of brain tumor detection, particularly in cases
irritability (25%), and lethargy (20%). (7) Macrocephaly of midbrain, pineal, cerebellar, and brainstem tumors. Par-
usually is detected on routine health visit screenings inaud syndrome, a constellation of findings that include
and must be distinguished from other familial, traumatic, paralysis of upgaze, pupils that are mid-dilated and poorly
and neurogenetic causes. Two signs that can be over- reactive to direct light, convergence or retraction nystag-
looked in young children are failure to thrive and early mus, and eyelid retraction, is commonly seen with dorsal
handedness. In the case of failure to thrive, children midbrain tumors. Children who have cerebellar tumors,
may have a prolonged history of poor weight gain with- especially with involvement of the floculonodular lobe, will
out an identifiable cause, and despite an exhaustive gas- present with nystagmus in any direction. Limited upgaze
trointestinal evaluation, eventually neuroimaging reveals or upgaze nystagmus is always pathologic and should
a midline tumor. In cases of diencephalic syndrome (a prompt further evaluation.
constellation of severe emaciation, normal or precocious Another syndrome presenting with abnormal eye
intellectual development, and normal linear growth), movements worth mentioning in the context of pediatric
a hypothalamic/chiasmatic tumor is present on neuroi- neuro-oncology is opsoclonus myoclonus syndrome.
maging that is almost always a low-grade glioma (with This syndrome represents a paraneoplastic phenomenon
or without hydrocephalus). Remarkably, after treatment characterized by involuntary conjugate eye movements of
with surgery or chemotherapy, there is marked improve- large amplitude and myoclonic jerks; it is usually associ-
ment in weight gain that correlates with tumor shrinkage. ated with an extra-CNS neuroblastoma. These children
Early or changing handedness can be a sign of upper mo- can present with a cerebellar syndrome (eg, fast oscillat-
tor neuron injury and may be seen with both cortical- ing nystagmus, tremor, ataxia, dysmetria, irritability) in
based and spinal cord tumors. A list of some of the more the absence of neuroimaging findings that may mimic
common warning signs in the presentation of childhood a postinfectious syndrome.
brain tumors that may warrant neuroimaging is shown in As mentioned, visual field abnormalities are common in
Table 1. tumors involving the optic pathway (eg, nerves, chiasm,

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


central nervous system brain tumors

Signs and Symptoms Associated With


Table 1.
cranial neuropathies that would
raise suspicion for a brainstem tu-
Delayed Diagnosis of Childhood Brain Tumors mor 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 as-
vomiting, enlarging head sess for possible asymmetries in bulk,
Failure to thrive, anorexia Suprasellar, hypothalamic
Visual complaints, abnormal eye Optic pathway, suprasellar, brain
tone, and strength. Children who
movements stem, posterior fossa have longstanding upper motor neu-
Tics, tremor, movement disorder Basal ganglia, thalamus, midbrain ron injury secondary to a low-grade
Early handedness Cortex, subcortical, brain stem, spinal cortical, subcortical, or brainstem tu-
cord mor involving the cortical spinal
Facial nerve palsy Brain stem, cerebellar pontine angle
Hearing loss Cerebellar pontine angle
tracts will have increased tone as well
Precocious puberty, nocturnal enuresis Suprasellar as hemiatrophy of the affected limb.
Head tilt, torticollis Cerebellar pontine angle, These physical findings can provide
cervicomedullary junction useful clinical insight with regard to
tumor grade and biologic behavior,
because hemiatrophy and hypertonia
represent longstanding upper motor
tracts, thalamus, radiation, visual cortex) and, if not tested neuron injury and correlate with low-grade tumor pathol-
for, can be missed. (8) The easiest way to assess visual fields ogy. In young children, in whom individual muscle groups
in young patients is to use two colorful objects. While are difficult to test, one can look for hand preference when
maintaining central fixation with one object, the second grasping for objects. In older children, the presence of
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 pa- with the hands open is a sensitive test for extremity
tients, it is necessary that each eye be tested individually weakness.
while maintaining central fixation to test accurately for vi- Asymmetries in sensation (cold, light touch, and pin-
sual fields. prick) can be clues to cortical tumors, spinal cord tumors,
A fundoscopic examination is crucial not only in assess- and, in the case of facial sensation, dysfunction of the di-
ing for papilledema but also in detecting disc pallor, com- visions of the trigeminal nerve located throughout the
monly seen in tumors involving the optic nerve and chiasm brain stem.
and indicative of optic nerve damage. Both the con- Evaluation of reflexes can be very helpful, especially if
ventional and panoptic ophthalmoscope may be used to there are asymmetries. The upper extremity reflexes (bi-
perform the fundoscopic examination. The panoptic oph- ceps, triceps, and brachioradialis) generally are more diffi-
thalmoscope allows for visualization of the entire disc and cult to obtain in young children; however, asymmetries are
generally is regarded as more user-friendly than the con- pathologic and can be clues to tumor location. In the
ventional ophthalmoscope. Regardless of the equipment lower extremities, asymmetries in the patellar and Achilles
used, in an uncooperative or young child, a formal dilated reflexes are generally associated with a Babinski response,
examination performed by an ophthalmologist may be re- indicative of upper motor neuron dysfunction.
quired to obtain accurate results. Coordination testing is extremely important in children
Patients afflicted with brainstem tumors can present who have suspected cerebellar and brainstem tumors. The
with a multitude of cranial neuropathies. Facial nerve classic finger-to-nose testing must be performed to assess for
palsy is a common presentation of most brainstem tu- cerebellar dysmetria. It is critical for the child to extend the
mors involving the pons. Often confused with having extremity fully and reach for the examiner’s finger. Cerebel-
Bell’s palsy, these patients may have other cranial neu- lar testing can be done in both the arms and the legs. Alter-
ropathies (eg, esotropia, decreased hearing, drooling, natively, the patient may hold out a finger and mirror the
dysphagia) specifically involving abducens, vestibulo- examiner’s finger movements in the extended position. This
cochlear, glossopharyngeal, vagus, and hypoglossal mirror testing is extremely sensitive in assessing cerebellar
nerves in isolation or in various combinations. Any pa- dysfunction, and in the case of patients who have cerebellar
tient presenting with new-onset facial palsy should have tumors, will result in an “overshoot” of the movement. A
a thorough neurologic examination to exclude other rather quick and sensitive screening test that can be

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


central nervous system brain tumors

Key Components of the Neurologic Examination in a Child Who


Table 2.

Has a Suspected CNS Tumor


Examination Pertinent Findings Suggestive of a Tumor
Mental status (level of alertness, speech and language) Encephalopathy, progressive neurocognitive decline
Cranial nerve 2 (visual fields, fundoscopic examination) Visual field deficit, papilledema
Cranial nerves 3, 4, 6 (extraocular movements, efferent Nystagmus (upgaze in particular), gaze paralysis in any
pupillary function) direction, mid-position, poorly reactive pupils
Cranial nerve 7 (facial symmetry) Facial weakness (upper versus lower motor neuron
distribution)
Cranial nerve 8 (hearing, balance) Decreased hearing to finger rub (unilateral or bilateral),
vertigo
Cranial nerves 9, 10, 12 (palate elevation, swallowing, Drooling, dysphagia
tongue movements)
Motor examination (bulk, tone, proximal and distal strength) Early handedness, delayed motor milestones, pronator drift,
focal changes in tone with associated atrophy
Reflexes (biceps, triceps, brachioradialis, patellar, Achilles) Hyperreflexia with Babinski sign
Cerebellar function (finger to nose testing, mirror testing, Dysmetria, overshoot on mirror testing, marked asymmetry
rapid finger and toe tapping) of finger and/or toe tapping (must be differentiated from
weakness)
Gait (heel, toe, tandem straight line) Wide-based unsteady gait, inability to perform straight-line
test, circumduction of gait
Sensory examination Sensory deficits in a focal anatomic distribution

performed easily is to have the child rapidly tap his fingers


Neuroimaging Features of Childhood Brain
against his thumbs and his feet on the floor. Asymmetries of
Tumors
these fine motor movements may be indicative of cerebellar
Any child who has an abnormal result on neurologic exam-
dysfunction, focal motor weakness, or both.
ination in the setting of the aforementioned symptoms
Gait assessment is an important part of the neurologic
should have neuroimaging to rule out a brain tumor. The
examination and can be accomplished solely by observa-
choice of neuroimaging depends on the urgency of the
tion. Patients who have cerebellar tumors, particularly those
symptoms and the degree of neurologic abnormality. Chil-
involving the midline cerebellum, will exhibit a classic wide-
based ataxic gait, as well as an inability to perform tandem dren who manifest altered mental status, behavioral changes,
straight-line walking. Children who have cortical spinal or cognitive decline associated with headache, nausea, vom-
tract involvement will exhibit a hemiparetic gait, with cir- iting, and ataxia in the absence of infection should be re-
cumduction of the leg and asymmetries in the swing phase ferred to the emergency department. In these situations,
of the arms. In all cases of gait disturbance, it is important to a noncontrast computed tomography (CT) scan of the head
consider spinal cord tumors in the differential diagnosis. generally is performed based on availability and urgency.
Finally, it is always prudent to perform a thorough skin It is important to note that some tumors, particularly
examination, looking for neurocutaneous stigmata of dis- tumors of the brainstem, cerebellum, and suprasellar re-
ease. In particular, the presence of café au lait macules and gion as well as infiltrative tumors of the white matter,
axillary freckling should raise suspicion for neurofibromatosis can be missed on CT neuroimaging. Figure 3 shows exam-
and trigger fundoscopic examination and assessment for vi- ples of the CT appearances of various pediatric brain tu-
sual deficits (NF-1) and hearing deficits (NF-2). Patients mors with their associated signs and symptoms. CT
who have ash leaf spots, shagreen patches, and facial angio- neuroimaging is sensitive in detecting both blood and cal-
matosis should undergo head circumference measurement cification and continues to have a role in the ongoing man-
and a fundoscopic examination. In children who have agement of pediatric brain tumors, often because there
known or suspected tuberous sclerosis who present with may be no sedation requirement because the length of
headache, vomiting, or irritability, the diagnosis of obstruc- time for the procedure is short. Both coronal and sagittal
tive hydrocephalus secondary to a subependymal giant cell reformatting of CT sequences are available at most centers
astrocytoma should be considered. and can provide additional anatomic information.

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


central nervous system brain tumors

A CT scan with contrast is rarely necessary in the emer- such as MRI perfusion and spectroscopy, can be used to
gency setting of a patient suspected of having a brain tu- differentiate tumor from mimickers. Although not used
mor unless an infectious cause (eg, cerebral abscess) is in routinely in every case, it is hoped that additional MRI se-
the differential diagnosis. Despite the utility of a CT scan quences can be used reliably to distinguish a tumor from
in the emergency setting, magnetic resonance imaging radiation necrosis and help to predict responses to radia-
(MRI) is the standard of care for all children who have tion, chemotherapy, or biologic therapy.
a known or suspected brain tumor. MRI is the most sen- Although the MRI is an extremely valuable tool in the
sitive neuroimaging modality for detecting a brain tumor, practice of neuro-oncology, it has its limitations. For ex-
with and without intravenous gadolinium contrast. Al- ample, in patients who have orthodontic braces, there is
though not every CNS tumor shows enhancement, the ga- often magnetic susceptibility artifact that can limit the in-
dolinium is particularly helpful in detecting those patients terpretation of suprasellar tumors in particular. In small
who have disseminated leptomeningeal metastatic disease children, sedation is required to obtain an adequate study
at presentation. Therefore, all children who have newly because motion artifact is common in this age group.
discovered brain tumors on neuroimaging should rou- MRIs have been notoriously ineffective at detecting
tinely have an MRI with contrast of the entire spinal axis. blood and mineralization; however, this limitation is cir-
Occasionally, abnormalities will be encountered on an cumvented with newer sequences, including susceptibil-
MRI that could be consistent with other disorders, such ity weighted imaging. The most significant limitation of
as demyelinating or postinfectious diseases, which may in- MRI is its inability to render a pathologic diagnosis. Al-
volve the deep white matter, basal ganglia, or thalamus. though there are specific neuroimaging features of the var-
Under these circumstances, additional MRI sequences, ious pediatric brain tumor subtypes, there is tremendous

Figure 3. Computerized tomography neuroimaging findings and associated symptoms of childhood brain tumors.

Pediatrics in Review Vol.34 No.2 February 2013 69


central nervous system brain tumors

overlap, and therefore a specific diagnosis cannot be achieved the scope of the primary care physician or emergency de-
based on MRI appearance alone. partment team to discuss tumor histology, treatment
With the exception of the CNS germinoma, which can strategies, and outcomes. However, it is important to
display elevations of serum and CSF markers (a-fetoprotein keep the patients (when appropriate) and parents in-
and b-human chorionic gonadotropin), the final diag- formed of the diagnostic process. This task generally is
nosis of a brain tumor is made by histologic examination performed best in a conference room setting, where neu-
after biopsy or resection. roimages can be reviewed with the family and the neuro-
Examples of MRI neuroimaging features of pediatric surgical/neuro-oncology team may be introduced.
brain tumors with associated symptoms are shown in Fig 4. 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
Acute Management of the Newly Diagnosed geographic locations, and there is no single cause for devel-
Patient oping a brain tumor, a disorder that cannot be prevented.
The management of the child newly diagnosed as having Parents and clinicians often are plagued with guilt by
a brain tumor usually begins in the emergency depart- delayed diagnosis due to unusual or vague symptoms.
ment after neuroimaging. In general, the management There has been no study to date that has correlated early
of neuro-oncology patients is no different from that of detection of pediatric brain tumors with changes in over-
patients who have other acute neurologic emergencies. all or event-free survival. Children generally present for
Establishing an airway, sufficient breathing, and effective medical attention when their neurologic symptoms im-
circulation remain the most crucial immediate priorities. pede their ability to play.
In cases of acute obstructive hydrocephalus with her- Social workers, child life specialists, and neuropsychol-
niation syndrome, emergent neurosurgical consultation ogists provide critical support to families and patients
for either surgical resection or emergent temporizing during diagnosis and throughout the course of care.
ventricular decompression is required. Preoperative labo- Once a pathologic diagnosis is firmly established, a multi-
ratory testing should include a complete blood cell count, disciplinary conference is required to review the diagno-
coagulation studies, and blood type and cross-matching. sis, treatment plan, and prognosis.
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 tu- Therapeutic Strategies and Outcomes
mors often have multiple endocrinopathies of both ante- Neurosurgery generally is the first and most important in-
rior and posterior pituitary function. tervention for children newly diagnosed as having a brain
A baseline ophthalmologic evaluation, including visual tumor. The ultimate goal of surgery is to obtain a com-
field testing and fundoscopic evaluation, is important in plete resection without postoperative complications.
preoperative evaluations because most patients do not Sometimes a complete resection is not feasible due to tu-
complain of visual field deficits at presentation. Depend- mor location, in which case a subtotal resection or biopsy
ing on the degree of vasogenic edema, intravenous cor- is performed. In children who have posterior fossa tumors
ticosteroids with a gastrointestinal-protective agent are (eg, medulloblastoma, juvenile pilocytic astrocytoma,
given conventionally before and after surgery. Although ependymoma), a gross total resection correlates with im-
there is little evidence to support the use of corticoste- proved event-free and overall survival.
roids with regard to overall outcome, corticosteroids However, the posterior fossa is a potentially dangerous
can relieve headache, nausea, and vomiting and remain location and prone to postoperative complications. Pos-
a generally accepted treatment. terior fossa mutism syndrome, a constellation of mutism,
If the diagnosis is based on CT imaging alone, a pre- hypotonia, and irritability, can occur in the immediate
operative MRI of the brain and spine (with and without postoperative period and is presumed to be due to mid-
gadolinium) is necessary for surgical planning and stag- line cerebellum connection disruption. Posterior fossa
ing. A general schematic of acute management strategies mutism can be partially or completely reversible over
in patients newly diagnosed with a brain tumor is listed in weeks to months and has been reported with varying de-
Table 3. grees of severity in up to 10% to 20% of children who un-
Equally important in the management of newly diag- dergo posterior fossa surgery.
nosed patients is providing psychosocial support during In children who have cortical-based tumors (eg, low-
the initial confirmation of the diagnosis. It is beyond grade astrocytoma, ependymoma, oligodendroglioma,

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


central nervous system 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 Children diagnosed with tectal or pineal tumors often
total resection. In those patients who have high-grade tu- undergo a biopsy approach, given the potential risk of
mors of any location, maximum tumor resection and ad- surgical morbidity, and frequently also receive a CSF di-
juvant therapy are required, based on the high rate of versional procedure (ventricular peritoneal shunt versus
reoccurrence and dissemination. In children who have endoscopic third ventriculostomy) in cases of obstructive
deep-seated tumors (ie, thalamic, basal ganglia, pineal- hydrocephalus. The decision to place a shunt in a child
tectal tumors), a biopsy often is sufficient to achieve a di- who has a malignant brain tumor with associated hydro-
agnosis, and tumor debulking is performed in cases in cephalus sometimes is based on medical necessity, but the
which there is significant mass effect. procedure carries a 5% to 7% risk of extraneural seeding.
In the case of CNS germinoma, a diagnosis can be Those who have large posterior fossa tumors frequently
made on the basis of elevation of serum or CSF tumor require a CSF diversional procedure because prolonged
markers (a-fetoprotein and b-human chorionic gonado- CSF obstruction is associated with papilledema and po-
tropin) alone. A biopsy, although generally favored, is tential optic nerve infarction.
not always required to establish a diagnosis of Despite the precarious location of the tumor, children
CNS germinoma. A gross total resection in children who have brainstem tumors can undergo safe resection to
who have extensive craniopharyngiomas can be cura- achieve cure in cases of dorsal exophytic cervicomedullary
tive; however, gross total resection is often associ- tumors. Patients who have diffuse intrinsic pontine gli-
ated with resulting visual field deficits and multiple oma, the most malignant of childhood brain tumors,
endocrinopathies. generally do not undergo biopsy unless enrolled in

Pediatrics in Review Vol.34 No.2 February 2013 71


central nervous system brain tumors

the patient, pathologic diagnosis,


General Management Strategy of Newly
Table 3. degree of residual tumor, presence

Diagnosed Pediatric Brain Tumors or absence of dissemination, and


availability of clinical trials. If the
Airway, breathing, circulation stabilization
reader is interested in the manage-
Neurosurgery/neuro-oncology consultation ment of a specific tumor type, there
NPO are numerous textbooks, published
Presurgical laboratory tests (electrolytes, CBC, coagulation studies, blood type and clinical trials, and review articles that
cross-matching) outline the evidence-based manage-
Intravenous steroids (dexamethasone) with GI-protective agent
Magnetic resonance imaging of the brain and spine with and without intravenous
ment strategies and controversies of
contrast specific pediatric tumor subtypes.
Preoperative endocrine laboratory tests for suprasellar tumors For tumors of low-grade histo-
Ophthalmologic examination logic type in which gross total resec-
Seizure 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 re-
Lumbar puncture for CSF cytology and tumor markers (for suspected CNS sidual low-grade tumors generally
germinoma) is generally performed 7 to 10 days postoperatively if there are no are observed for progression. If they
contraindications. demonstrate growth on surveillance
CBC¼complete blood cell count, CNS¼central nervous system, CSF¼cerebrospinal fluid, neuroimaging (every 4–6 months),
GI¼gastrointestinal, NPO¼nothing by mouth. they are treated with further surgery,
chemotherapy, or radiation therapy,
depending on age, tumor location,
a clinical trial, because the diagnosis can be made by the degree of recurrence, and symptoms. Children who have
appearance of a characteristic expansile mass centered in malignant gliomas require radiation therapy postopera-
the pons with minimal or no contrast enhancement on tively, in combination with the experimental biologic
MRI. Occasionally, a biopsy is warranted in these cases, agents (eg, molecular-based targeted therapy) or oral che-
especially when there are focal, well-defined enhancing motherapy agents such as temozolomide. The most prom-
lesions, to exclude infectious or demyelinating mimickers inent role of chemotherapy is in children who have
of brainstem gliomas. embryonal tumors or CNS germinomas and in younger
An additional tumor, optic nerve glioma, can be diag- children who have progressive low-grade gliomas.
nosed on the basis of neuroradiographic features alone. Based on strong research evidence, (1) it has been shown
These tumors often are low-grade gliomas associated with that a combination of chemotherapy involving either a two-
NF-1 and are seen easily on dedicated MRI sequences of drug regimen (carboplatin and vincristine) or a four-drug
the optic nerves. Very rarely, meningiomas and metastatic regimen (procarbazine, thioguanine, lomustine, and vincris-
disease can present with optic nerve pathology. Children tine) can improve event-free survival in children diagnosed
diagnosed as having optic nerve gliomas (with or without with progressive low-grade glioma. (9)
neurofibromatosis) are treated conservatively with observa- In children who have embryonal tumors (medulloblas-
tion but undergo chemotherapy if they demonstrate visual toma, ependymoma, or atypical teratoid rhabdoid tu-
dysfunction or tumor progression. In summary, the mors), chemotherapy is often used in conjunction with
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
achieve a gross total resection whenever feasible, and such children who have average-risk medulloblastoma (age
management remains the ultimate goal for successful >3 years, <1.5-cm2 residual disease, nondisseminated dis-
treatment. ease, and nonanaplastic histology), a combination of cra-
Once neurosurgical intervention and sufficient healing niospinal radiation with adjuvant chemotherapy followed
of surgical wounds are achieved, additional treatments by maintenance chemotherapy is used. Chemotherapy
may be required, including chemotherapy, radiation ther- can be used either at standard doses or at higher doses
apy, or a combination of both. These adjunct therapies to achieve greater CNS penetration that would require au-
are chosen based on the pathologic diagnosis and amount tologous stem cell support secondary to myeloablative
of residual tumor. The nonsurgical management of child- chemotherapy. Current trials are underway to investigate
hood brain tumors is complex and depends on the age of the utility of a reduced dose of craniospinal radiation to

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


central nervous system brain tumors

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

Pediatrics in Review Vol.34 No.2 February 2013 73


central nervous system brain tumors

Management of Progressive or Recurrent CNS tumors may experience seizures at any time during
Disease their treatment. Administering non–enzyme-inducing
The management of progressive brain tumor disease poses anticonvulsants (eg, levetiracetam) whenever possible is
significant challenges, and pediatricians should be aware of a requirement for many clinical trials involving investiga-
the issues that patients and families face. Despite combined tional drugs.
surgery, chemotherapy, and radiation treatments, a signif- Children undergoing cranial radiation may experience
icant proportion of children will have progressive or recur- fatigue, nausea, or vomiting during their treatment. On
rent disease. The risk of disease recurrence is dependent on occasion, stimulant and nonstimulant medications can
the patient’s age, tumor pathology, extent of resection, be used to treat radiation somnolence. In the case of ra-
and previous treatment. In children who experience local diation or chemotherapy-related emesis, antiemetic med-
relapse, surgery generally is offered, depending on the an- ications or low-dose corticosteroids can be very helpful in
atomic site of relapse. If patients have not received radia- controlling symptoms.
tion therapy to the affected area, radiation generally is The neuro-oncology team manages the usual adverse
offered. Even when a patient has received previous radia- effects of chemotherapy on the hematopoietic system
tion, radiosurgery techniques (stereotactic, highly focused (neutropenia, anemia, and thrombocytopenia); however,
radiation) have been used to prolong survival. it is crucial that the primary care physician be aware of
Most commonly, as with other malignancies, children when the patient is undergoing treatment to recognize
who experience progressive or recurrent disease are of- potential complications of therapy. In children who are
fered enrollment in clinical trials. Most clinical trials of receiving craniospinal radiation, complete blood cell
treatments for recurrent childhood brain cancer involve counts are performed weekly because of the risk for ane-
Phase I studies, designed to test a new drug’s safety mia associated with marrow disruption due to radiation.
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 Late Effects of Treatment
agents, and quality of life. All clinical trials in the United Improved patient survival has presented a new era of late
States and many international trials are registered on effects of tumor therapies that the primary care provider
www.clinicaltrials.gov. These clinical trials can be re- must be able to recognize. As with other pediatric malig-
searched by patients, families, and clinicians. Each trial nancies, treatment with chemotherapy poses a potential
consists of both inclusionary and exclusionary criteria that risk for future hematogenous malignancies. In children
must be met before enrollment. who have received craniospinal radiation, subsequent
Neuro-oncology therapy is changing constantly, and thyroid cancers, skin cancers, meningiomas, and second-
new clinical trials are added weekly. In patients for whom ary high-grade gliomas all have been reported. (11) Un-
clinical trials are not an option, combinations of biologic der these circumstances, a compelling argument can be
and chemotherapic regimens, with or without radiation, made for performing yearly MRI examinations in chil-
have been used, with varying degrees of success in delay- dren who have undergone previous cranial radiation
ing the progression of the disease. 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 he-
Acute and Subacute Effects of Treatment matogenous and systemic secondary malignancies. High-
The primary care physician should understand the acute frequency hearing loss is extremely prevalent in children
and long-term effects of brain tumor treatment. Patients who have received platinum-based chemotherapies, and
may have acute treatment-related effects from surgery, such children must have routine audiometric evaluations.
radiation, and chemotherapy, depending on the tumor Other potential late effects of chemotherapy on organ
type and therapy received. In the case of surgery, patients function include disruption of cardiac, renal, pulmonary,
can experience headaches after the surgical procedure. and hepatic function. The effect of chemotherapy on fer-
Headaches generally are relieved with anti-inflammatory tility of both genders is the subject of current investigation.
medications; however, if fever is present, an abscess or in- Radiation therapy, despite its critical role in the manage-
fection due to CSF leak must be considered. ment of pediatric brain tumors, has the highest number of
Children receiving chemotherapy might experience al- long-term sequelae that the primary care physician should
lergic reactions or acute neurologic complaints, such as recognize. (12)(13)(14)(15) The most common, and per-
foot drop or cranial neuropathies. Children who have haps most significant, effect of radiation therapy is its

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


central nervous system brain tumors

impact on neurocognition. Children younger than 8 years It is unclear whether this condition is due to a direct ef-
are at the highest risk for radiation-related neurocognitive fect of the tumor diagnosis or of therapy. Regardless, pa-
injury. Those patients who receive craniospinal radiation tients should be screened routinely for signs and symptoms
are at risk for declines in IQ of 2 to 4 points per year of depression. Screening can be performed by both the
(10–20 points overall), depending on radiation dosage, tu- neuro-oncology team and the pediatrician. When depres-
mor location, and age of the child. Subsequently, these sion is suspected, a referral to child psychiatry or initiation
children often have difficulty with learning and memory of antidepressant therapy may be warranted. In terms of
and may require special education services. Studies are on- the psychosocial consequences of brain tumors, a high di-
going to determine whether pharmacologic interventions vorce rate among parents, disrupted sibling relationships,
have any impact on improving neurocognition in this pop- and problems with peer-to-peer interactions have been ob-
ulation of children. served. A summary of the common late effects of brain tu-
Endocrinopathies are commonly seen in patients who mor therapy is shown in Table 4.
have received either whole brain or suprasellar boosts of ra-
diation. Although the hypothalamic-pituitary axis hor- Future of Pediatric Neuro-Oncology
mones often are measured before, during, and after The field of pediatric neuro-oncology is evolving rapidly,
therapy, the long-term consequences of treatment-related thanks in part to the advances in molecular biology. Many
endocrinopathies acquired during childhood are unknown. common primary brain tumors now can be categorized
Another important long-term neurologic complica- according to molecular markers, which someday soon
tion specific to children who have received cranial radia- will serve as the basis of risk stratification in clinical trials.
tion is neurovascular disease. Depending on the radiation Our improved knowledge of the molecular mechanisms
dose and location, children are at increased risk for cere- of neuro-oncogenesis has led to the discovery of an enor-
bral vasculopathy, including Moyamoya disease, which mous number of molecular-targeted therapies (ie, bio-
increases the risk for a future stroke. The mechanism of logic agents) that currently are being studied in clinical
radiation-related vasculopathy is not entirely known but trials for recurrent or refractory disease. These drugs
is different from the atherosclerotic or cardioembolic are designed specifically to disrupt known tumor-specific
pathophysiology of stroke seen in adults. Unfortunately, molecular signaling pathways. It is the hope that one day,
pharmacologic intervention is difficult to apply due to the more specific targeted biologic therapies will replace con-
lack of data on whether preventive therapy (eg, aspirin, ventional chemotherapy or radiation in the treatment of
cholesterol-lowering drugs, antiplatelet agents) decreases childhood brain tumors.
the risk of radiation-associated childhood strokes. One of the great limitations in achieving success of bi-
Children who have been treated with either chemo- ologic-based treatments is the ability of these drugs to cross
therapy or radiation therapy for a brain tumor may have the blood–brain barrier. To overcome this gatekeeper,
chronic headaches. These headaches can have features of a number of treatment strategies, including gene-based de-
migraines, tension-type headaches, cluster headaches, or livery systems, immunotherapies, and convection-based
a combination of all three. The exact pathophysiologic drug delivery, currently are being investigated.
mechanism and true incidence are not fully understood. Advances in radiation oncology are necessary for im-
A certain proportion of patients will develop chronic daily proving neurocognitive outcomes without sacrificing ther-
headaches and require both prophylactic and abortive apeutic efficacy. It is unknown whether proton beam
headache regimens. Unfortunately, in some cases, it is therapy will be superior to conventional photon beam ther-
difficult to determine whether the headache is related apy, and results may not be known for many years. An im-
to the disease or to the sequelae of treatment. It is impor- proved understanding of the molecular mechanisms of
tant to recognize that headaches could be a sign of dis- radiation-related neurocognitive injury will allow for the de-
ease recurrence and may be present before there is velopment and implementation of neuroprotective agents at
MRI evidence of progressive or recurrent disease. A thor- the initiation of therapy. Likewise, advances in neu-
ough headache history may be helpful in distinguishing roimaging will allow detection of tumor reoccurrence ear-
whether there is a change in the headache pattern from lier and more accurate differentiation of treatment-related
baseline that warrants neuroimaging. changes from disease reoccurrence.
Less understood late effects of brain tumor treatment Determining the genetic underpinnings of neuro-
are depression and other psychosocial consequences. A oncologic disease includes understanding epigenetic fac-
wide range of patients of all ages, with all tumor types, tors that govern neuro-oncogenesis. Today, a variety of
tumor locations, and therapies, are at risk for depression. mouse models exist that spontaneously and at great

Pediatrics in Review Vol.34 No.2 February 2013 75


central nervous system brain tumors

The pediatrician serves as a crucial liaison between pediat-


Potential Late Effects of
Table 4. ric and adult medicine in providing continuity of care. It is

Pediatric Brain Tumor Therapy the hope that improved understanding of the biology of
disease will translate into novel therapies and improved
1. Endocrinopathy (hypothyroidism, growth hormone
survivals of children diagnosed with brain tumors.
deficiency, corticotropin deficiency, precocious or
delayed puberty, diabetes insipidus)
2. Secondary neoplasms (hematogeneous, skin, thyroid,
CNS)
3. Cerebral vasculopathy (stroke, Moyamoya disease,
Summary
angiitis)
4. Neurocognitive effects (learning, memory, IQ) • Based on strong evidence, brain tumors, although rare,
5. Sensorineural hearing loss are the No. 1 cause of death among all childhood
6. Scoliosis cancers.
7. Osteopenia • Based on consensus, the morbidity and mortality
8. Primary headache disorder associated with childhood brain tumors are
9. Epilepsy determined by many factors, particularly tumor
10. Infertility/dysmenorrhea pathology, anatomic location, and treatment.
11. Depression/anxiety • Based on strong evidence, headache occurs in
12. Obesity/diabetes approximately one third of patients newly diagnosed
13. Neuropathy with pediatric brain tumors.
14. Ocular effects (vision loss, amblyopia, cataracts) • Based on consensus, brain tumors are managed by
15. Cardiomyopathy surgery, chemotherapy, or radiation, depending on
16. Renal insufficiency tumor type, location and dissemination, and age.
• Based on strong evidence, in treating brain tumors,
CNS¼central nervous system. chemotherapy places the child at risk for future
malignancies and radiation therapy places the child at
risk for developing neurocognitive deficits.

frequency form brain tumors similar to childhood disease.


Primary tumor cell cultures have been established for a va-
riety of pediatric brain tumors and are being used to study References
individual tumor growth patterns, as well as the potential 1. CBTRUS, Central Brain Tumor Registry of the United States.
CBTRUS statistical report: primary brain and central nervous
responsiveness of tumors to a variety of chemotherapeu- system tumors diagnosed in the United States in 2004-2008.
tic and biologic therapies. As our knowledge of the role of Available at: www.cbtrus.org. Accessed July 12, 2012
stem cells in disease formation and progression improves, 2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer
innovative stem cell therapies may play a role in the future Statistics Review, 1975-2008, Bethesda, MD: National Cancer
of neuro-oncologic treatment. It is our belief that one or Institute. Available at: http://seer.cancer.gov/csr/1975_2008/.
Accessed July 12, 2012
all of these advances in molecular medicine will allow us 3. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO
to achieve individualized brain tumor therapies for our classification of tumours of the central nervous system. Acta
patients and give the best hope for cure. Neuropathol. 2007;114(2):97–109
4. Leary SE, Olson JM. The molecular classification of medullo-
blastoma: driving the next generation clinical trials. Curr Opin
Role of the Pediatrician Pediatr. 2012;24(1):33–39
Pediatric brain tumors are a rare but serious disease of 5. Kool M, Korshunov A, Remke M, et al. Molecular subgroups of
childhood that require a multidisciplinary approach to di- medulloblastoma: an international meta-analysis of transcriptome,
agnosis, ongoing management, and recognition of late genetic aberrations, and clinical data of WNT, SHH, Group 3, and
Group 4 medulloblastomas. Acta Neuropathol. 2012;123(4):
effects of treatment. The role of the pediatrician is ex-
473–484
tremely important in all aspects of brain tumor manage- 6. Ginn KF, Gajjar A. Atypical teratoid rhaboid tumor: current
ment. A heightened awareness of the signs and symptoms therapy and future directions. Front Oncol. 2012;2:114
of childhood brain tumors in conjunction with a focused 7. Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D.
neurologic examination may lead to an earlier diagnosis. Presentation of childhood CNS tumours: a systematic review and
meta-analysis. Lancet Oncol. 2007;8(8):685–695
Children who are long-term survivors of brain tumors face
8. Harbert MJ, Yeh-Nayre LA, O’Halloran HS, Levy ML, and
unique challenges with regard to a multitude of potential Crawford JR. Unrecognized visual field deficits in children with
late effects of therapy and therefore require meticulous primary central nervous system brain tumors. J Neurooncol. 2012;
continuity of care beyond childhood and into adulthood. 107(3):545–549

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


central nervous system brain tumors

9. Ater JL, Zhou T, Holmes E, et al. Randomized study of two 13. Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ.
chemotherapy regimens for treatment of low-grade glioma in Change in neurocognitive functioning after treatment with cranial
young children: a report from the Children’s Oncology Group. radiation in childhood. J Clin Oncol. 2004;22(4):706–713
J Clin Oncol. 2012;30(21):2641–2647 14. Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE.
10. Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U. Late neurocognitive sequelae in survivors of brain tumours in
Proton versus photon radiotherapy for common pediatric brain childhood. Lancet Oncol. 2004;5(7):399–408
tumors: comparison of models of dose characteristics and their 15. Armstrong GT, Stovall M, Robison LL. Long-term effects of
relationship to cognitive function. Pediatr Blood Cancer. 2008;51 radiation exposure among adult survivors of childhood cancer:
(1):110–117 results from the Childhood Cancer Survivor Study. Radiat Res.
11. Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes 2010;174(6):840–850
among adult survivors of childhood central nervous system
malignancies in the Childhood Cancer Survivor Study. J Natl Suggested Reading
Cancer Inst. 2009;101(13):946–958 Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors.
12. Reimers TS, Ehrenfels S, Mortensen EL, et al. Cognitive New York, NY: Springer-Verlag; 2010
deficits in long-term survivors of childhood brain tumors: Keating RF, Goodrich JT, Packer RJ, eds. Tumors of the Pediatric
identification of predictive factors. Med Pediatr Oncol. 2003;40 Nervous System. New York, NY: Thieme Medical Publishers Inc;
(1):26–34 2001

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1. The symptom that most warrants emergent neuroimaging for a suspected brain tumor in a previously well 4-
year-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.

Pediatrics in Review Vol.34 No.2 February 2013 77


central nervous system 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.

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


Article gastrointestinal disorders

Pediatric Pancreatitis
Arvind I. Srinath, MD,*
Educational Gaps
Mark E. Lowe, MD, PhD†
1. The incidence of acute pancreatitis has increased in pediatric patients over the past
two decades, approaching the incidence in adults.
Author Disclosure 2. While pancreatic rest, antiemetics, analgesia, fluid support, and monitoring for
Drs Srinath and Lowe complications remain the mainstays of acute pancreatitis management, clinicians
have disclosed no should know that approaches to pancreatic rest and fluid management have changed,
financial relationships as have long-time teachings on the use of opiods and the institution of nutrition.
relevant to this article.
This commentary does
Objectives After completing this article, readers should be able to:
not contain
a discussion of an 1. Differentiate between acute and chronic pancreatitis.
unapproved/ 2. Know how to diagnose acute pancreatitis.
investigative use of 3. List common causes for acute, recurrent, and chronic pancreatitis.
a commercial product/ 4. Explain the utility of clinical symptoms, biochemical testing, and radiographic
device. imaging in diagnosing acute and chronic pancreatitis.
5. Understand the management of acute pancreatitis and chronic pancreatitis.

Introduction
Pancreatitis is an inflammatory 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 pa-
tients have a single episode of pancreatitis. A small number of patients have recurrent epi-
sodes of acute pancreatitis and are at risk of developing CP.
Pancreatitis in pediatric patients is an increasingly recognized disorder. Although stan-
dard diagnostic criteria for pancreatitis exist, their intricacies deserve close attention, espe-
cially in pediatrics. Research over the past decade has demonstrated differences between
pancreatitis in children and adults, particularly in presentation, etiology, prognosis, and na-
ture of acute recurrent pancreatitis (ARP). Many of the tra-
ditional thoughts about management have been challenged,
Abbreviations and the treatment of pancreatitis is evolving.

ARP: acute recurrent pancreatitis


CFTR: cystic fibrosis transmembrane conductance
Acute Pancreatitis in Pediatrics
regulator
Epidemiology
Acute pancreatitis occurs in all age groups, even in infants. Re-
CP: chronic pancreatitis
cent studies from the United States, Mexico, and Australia
CT: computed tomography
have reported an increasing incidence of pediatric acute pan-
ERCP: endoscopic retrograde cholangiopancreatography
creatitis over the past 2 decades. (1) Currently, the best esti-
EUS: endoscopic ultrasound
mates suggest that there are 3.6 to 13.2 pediatric cases per
IgG4: immunoglobulin G4
100,000 individuals per year, an incidence that approaches
MRCP: magnetic resonance cholangiopancreatography
the incidence of disease in adults. Much of the increased di-
PRSS-1: cationic trypsinogen gene
agnosis of acute pancreatitis results from greater physician
SPINK-1: serine protease inhibitor Kazal type 1
awareness, as evidenced by a concurrent increase in biochem-
TPN: total parenteral nutrition
ical testing (amylase and lipase levels) for pancreatitis.

*Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of University of Pittsburgh
Medical Center (UPMC), Pittsburgh, PA.

Director, Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Vice Chairman of Pediatrics, Children’s Hospital of
Pittsburgh of UPMC, Pittsburgh, PA.

Pediatrics in Review Vol.34 No.2 February 2013 79


gastrointestinal disorders pancreatitis

Pathophysiology
Acute pancreatitis results from injury of the pancreas Causes of Acute
Table 1.
and a subsequent inflammatory response that may in-
volve adjacent and distant tissues and organs. The pre-
Pancreatitis in Children
vailing theory of the pathophysiology of pancreatitis Common
includes several distinct steps. First, an event initiates Biliary disorders
a process of acinar cell injury. The cell injury produces Systemic conditions
pancreatic edema and a local inflammatory response, Medications
with release of inflammatory mediators. The produc- Trauma
Idiopathic
tion of cytokines and chemokines provoke a systemic Less common
inflammatory response. The magnitude of this inflam- Infection
matory response determines the clinical severity of Metabolic diseases
acute pancreatitis and can lead to complications such Genetic/hereditary disorders
as pancreatic necrosis, shock, and distant organ Rare
Autoimmune pancreatitis
failure. Anatomic pancreaticobiliary abnormalities
Much current research focuses on the nature of the ac-
inar cell injury. The prevailing model is that nonphysio-
logic calcium signals initiate the premature intracellular
activation of trypsinogen to trypsin (Fig 1). Trypsin, in Etiology
turn, activates other digestive proenzymes. The activated The disorders associated with pancreatitis fall into sev-
digestive enzymes then mediate acinar cell injury. Re- eral broad categories (Table 1). The prevalence of dif-
cently, this autodigestion model has been challenged. ferent causes varies greatly among studies of acute
In some, if not all, patients with pancreatitis, an aberrant pancreatitis in childhood. The variation likely results
unfolded protein response and the resultant endoplasmic from the inherent limitations of retrospective studies,
reticulum stress may initiate apoptotic pathways and in- the bias or experience of the clinicians caring for children
flammatory signals. (2) who have pancreatitis, incomplete investigations for
causes, the greater number of pa-
tients recognized to have pancreati-
tis, and the recognition of new
etiologies in childhood.
BILIARY DISEASE. Gallstone pan-
creatitis is a more common cause of
acute pancreatitis in children than
previously believed. Gallstone pancre-
atitis or other biliary disease should
be suspected if the patient has eleva-
tions in transaminase levels and/or
hyperbilirubinemia.
SYSTEMIC ILLNESS. In recent stud-
ies, acute pancreatitis associated with
systemic illnesses accounted for more
than 20% of reported cases. Typi-
cally, these children were in an inten-
sive care unit. Pertinent associations
include sepsis, shock (alone or
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 with sepsis), hemolytic uremic syn-
zymogen activation and resulting pancreatic injury and cytokine response, as well as drome, and systemic lupus ery-
potential systemic inflammatory response. Ca2D[calcium. Reprinted with permission from thematosus. Of these diseases,
Bai HX, Lowe ME, Husain SZ. What have we learned about acute pancreatitis in children? J hemolytic uremic syndrome has had
Pediatr Gastroenterol Nutr. 2011;52(3):263 (License Number: 2886070809948). the highest prevalence. (3)(4) The

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


gastrointestinal disorders pancreatitis

pathophysiologic mechanism is uncertain, although it is duct, and histologic features. In children, IgG4 elevation
likely multifactorial. Inflammatory bowel disease can cause may not be present, even with typical histology. In gen-
pancreatitis due to periampullary obstructive small intes- eral, and regardless of serum IgG4 status, pediatric (and
tinal disease, cholelithiasis, associated primary sclerosing adult) patients with type 1 or type 2 autoimmune pancre-
cholangitis, and the effects of immunomodulating med- atitis respond to corticosteroid therapy. (6)
ications (mesalamine and 6-mercaptopurine). It is not
ANATOMIC PANCREATOBILIARY ABNORMALITIES. Pan-
unusual for infectious symptoms to be temporally associ-
creaticobiliary abnormalities such as pancreas divisum
ated with the onset of acute pancreatitis. With a few excep-
(Fig 2), abnormal junction of the common bile duct
tions, such as the mumps virus, few viruses clearly cause
and main pancreatic duct (common channel syndrome),
acute pancreatitis. (3)
choledochal cysts, and annular pancreas increase the risk
for acute pancreatitis. Pancreas divisum is present in up to
MEDICATIONS. A variety of medications increase the
15% of the population. This anatomic abnormality occurs
risk for pancreatitis. Commonly reported associations
when the dorsal and ventral anlage of the pancreas fuse
implicate L-asparaginase, valproic acid, azathioprine,
incompletely, leading to lack of communication between
mercaptopurine, and mesalamine as triggers of pan-
the dorsal (Santorini) and ventral (Wirsung) pancreatic
creatitis. (3) The mechanism behind medication-
ducts. Despite its proposed obstructive mechanism lead-
associated pancreatitis is unclear. In susceptible patients,
ing to acute pancreatitis, clinical causality is still contro-
the medication or its metabolites likely disrupt acinar cell
versial. Recent studies suggest that the presence of a
metabolism.
SPINK-1 (serine protease inhibitor Kazal type 1) or
CFTR (cystic fibrosis transmembrane conductance re-
TRAUMA. Although the prevalence of pancreatitis asso-
ceptor) mutation along with pancreas divisum increases
ciated with trauma is probably not as high as previously
the risk of acute pancreatitis and accounts for the obser-
thought, trauma remains an important cause of pancreati-
vation that only a fraction of people who have pancreas
tis. Most often, unintentional blunt trauma causes damage
divisum develop acute pancreatitis. (7)
to the pancreas, but child abuse can result in traumatic
pancreatitis as well. (5)

IDIOPATHIC. Despite improvements in diagnostic test-


ing, the rate of idiopathic pancreatitis continues to be sig-
nificant and unchanged. (3)(4)

METABOLIC. Although metabolic diseases are uncom-


mon causes of acute pancreatitis, it is important to recog-
nize them because treatment can prevent recurrent
episodes. Disorders that cause hypercalcemia, hypertri-
glyceridemia, and inborn errors of metabolism have all
been associated with acute pancreatitis.

GENETIC/HEREDITARY. The common genetic muta-


tions associated with pancreatitis generally cause ARP
or CP and are discussed in the following text.

AUTOIMMUNE PANCREATITIS. Autoimmune pancrea-


titis has become increasingly recognized in childhood. Figure 2. Magnetic resonance cholangiopancreatography show-
ing pancreas divisum. Dorsal (yellow arrow) and ventral (red
Autoimmune pancreatitis occurs in two forms (types 1
arrow) pancreatic ducts with separate insertion of dorsal
and 2). Type 2 seems to be more common in children
pancreatic duct into minor papillae. The rest of the biliary tree
and has an association with inflammatory bowel disease is delineated: common bile duct (blue arrow), common hepatic
and other autoimmune diseases. In adults, the diagnosis duct (green arrow), right hepatic duct (white arrow), and left
of type 1 autoimmune pancreatitis relies on elevated lev- hepatic duct (orange arrow). Courtesy: William M. Peterson II,
els of immunoglobulin G4 (IgG4), diffuse or segmental MD, and Sameh Tadros, MD, MSc, Department of Radiology;
enlargement of the pancreas, strictures of the pancreatic Children’s Hospital of Pittsburgh of UPMC.

Pediatrics in Review Vol.34 No.2 February 2013 81


gastrointestinal disorders pancreatitis

Diagnosis argument for early imaging. Endoscopic ultrasonography


Acute pancreatitis can occur in mild and severe forms. Al- (EUS) and magnetic resonance cholangiopancreatography
though the definition of the two forms can vary depend- (MRCP) identify cholelithiasis best. (9)(10) MRCP is
ing on the author, in general, mild pancreatitis is limited magnetic resonance imaging of the biliary tree and sur-
to the pancreas and the peripancreatic fat, whereas severe rounding structures (pancreas and liver). Because fluid
disease includes pancreatic necrosis, involvement of other in the pancreaticobiliary ducts appears bright, they can
organs, cardiovascular collapse, infection, or fluid collec- be visualized easily. Although MRCP is expensive and re-
tions. Most children (‡90%) have mild disease. (5) quires general anesthesia in younger children, it has largely
Acute pancreatitis in pediatric patients requires at least supplanted endoscopic retrograde cholangiopancreatogra-
two of three criteria: (1) abdominal pain suggestive of or phy (ERCP) as the preferred diagnostic study for biliary
compatible with acute pancreatitis (ie, abdominal pain of and pancreatic ductal disease because it is less invasive and
acute onset, especially in the epigastric region); (2) serum does not cause pancreatitis, which can occur after ERCP.
amylase or lipase activity at least three times greater than EUS is not widely available in pediatric centers. Trans-
the upper limit of normal; and (3) imaging findings com- abdominal ultrasonography represents a reasonable com-
patible with acute pancreatitis. promise for evaluating patients who have suspected
gallstone disease. Ultrasonography also may provide cor-
ABDOMINAL PAIN SUGGESTIVE OF OR COMPATIBLE roboration of acute pancreatitis and assist in identifying
WITH ACUTE PANCREATITIS. Abdominal pain has a fre- causes. Findings can include pancreatic edema, dilated
quency of 80% to 95% in pediatric patients who have acute main pancreatic duct, pancreatic calcifications, and fluid
pancreatitis. Specifically, pancreatitis has been shown to pres- collections.
ent with epigastric pain in 62% to 89% of patients and dif- Contrast-enhanced computed tomography (CT) of
fusely in 12% to 20% of patients. The classic presentation the abdomen is a second option for imaging the pancreas.
of epigastric pain radiating to the back occurs in only 1.6% A CT scan can show the same findings as ultrasonography
to 5.6% of patients. Epigastric pain plus back pain is present and also may provide information about the presence or
in fewer than 10% of patients. (3) Assessing pain in children absence of pancreatic necrosis. In general, CT scans are
who are nonverbal, have static encephalopathy, or are devel- most useful several days into the course of acute pancre-
opmentally delayed can be challenging. Parental report of ir- atitis if the patient fails to improve or if the pancreas is
ritability is a common presenting sign in nonverbal children. inadequately visualized on ultrasonography.
In infants and toddlers, abdominal distension, vomiting, and
fever were common presenting complaints. (8) Management
The management of acute pancreatitis traditionally has con-
sisted of pancreatic rest (no enteral feeding), antiemetics,
SERUM AMYLASE OR LIPASE ACTIVITY AT LEAST
analgesia, fluid support, and monitoring for complica-
THREE TIMES GREATER THAN THE UPPER LIMIT OF
tions. These treatments remain the mainstay of therapy,
NORMAL. Amylase and lipase values rise 2 to 12 hours
but the approach to pancreatic rest and fluid manage-
and 4 to 8 hours, respectively, after the onset of pancre-
ment has changed.
atic inflammation. It is important to note that the upper
The initial treatment is directed at stabilizing the pa-
reference values of serum amylase and lipase vary among
tient’s condition. Limited adult data suggest that aggres-
different laboratories; hence, reference values should al-
sive hydration in the first 24 hours decreases the risk of
ways be given when considering levels. At present, both
multiorgan system failure. (11) Thus, intravenous fluid
amylase and lipase should be measured because only one
boluses to rehydrate the patient and subsequent fluid ad-
or the other may be elevated in individual patients, even
ministration at 1.5 times maintenance rates are rec-
in the presence of radiographic evidence for pancreatitis.
ommended.
It is important to note that other diseases can cause ele-
Antiemetics and analgesia are necessary to provide
vations of amylase and lipase (Table 2).
comfort and to avoid increased energy expenditure. Opi-
oid analgesics in oral or parenteral forms usually are re-
IMAGING FINDINGS COMPATIBLE WITH ACUTE quired for pain control in acute pancreatitis. There is
PANCREATITIS. The utility and timing of radiographic no evidence to support the advantage of any particular
studies in children who have suspected acute pancreatitis medication. Despite the long-time teaching that morphine
remain controversial (Table 3). The frequency of gallstone should be avoided because it may cause paradoxical
pancreatitis in children provides the most compelling contraction of the sphincter of Oddi, this effect has

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


gastrointestinal disorders pancreatitis

Pediatric Conditions Associated With Elevation of Amylase or


Table 2.

Lipase Levels
Condition Amylase Lipase
Abdominal • Acute pancreatitis • Nonpancreatic abdominal pain
• Biliary tract disease • Acute cholecystitis
• Intestinal obstruction/ischemia • Esophagitis
• Mesenteric infarction • Intestinal obstruction/ischemia
• Peptic ulcer • Peptic ulcer
• Appendicitis
• Ruptured ectopic pregnancy
• Ovarian neoplasm
Salivary gland • Trauma
• Infection (ie, mumps)
• Sialolithiasis
• Irradiation
Thoracic • Pneumonia
• Pulmonary embolism
• Myocardial infarction
• Cardiopulmonary bypass
Infectious • Viral gastroenteritis • Human immunodeficiency virus infection
• Pelvic inflammatory disease
Metabolic • Diabetic ketoacidosis • Diabetic ketoacidosis
• Pheochromocytoma • Hypertriglyceridemia
Neoplastic • Ovarian, lung, esophageal, or thymic tumors
Drugs • Opiates
Trauma • Cerebral trauma
• Burns
Renal • Renal insufficiency • Renal insufficiency
• Renal transplantation
Inflammatory • Macroamylasemia • Macrolipasemia
• Celiac disease • Celiac disease
Miscellaneous • Cystic fibrosis
• Acute liver failure
• Viral gastroenteritis
• Pregnancy
• Eating disorders: anorexia, bulimia

not been demonstrated in clinical practice, and morphine can be resumed in the patients in another 24 hours. (5)
can be used safely in patients who have acute pancreatitis. (14) An increase in serum levels of pancreatic enzymes is
(12) not an indication to stop feedings.
A careful directed investigation for treatable causes of Patients who have severe pancreatitis also can be suc-
acute pancreatitis should be conducted (Table 1). The rou- cessfully fed early in the treatment course. Typically, these
tine use of antibiotics is not recommended; they should be patients are fed through enteral tubes or by using total
reserved for patients who have evidence of infected necrosis. parenteral nutrition (TPN). Enteral feeding is preferred
Perhaps the greatest change in the management of over TPN because of the complications associated with
acute pancreatitis is the early institution of nutrition. In the intravenous catheter and the expense of TPN. The
patients who have mild acute pancreatitis, oral feedings only clear indications for TPN include inability to tolerate
can be started within 24 to 48 hours after admission. enteral nutrition due to prolonged ileus, pancreatic fistu-
In the past, clear liquids were started, but recent studies lae, or complicating abdominal compartment syndrome.
in adults show that regular meals can be given. (13) Lim- The choice of enteral route, gastric or jejunal (which
ited data suggest that the practice of prescribing a low-fat bypasses the ampulla of Vater), is controversial and gen-
diet is not necessary. About 10% of patients will have ab- erally depends on the custom at individual institutions.
dominal pain after starting oral intake. Usually, feedings Both routes have been used successfully in adults who

Pediatrics in Review Vol.34 No.2 February 2013 83


gastrointestinal disorders pancreatitis

Utility of Radiographic Imaging for


Table 3.
to develop, although any fluid col-
lection is called a pseudocyst. Pseu-
Diagnosing Acute Pancreatitis docysts and other fluid collections
typically resolve despite the initial
Imaging Comments
size but occasionally may require
Abdominal ultrasonography Advantages drainage, which can be conducted
• Reasonable test to assess for gallstones by using interventional radiology,
• Short duration
• No radiation exposure
endoscopy, or surgery. Death is
• Usually available any time of day uncommon in pediatric patients
Disadvantages who have pancreatitis, and most re-
• Operator dependence ported deaths occur in patients who
• Potential for bowel gas to obscure have other significant disease, such
pancreas
Abdominal computed tomography Advantages
as trauma or sepsis. (3)(5)
• Better than ultrasonography for Outcomes in acute pancreatitis
detecting changes associated with are similar among pediatric age
pancreatitis groups, are better than in adults,
• Short duration and are not correlated with initial
• Usually available any time of day
• Utility lies in detecting pancreatic
amylase and lipase levels. There are
necrosis if suspected no existing scoring systems similar
Disadvantages to the APACHE (Acute Physiology
• Rather low sensitivity for detecting and Chronic Health Evaluation) or
changes associated with acute the Ranson system used in adults
pancreatitis
• Radiation exposure
that can accurately predict outcome
• Cannot visualize gallstones in pediatrics. (4)
Magnetic resonance Advantages
cholangiopancreatography • Good assessment of pancreatic
parenchyma, ducts, and gallstones Acute Recurrent Pancreatitis
Disadvantages ARP is defined as at least two epi-
• May not be available 24 hours a day sodes of acute pancreatitis per year,
• Limited in acutely ill patients due to
procedure time
or more than three episodes over
• Duration of test may necessitate a lifetime, in a patient without CP
sedation in younger children or a pancreatic pseudocyst. Reliable
estimates of the risk of recurrence
are not available in pediatric patients.
have severe acute pancreatitis. The choice of formula, el- Case series report that 10% to 35% of patients will have re-
emental or polymeric, is also a matter of local practice. currence. (3) The pathophysiology of recurrent episodes
Direct comparisons of elemental and polymeric formulas likely parallels the same pathways that are present in pa-
have failed to demonstrate differences in feeding tol- tients who experience a single episode, although these pa-
erance, morbidity, or mortality between the formulas. tients may have additional genetic modifiers that increase
(15) the likelihood of developing acute pancreatitis, given a par-
ticular trigger.
Complications
Table 4 details the potential local and systemic complica-
tions of acute pancreatitis in pediatric patients. These Etiology
complications also can be classified by early versus late on- As in patients who experience a single episode of pancre-
set. Pancreatic fluid collections are the most common atitis, many patients who have ARP have no identifiable
complication of acute pancreatitis in pediatrics and usually cause for their illness. Table 5 lists common etiologies as-
are caused by necrosis or trauma. Pseudocysts (Fig 3) sociated with ARP. Many of the causes discussed here can
are defined as a homogeneous collection of pancreatic lead to recurrent episodes of pancreatitis, including bili-
fluid encased by a membrane of granulation tissue. It ary disease, anatomic pancreaticobiliary abnormalities, in-
takes approximately 30 days for the granulation tissue flammatory bowel disease, and autoimmune pancreatitis.

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


gastrointestinal disorders pancreatitis

been associated with increased risk for pancreatitis.


Complications of Acute
Table 4. (16)(17)

Pancreatitis PRSS-1. Several mutations in the PRSS-1 gene that


encodes cationic trypsinogen cause hereditary pancreati-
Local
Inflammation
tis. Inheritance is autosomal dominant with an 80% pen-
• Localized to pancreas etrance. The mechanism by which mutations in PRSS-1
• Systemic extension lead to pancreatitis remains under investigation. Prevail-
Ileus ing theories are increased autoactivation of trypsinogen
Pancreatic edema (an inactive form stored in the acinar cell) to trypsin or
Pancreatic necrosis
Pancreatic abscess
increased resistance to inactivation of trypsin within the
Fat necrosis pancreatic hemorrhage acinar cell. Patients present in childhood with ARP and
Pancreatic pseudocyst later progress to CP with a high likelihood of exocrine
Pancreatic duct rupture and endocrine deficiency. The lifetime risk of pancreatic
Pancreatic duct stricture cancer is 40% or greater in these patients. (16)(17)
Thrombosis of adjacent blood vessels
Systemic SPINK-1. The gene product of SPINK-1 is produced in
Shock acinar cells and acts as a defense for premature tryspinogen
Sepsis activation. Several mutations in SPINK-1 increase suscep-
Hypermetabolic state tibility to ARP and CP. Patients who have homozygous or
Hypocalcemia
Hyperglycemia
compound heterozygous mutations have a higher risk than
Vascular leak syndrome patients who have heterozygous mutations. SPINK-1 mu-
Multiorgan system failure tations are considered disease modifiers because most peo-
Disseminated intravascular coagulation ple who have these mutations, even when homozygous, do
Pleural effusions not develop acute pancreatitis, ARP, or CP. The mecha-
Acute renal failure
Splenic artery pseudoaneurysm
nism of increased risk associated with SPINK-1 mutations
is thought to be related to decreased ability to inactivate
trypsin. Definitive evidence for this mechanism is not avail-
able and other mechanisms, such as toxicity from misfolded
protein, remain possible. (16)(17)
Other causes to consider after a second, distinct episode
CFTR. As with SPINK-1 mutations, CFTR mutations
of pancreatitis are discussed in the following text.
are considered disease modifiers. Heterozygous, com-
GENETIC MUTATIONS ASSOCIATED WITH PANCREATITIS. pound heterozygous, and homozygous mutations increase
In the last 15 years, mutations in several genes have 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; Children’s Hospital of Pittsburgh of UPMC.

Pediatrics in Review Vol.34 No.2 February 2013 85


gastrointestinal disorders pancreatitis

increased rates of CTRC mutations in patients who have


Causes of Acute
Table 5. ARP and CP. The mutations are disease modifiers. Be-
Recurrent and Chronic cause CTRC can inactivate trypsin in vitro, it has been
suggested that this gene acts to protect acinar cells from
Pancreatitis inapproporiate trypsinogen activation. (16)(17)

Biliary calculi DRUG-INDUCED PANCREATITIS. A careful review of any


• Macrolithiasis medications and home remedies used by the patient
• Microlithiasis (<2 mm)a should be conducted, and any medications associated
• Sludgea with pancreatitis should be discontinued.
Congenital pancreaticobiliary abnormalities
• Anomalous pancreaticobiliary junction SPHINCTER OF ODDI DYSFUNCTION. The role of sphinc-
• Choledochal cyst ter of Oddi dysfunction in causing ARP in children is un-
• Annular pancreas
• Pancreas divisumb clear. No studies have suggested that sphincterotomy
Geneticc (cutting the muscles around the sphincter) has any effi-
• Hereditary pancreatitis, PRSS-1 mutation cacy in treating children with ARP.
• SPINK-1 mutationb
• CFTR mutation METABOLIC. The metabolic causes for ARP (hypercal-
Duodenal inflammation cemia, hypertriglyceridemia, and inborn errors of metab-
• Crohn disease olism) have not been studied extensively but may be rare
• Celiac disease triggers for ARP.
• Infection
Medications DUPLICATION CYSTS. Duplication cysts of the duode-
Sphincter of Oddi dysfunction num or stomach should be considered; these lesions
Metabolic
• Hypercalcemia may lead to ARP secondary to pancreaticobiliary obstruc-
• Hypertriglyceridemia tion, based on their location. They can be difficult to
Intestinal duplication cyst detect and may be apparent only after multiple investi-
• Gastric gations with different imaging modalities. It is impor-
• Duodenal tant to note that duodenal duplication cysts can
Autoimmune
• Localized to pancreas oppose the head of the pancreas closely and be inter-
• Systemic disorder preted as a pseudocyst.
Idiopathicc
CFTR¼cystic fibrosis transmembrane conductance regulator; PRSS-
Diagnosis and Management
1¼cationic trypsinogen; SPINK-1¼serine protease inhibitor Kazal type The diagnostic criteria for each ARP episode and its treat-
1.
a
Controversial associations.
ment are the same as described earlier for acute pancre-
b
Only causative if present with another predisposing factor (eg, CFTR atitis. It is important to thoroughly explore all potential
heterozygote mutation).
c
Most common causes of chronic pancreatitis in pediatric patients.
causes and triggers because many are preventable and
knowledge of the cause can guide management and
prognosis.
patients who have heterozygous mutations than it is for In cases of ARP, genetic screening for PRSS-1 and
patients with two affected alleles. In general, one or both SPINK-1 mutations should be conducted. Although
affected alleles results in a CFTR protein with some func- complete gene sequencing of CFTR is available, this in-
tion. These patients lack other clinical features of cystic vestigation is not necessary for all patients. A sweat test
fibrosis or have mild disease in other organs and are should be performed. Patients who have mild/variable
pancreatic-sufficient at presentation, although some will CFTR mutations will have values in the indeterminate
develop pancreatic insufficiency over time. When inter- or low positive zones. The presence of a CFTR mutation
preting results of a genetic screen of the CFTR gene, it is can then be confirmed by using complete gene sequenc-
important to remember that the effect of many changes ing. Patients who have CFTR mutations should be re-
in the gene sequence on protein function is unknown. ferred to a CF center for additional evaluation.
(16)(17) The anatomy of the biliary and pancreatic ducts
should be determined by using MRCP. This study also
CTRC. The chymotrypsin C gene (CTRC) encodes can identify annular pancreas or congenital pancreatic
for the digestive enzyme chymotrypsin C. There are cysts. Select patients may require ERCP to confirm and

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


gastrointestinal disorders pancreatitis

possibly treat ductal anomalies. For instance, pancreas di- CLINICAL FEATURES. For many patients, recurrent epi-
visum is treated by using sphincterotomy and stenting sodes of pancreatitis will raise concerns about CP. Pa-
of the minor papilla. Additional evaluation for systemic tients present with mild to intense abdominal pain,
inflammatory disease, especially for Crohn disease, usually epigastric. The pain can be constant or intermit-
should be considered. Upper endoscopy can identify in- tent and often is described as deep and penetrating, with
flammatory or mass lesions that may partially obstruct the radiation to the back. Many times the pain is episodic, as
ampulla. Autoimmune pancreatitis may be suggested by in ARP. There are numerous causes of this pain. The pain
results of the MRCP. IgG4 should be measured although can result from obstruction of pancreatic ducts by fibro-
its utility in identifying children who have autoimmune sis or stones, inflammation of the parenchyma (acute-
pancreatitis has been questioned. Imaging studies, usu- on-CP), perineural inflammation, or pain imprinting in
ally ultrasonography or CT scan, will identify duplication the peripheral or central nervous system. Rarely, patients
cysts. Because current opinion holds that ARP progresses present with symptoms of malabsorption, such as weight
to CP, effective management has the potential to stop loss, fatty stools, or diarrhea. Even rarer are patients who
this progression. present with jaundice from extrahepatic biliary obstruc-
tion caused by pancreatic fibrosis or a pseudocyst. An oc-
Chronic Pancreatitis casional patient will have an upper gastrointestinal
Definition hemorrhage from venous thrombosis as the presenting
CP is defined as a process leading to irreversible destruc- sign. Diabetes develops late in the course of CP, and chil-
tion of the pancreatic parenchyma and ducts and loss of dren seldom, if ever, present with symptoms of diabetes.
exocrine function. Many of these patients have a history
IMAGING. Imaging studies provide evidence of mor-
of ARP before the irreversible changes in pancreatic anat-
phologic change in the gland or ducts. Transabdominal
omy and function become apparent. (18)
ultrasonography, CT, MRCP, ERCP, and EUS each
can provide evidence of chronic change in the pancreas.
Epidemiology
Currently, MRCP is the imaging method of choice. This
CP can present at all ages in children. Classic cystic fibro-
modality has limitations in that the side branches of the
sis is the most common cause in children and will not be
main pancreatic duct are not well defined. ERCP is better
discussed further in this review. The incidence and prev-
at defining ductal anatomy but usually is not required.
alence of CP in childhood are not known.
CT can reliably detect calcification, gland atrophy, fat re-
placement, and ductal dilation but is not as sensitive for
Etiology
duct changes as MRCP or ERCP. In adults, EUS has
The causes of CP are the same as those of ARP (Table 5).
gained acceptance for detecting changes in CP, although
In children, CP is usually idiopathic or associated with
there is disagreement about the standards for diagnosing
mutations in PRSS-1, SPINK-1, CFTR, or CTRC genes,
chronic changes by using this method.
alone or in combination.
PANCREATIC FUNCTION TESTING. Pancreatic function
Pathophysiology testing can identify pancreatic insufficiency and support
CP results from the sequelae of long-standing destructive the diagnosis of CP. Duodenal intubation with secretin-
inflammation. Current theory suggests that CP begins cholecystokinin stimulation remains the reference stan-
with acute pancreatitis and progresses to fibrosis. Instead dard for diagnostic testing, but this option is not widely
of resolution, as in acute pancreatitis, the destructive pro- available. More commonly, pancreatic secretions are
cess continues in susceptible individuals. Susceptibility collected at upper endoscopy. This approach likely
and rate of progression are likely influenced by genetic underestimates pancreatic secretion, leading to the in-
and environmental modifiers. (18) correct diagnosis of pancreatic insufficiency in some pa-
Diagnosis tients. In recent years, fecal elastase has been used to
The diagnosis of CP is clinical and based on a combina- screen for pancreatic insufficiency. This test is widely
tion of symptoms, imaging studies, and functional insuf- available, easy to conduct, and can be performed even
ficiency. It is important to consider all of these parameters if patients are taking pancreatic enzyme supplements.
when CP is suspected in a patient, because diagnosis of- Like all indirect tests, fecal elastase has poor sensitivity
ten is delayed. With advanced disease, amylase and lipase for detecting mild to moderate pancreatic insufficiency.
levels will not be elevated, even in the presence of dis- Lastly, watery stools dilute the fecal elastase concentra-
abling pain. tion, and false-positive findings can occur. The 72-hour

Pediatrics in Review Vol.34 No.2 February 2013 87


gastrointestinal disorders pancreatitis

fecal fat collection remains the best test for steatorrhea. Complications
As with other noninvasive tests, the 72-hour fecal fat col- Long-term natural history studies are beginning to delin-
lection result is abnormal only with advanced disease. Fat eate the prognosis of CP. Contrary to previous teaching,
testing should not be used alone for diagnosis because the pain of CP does not “burn out.” The pain may vacillate
disease of the intestinal mucosa can cause steatorrhea. in intensity and frequency, but it will not resolve with time.
Both pancreatic insufficiency and diabetes appear later in
Management the course. Diabetes may take 2 or 3 decades to become
The stage and etiology of CP determine its management. clinically significant. Even so, pediatric patients will likely
When recurrent episodes of acute pancreatitis dominate develop diabetes in their lifetime. Pancreatic cancer is
the clinical course, the management is identical to that a long-term risk for all pediatric patients who have CP.
of acute pancreatitis. With disease progression, chronic In hereditary pancreatitis, pancreatic cancer appears first
pain management and therapy for pancreatic insufficiency in the fourth decade (incidence of 0.5%), and the incidence
are required. In a few pediatric patients, diabetes will re- increases with age. (21) The high probability of pancreatic
quire treatment. cancer is a factor in deciding whether to proceed with total
Because unrelenting pain affects many patients, most pancreatectomy and islet cell autotransplant.
of the therapeutic effort centers on pain control. At first,
acetaminophen may be effective, but therapy generally
advances to narcotics. Other approaches to pain control
are used, but none has clear efficacy. Pancreatic enzyme
supplements and antioxidant therapy (selenium, ascorbic
Summary
acid, b-carotene, a-tocopherol, and methionine) are pre- • The prevalence of acute pancreatitis is increasing in
scribed frequently as therapeutic trials. pediatrics (based on strong research evidence). (1)
Endoscopic treatment for CP should be considered only • There are etiologic differences between pediatric and
adult patients who develop acute pancreatitis, with
when ductal strictures or pancreatic duct stones are present
a notable rate of idiopathic cases (based on strong
or for symptomatic pseudocysts. The role of endoscopic research evidence). (3)(4)
sphincterotomy and stent placement remains controver- • An elevated amylase or lipase level in the absence of
sial. Surgical approaches are still used in select patients. clinical symptoms or radiologic findings is not
Localized disease can be treated with partial pancreatic diagnostic of pancreatitis, although pediatric patients
who have pancreatitis may have a wide variety of
resection.
presenting clinical symptoms (based on strong
Total pancreatectomy with islet cell autotransplant is research evidence). (3)(8)
currently offered to patients who have genetic causes of • Normal values of amylase and lipase differ among
pancreatitis and to those afflicted with unrelenting pain. laboratories.
Although many patients have pain relief, a number of pa- • Successful early feeding is possible in treating acute
pancreatitis and may not necessitate a low-fat diet or
tients continue to have pain. In up to 20% of adults, the
bypass of the ampulla of Vater (based on some
pain is as intense as it was before the resection. One third research evidence as well as consensus). (5)(15)
of these patients have no insulin requirement; another one • Chronic pancreatitis is a specific diagnosis
third will require low doses of insulin; and the remaining characterized by irreversible pancreatic changes and
one third will develop brittle diabetes. Preadolescents are can be diagnosed only via radiologic and biochemical
evidence, in addition to clinical symptoms (based on
more likely to be insulin-independent than are older chil-
strong research evidence). (16)
dren 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. Unfortu-
nately, no guidelines exist to direct decision-making.
References
1. Morinville VD, Barmada MM, Lowe ME. Increasing incidence
(19)(20) of acute pancreatitis at an American pediatric tertiary care center: is
Pancreatic insufficiency is treated with pancreatic en- greater awareness among physicians responsible? Pancreas. 2010;39
zyme replacement therapy. The goal is to restore diges- (1):5–8
tive function and maintain weight gain and growth. 2. Kubisch CH, Logsdon CD. Endoplasmic reticulum stress and
the pancreatic acinar cell. Expert Rev Gastroenterol Hepatol. 2008;2
Because no studies of the effective dose range exist for
(2):249–260
patients who have pancreatitis, the recommendations 3. Bai HX, Lowe ME, Husain SZ. What have we learned about
for treating patients who have cystic fibrosis are used acute pancreatitis in children? J Pediatr Gastroenterol Nutr. 2011;
for enzyme dosing in patients who have CP. 52(3):262–270

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4. Lautz TB, Chin AC, Radhakrishnan J. Acute pancreatitis in 14. Jacobson BC, Vander Vliet MB, Hughes MD, Maurer R,
children: spectrum of disease and predictors of severity. J Pediatr McManus K, Banks PA. A prospective, randomized trial of clear
Surg. 2011;46(6):1144–1149 liquids versus low-fat solid diet as the initial meal in mild acute
5. Lowe ME, Greer JB. Pancreatitis in children and adolescents. pancreatitis. Clin Gastroenterol Hepatol. 2007;5(8):946–951,
Curr Gastroenterol Rep. 2008;10(2):128–135 quiz 886
6. Sugumar A, Chari ST. Autoimmune pancreatitis. J Gastroenterol 15. Petrov MS, van Santvoort HC, Besselink MG, Cirkel GA,
Hepatol. 2011;26(9):1368–1373 Brink MA, Gooszen HG. Oral refeeding after onset of acute
7. Bertin C, Pelletier AL, Vullierme MP, et al. Pancreas divisum is pancreatitis: a review of literature. Am J Gastroenterol. 2007;102
not a cause of pancreatitis by itself but acts as a partner of genetic (9):2079–2084, quiz 2085
mutations. Am J Gastroenterol. 2012;107(2):311–317 16. LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin
8. Kandula L, Lowe ME. Etiology and outcome of acute pancre- Gastroenterol. 2011;27(5):467–474
atitis in infants and toddlers. J Pediatr. 2008;152(1):106–110, 110.e1 17. Rosendahl J, Landt O, Bernadova J, et al. CFTR, SPINK1,
9. O’Neill DE, Saunders MD. Endoscopic ultrasonography in CTRC and PRSS1 variants in chronic pancreatitis: is the role of
diseases of the gallbladder. Gastroenterol Clin North Am. 2010 mutated CFTR overestimated [published online ahead of print
Jun;39(2):289–305 March 17, 2012]? Gut.
10. Yeh BM, Liu PS, Soto JA, Corvera CA, Hussain HK. MR imaging 18. Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic
and CT of the biliary tract. Radiographics. 2009;29(6):1669–1688 pancreatitis. Lancet. 2011;377(9772):1184–1197
11. Nasr JY, Papachristou GI. Early fluid resuscitation in acute 19. Schmulewitz N. Total pancreatectomy with autologous islet
pancreatitis: a lot more than just fluids. Clin Gastroenterol Hepatol. cell transplantation in children: making a difference. Clin Gastro-
2011;9(8):633–634 enterol Hepatol. 2011;9(9):725–726
12. Thompson DR. Narcotic analgesic effects on the sphincter of 20. Rodriguez Rilo HL, Ahmad SA, D’Alessio D, et al. Total
Oddi: a review of the data and therapeutic implications in treating pancreatectomy and autologous islet cell transplantation as a means
pancreatitis. Am J Gastroenterol. 2001;96(4):1266–1272 to treat severe chronic pancreatitis. J Gastrointest Surg. 2003;7(8):
13. Moraes JM, Felga GE, Chebli LA, et al. A full solid diet as the 978–989
initial meal in mild acute pancreatitis is safe and result in a shorter 21. Howes N, Lerch MM, Greenhalf W, et al. European Registry
length of hospitalization: results from a prospective, randomized, of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC).
controlled, double-blind clinical trial. J Clin Gastroenterol. 2010;44 Clinical and genetic characteristics of hereditary pancreatitis in
(7):517–522 Europe. Clin Gastroenterol Hepatol. 2004;2(3):252–61

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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, mid-
epigastric 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, mid-
epigastric 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.

Pediatrics in Review Vol.34 No.2 February 2013 89


gastrointestinal disorders 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. Has a small (<10%) lifetime risk of developing pancreatic cancer.
B. Has decreased risk related because of her adequate insulin production.
C. Is at small risk for developing pancreatic cancer in her 30s.
D. Is at the same risk as the general population.
E. 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 boy’s father and paternal grandmother also
have a history of recurrent pancreatitis. The boy’s grandmother had pancreatic cancer and is deceased. The
boy’s father takes pain medication daily for chronic pancreatitis. On further testing, the most likely study to
elucidate the etiology of this boy’s 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. He should undergo endoscopic sphincterotomy before considering pancreatectomy.
B. His life-time risk for diabetes is much higher with the surgery.
C. His risk for diabetes after pancreatectomy is related to islet cell yield with the procedure.
D. Pancreatic enzyme function is preserved after pancreatectomy.
E. The pain from his pancreatitis will resolve after pancreatectomy.

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


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
Author Disclosure occlusion and hyperkeratinization, with comedo formation, as well as microbial coloniza-
Drs Sawni and Singh
tion of pilosebaceous follicles by Propionibacterium acnes, leading to inflammatory papules
and pustules. Conventional treatments for acne include salicylic acid, benzoyl peroxide, ret-
have disclosed no
inoids, and antibiotics (topical and systemic). However, symptoms may not always im-
financial relationships prove, and patients may have adverse reactions to conventional treatments and thus
relevant to this article. seek alternative treatments. Antibiotic resistance in P acnes also has been rising, thus pro-
This commentary does moting the need to look at alternative therapies. (2)
contain a discussion of
an unapproved/ Dietary and Lifestyle Factors
investigative use of The influence of diet on acne has been debated for decades. One review of the literature
a commercial product/
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
device.
link between acne and foods such as dairy products, chocolate, and fatty foods. (4) How-
ever, with more recent focus on diet and nutritional supplements, emerging research sug-
gests that diet may be a factor, particularly in mediating the inflammation 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 stimu-
late 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 beneficial 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 gly-
cemic 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 acne-
stimulating effect. (12)
These cohort studies, however, can only suggest correlation, not causation. Stress also
has been blamed as a trigger for acne flares. Two independent groups of researchers studied
high school and university students and found that increased
stress levels during examination periods correlated with in-
creased acne severity. (13)(14) The mechanism by which
Abbreviations stress negatively affects acne is unclear, but practicing
EFAs: essential fatty acid mind–body therapies, such as yoga, to reduce stress
LTB4: leukotriene B4 may be beneficial for patients who have acne as well.

*Pediatric Education, Hurley Children’s Hospital/Hurley Medical Center, Flint, MI.



Department of Dravyaguna (Medicinal Plants), Sri Dhanwantry Ayurvedic College, Chandigarh, India.

Pediatrics in Review Vol.34 No.2 February 2013 91


complementary medicine

Nutritional Supplements and Phytochemicals bark has been used to treat acne because of its naturally
Arachidonic acid (omega-6 fatty acid, which is a major astringent properties. (24) To date, no randomized trials
part of a Western diet) is a precursor to the manufacture have been conducted to substantiate the use of this agent,
of proinflammatory leukotriene B4 (LTB4). The involve- but it is used often in acne products.
ment of LTB4 in the pathogenesis of acne has been de-
scribed; a study looking at the administration of a novel Tea Tree Oil
LTB4 blocker found a 70% reduction in inflammatory Green tea extract and tea tree oil have been investigated in
acne lesions. (15) the treatment of acne. Tea tree oil is an essential oil of the
The anti-inflammatory properties of omega-3 essential native Australian tree Melaleuca alternifolia and has been
fatty acids (EFAs), including LTB4 inhibition, are well shown to have antibacterial and antifungal properties. (25)
known. (16) To the best of our knowledge, there are no A randomized, double-blind, placebo-controlled study in-
studies that have looked at the direct effect of supplemen- vestigated the efficacy of 5% topical tea tree oil gel in 60
tation with omega-3 EFAs on acne, although a diet high patients (age 15–25 years) who had mild to moderate
in omega-3 EFAs may have a synergistic effect with a low- acne vulgaris. Total lesion count (TLC) and acne severity
glycemic-load diet on improving acne. (6)(17) index (ASI) scores were used to determine efficacy of the
Lactoferrin (a whey milk protein/iron-binding protein) treatment. (26) Tea tree oil gel was 3.55 times (for TLC
as a dietary supplement also has been shown to decrease score) and 5.75 times (for ASI score) more effective than
skin inflammation due to its broad antibacterial and anti- placebo.
inflammatory activities. (18) Two trials, one an open-label, A single-blind, randomized clinical trial of 124 patients
single-arm study and the other a double-blind, placebo- who had mild to moderate acne was conducted to evaluate
controlled study, looked at the efficacy and tolerability the efficacy and skin tolerance of 5% tea tree oil with 5%
of lactoferrin in adolescents and young adults who benzoyl peroxide lotion. (27) After 3 months of treatment,
had mild to moderate facial acne vulgaris. (19)(20) They both 5% tea tree oil and 5% benzoyl peroxide reduced acne
found a significant reduction in the inflammatory acne le- significantly, but fewer adverse effects were reported with
sion count in the lactoferrin group. The results suggest the use of tea tree oil (44% vs 79%). The onset of action
that dietary supplementation with bovine lactoferrin in was slower, however, in the tree tea oil therapy group.
mild to moderate acne vulgaris can decrease acne lesions. Green tea has catechins, which are phytochemical phe-
Another nutritional supplement called APC (methi- nolic compounds that have anti-inflammatory effects. Two
onine-based zinc complex, chromium, and vitamins with studies assessed the efficacy of topical 2% green tea lotion
antioxidants) was studied in an observational pilot study (natural plant extract) in the treatment of mild to moderate
of 48 patients (age 15–35 years) who have acne. The oral acne vulgaris in adolescents and young adults. Topical 2%
form of this supplement was given thrice daily for 3 green tea lotion was found to be significantly effective
months. At the end of treatment (week 12), there was a sta- for mild to moderate acne vulgaris. (26)(28)(29) Several
tistically significant improvement in the global acne count, other natural ingredients, such as colloidal oatmeal, feverfew,
with a decrease in pustules and papules (P < .001). (21) licorice, aloe vera, chamomile, curcumin, soy, coffeeberry,
Resveratrol is a natural compound produced by some mushroom extracts, pine bark extract, vitamin E, vitamin
spermatophytes, such as grapes and other plants, that has C, and niacinamide, have antioxidant, anti-inflammatory,
been shown to be anti-inflammatory and active against or moisturizing properties; thus, these ingredients may be
several bacteria, including P acnes. (22) A single-blind pi- effective adjuncts with other acne therapies to decrease
lot study of 20 patients assessed the therapeutic effects of the erythema associated with inflammatory acne. (30)
resveratrol on acne vulgaris. (23) Resveratrol gel was ap-
plied daily on the right side of the face for 60 days, com- Ayurvedic Herbs
pared with a control hydrogel on the left side of the face. Two randomized, double-blind, placebo-controlled clin-
There was a 53.75% mean reduction in the global acne ical studies exploring the efficacy of ayurvedic treatment
grading system score on the resveratrol-treated sides of (a Hindu system of traditional medicine) in acne have
the face compared with 6.10% on the control sides. been published. These studies indicate that some ayurve-
dic remedies might be effective for acne. One study dem-
onstrated that the combination of an oral ayurvedic
Biochemical Therapies preparation and a topical ayurvedic, multicomponent
Few herbal medicines have been evaluated systematically preparation (cream or gel) was more efficacious in treat-
in clinical trials. Witch hazel (Hamamelis virginiana) ing acne than oral therapy alone. (31) Another study

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


complementary medicine

found that treatment with an oral preparation of sunder of infrared nonablative lasers to target sebaceous glands
vati resulted in a significant reduction in acne lesion count has resulted in the creation of a number of laser, light,
and was well tolerated. Treatment with three other oral and radiofrequency devices for acne. The main light
formulations that were studied failed to show any im- and laser therapies used to treat acne include intense
provement. (32) pulsed light; pulsed dye lasers; and broad-spectrum,
continuous-wave, blue and red visible light. A few studies
Traditional Chinese Medicine/Acupuncture have shown some positive results, and light and laser
A few small studies in adults have looked at the effective- treatments may be effective and safe for acne, although
ness of traditional Chinese herbs and acupuncture for the more studies are needed. (36)(37)
treatment of acne and found them to be promising.
A double-blind, controlled trial evaluated the efficacy 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 Summary
(papules and nodules of acne) to directly reduce inflamma-
• Preliminary evidence and small pilot studies, mostly in
tion of the acne site. After 12 treatment sessions, there was young adults, suggest that complementary and
a significant reduction in the inflammatory acne lesion alternative therapies may have some value in the
counts, the scores on a quality of life scale (Skindex-29, treatment of acne.
a self-administered questionnaire designed to measure the • Some emerging data suggest that dietary modification
effects of skin diseases on patients’ quality of life), and the (in particular, decreasing the glycemic index and
glycemic load), as well as supplementation with
subjective symptom scores from baseline in both groups. omega-3 essential fatty acids, may be beneficial in
A Chinese herbal compound, compound oldenlandis acne management.
mixture, was compared with angelica and sophora root • A few small pilot studies have reported efficacy of
pills in 120 patients who had acne, and the patients were some herbs and nutritional supplements, traditional
found to have 73% improvement in acne lesions. (34) A Chinese medicine, ayurvedic herbs, and phototherapy
in the treatment of acne.
meta-analysis evaluated the therapeutic effect and safety • More research and larger clinical trials are warranted
of acne treatment with acupuncture and moxibustion in the evaluation of the effectiveness of
compared with routine Western medicine. It was con- complementary therapies in treating acne.
cluded that comprehensive acupuncture/moxibustion
was safe and effective, and possibly better than routine
Western medicine, for the treatment of acne. (35)
Note: To view the references for this article, visit the Feb-
Light Therapy ruary issue at http://pedsinreview.aappublications.org
Acne therapy using various light sources that target Pro- and click on the “Complementary, Holistic, and Inte-
pionibacterium species seems promising. The development grative Medicine” article.

Pediatrics in Review Vol.34 No.2 February 2013 93


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 Presentation Chlamydia and gonorrhea, hemoglo-
A 17-year-old girl presents with inter- bin electrophoresis, serum lactic acid
mittent right upper extremity swell- dehydrogenase level, and uric acid
The reader is encouraged to write ing and pain over the past 2 years. level, are normal or negative.
possible diagnoses for each case before Her symptoms began after an episode Radiographs of cervical spine, chest,
turning to the discussion. of Bell’s palsy. She describes swelling right elbow, forearm, and hand as well
and an “electrical shooting” pain in as magnetic resonance imaging (MRI)
the right shoulder that radiates to- of the brain, cervical spine, and entire
The editors and staff of Pediatrics in
ward her hand, followed by a cool feel- arm are normal. Right upper extrem-
ing of the hand and decreased range ity vascular duplex ultrasonography
Review find themselves in the
of motion of the arm. The episodes shows normal flow without evidence
fortunate position of having too many occur during both summer and winter of a deep venous thrombosis.
submissions for the Index of Suspicion and can last anywhere from 2 to 30
column. Our publication slots for Index days. Initially, between these episodes,
of Suspicion are filled through 2013. she regained normal function, but re- Case 2 Presentation
Because we do not think it is fair to
cently has noted residual weakness. A previously healthy 7-year-old His-
She denies any history of trauma, fe- panic girl presents with pain behind
delay publication longer than that, we
ver, rash, or muscle weakness. the left ear. The mother reports that
have decided not to accept new cases On examination, there is swelling 3 days ago, while she was combing
for the present. We will make an of the entire right arm. The nails are her daughter’s hair, the patient com-
announcement in Pediatrics in Review normal. The right arm is colder in plained of pain, and the mother no-
when we resume accepting new cases. comparison with the left and has de- ticed a red and irritated area behind
We apologize for having to take this
creased hair growth. Peripheral pulses the left ear. There has been no fever,
and capillary refill were normal. Pin- loss of appetite or weight, sick con-
step, but we wish to be fair to all
prick and temperature sensations are tacts, recent travel, trauma, or animal
authors. We are grateful for your intact, without hyperesthesia. Range contacts. Her family history is non-
interest in the journal. of motion of the right arm, forearm, contributory. Her immunizations are
and hand is compromised because of up to date, and a recent tuberculin test
pain. Except for her right arm, she is result was negative.
Author Disclosure warm, well perfused, and free of joint On physical examination, the girl
Drs Castillo, Flores, Nunez, and swelling. The muscle tone is normal, is not in acute distress. Her vital signs
and strength in the other muscle are within normal limits. Her weight
Torralbas have disclosed no financial
groups is 5/5. and height are both at the 75th per-
relationships relevant to this article.
Laboratory studies reveal an erythro- centile for age. In the left mastoid
This commentary does not contain cyte sedimentation rate of 15 mm/h, area there is a 2-cm yellowish-brown
discussion of unapproved/ C-reactive protein <0.5 mg/dL, white nodule and numerous satellite pap-
investigative use of a commercial blood cell count of 6.3 to 103/mL, and ules around the primary lesion. The
product/device. creatine phosphokinase level of 100 nodule is tender to palpation. A num-
U/L. The results of additional labo- ber of firm and nontender posterior
ratory studies, including antinuclear cervical nodes are palpable bilaterally.
antibody, rheumatoid factor, anti- Findings on the rest of the examina-
body test for Borrelia burgdorferi, tion are normal.
rapid plasma regain test for syph- Laboratory tests, including com-
ilis, urine-amplified DNA assay for plete blood count, erythrocyte

Pediatrics in Review Vol.34 No.2 February 2013 95


index of suspicion

sedimentation rate, and urinalysis, as is caused by a disruption of the auto- abnormal motor activity in the re-
well as levels of serum electrolytes, nomic nervous system. The Interna- gion of pain
blood urea nitrogen, creatinine, liver tional Association for the Study of 3. Exclusion of the diagnosis by
enzymes, and C-reactive protein are Pain (IASP) has divided CRPS into the existence of any condition that
normal. An imaging study explains two types based on the detection of would otherwise account for the
the lesion behind her left ear, and a nerve lesion. Type 1 is not associ- degree of pain and dysfunction.
the histologic findings of skin, bone, ated with an identifiable nerve lesion,
and lymph node biopsies confirm the whereas type 2, previously known as
All three criteria must be present
diagnosis. causalgia, presents evidence of obvi-
to make the diagnosis.
ous nerve damage. It is unclear what
No specific laboratory or imaging
causes the abnormal pain sensations
studies are available to establish the
that typify CRPS, but injury of the
Case 1 Discussion diagnosis of CRPS, and most experts
affected body part and stress seem
This patient was evaluated thoroughly agree that diagnostic studies are not
to play a role.
by consultants from anesthesiology, necessary to make the diagnosis.
Most cases of CRPS occur in the
neurology, and rheumatology. Her However, the following tests have
fourth decade after birth. However,
pain was poorly controlled with mor- been found useful in confirming the
the incidence of CRPS among chil-
phine. During her hospitalization, diagnosis:
dren is increasing.
the skin temperature along her right Three-phase bone scan and gado-
arm became normal, but she devel- linium MRI have been used to diag-
Diagnosis nose and stage the disease. Although
oped hyperesthesia and allodynia
The most widely accepted criteria for radiographs can be normal in as
(perception of pain from a nonpainful
the diagnosis have been published by many as 30% of patients, osteoporo-
stimulus) of her right arm. She also
IASP (1) and are as follows: sis may be demonstrated as early as
developed tenderness of the right tra-
pezius muscle. She was unable to 1. The presence of an initiating noxious 3 to 5 weeks after the onset of the
move her fingers because of weak- event or a cause for immobilization symptoms. Laser Doppler flow stud-
ness. Temperature sensation was de- 2. Continuing pain, allodynia, or ies have been used to monitor back-
creased over the entire surface of the hyperalgesia disproportionate to ground vasomotor control. A cold
arm. the inciting event pressor test performed in conjunc-
After ruling out other possible 3. Evidence at some time of edema, tion with thermographic imaging
causes, such as malignancy, postin- changes in skin blood flow, or ab- may demonstrate a vasoconstrictor
fectious reaction, and rheumato- normal motor activity in the area response.
logic diseases, it was felt that she of pain Treatment
met criteria for complex regional 4. Exclusion of the diagnosis by the A number of different treatment mo-
pain syndrome (CRPS). A trial of existence of any condition that dalities are available, including nerve
gabapentin and amitriptyline was would otherwise account for the blockades; medications such as topi-
begun and her symptoms improved. degree of pain and dysfunction. cal analgesics, gabapentin, tricyclic
Subsequently, she had a nerve block antidepressants, and corticosteroids;
placed, following which she regained and psychotherapy. Physical therapy
use of her arm. She has had some Criteria 2 through 4 must be pres-
ent for the diagnosis. is an essential and nonnegotiable part
residual weakness, for which she is of treatment. It is extremely impor-
receiving physical and occupational According to the IASP, the diag-
nostic criteria for CRPS II (also tant to restore normal function of
therapy. the affected body part through vigor-
known as causalgia) are as follows:
ous and intense physical therapy.
The Condition 1. The presence of continuing pain, Additionally, tactile stimulation can
CRPS type 1, formerly known as re- allodynia, or hyperalgesia after reduce the associated pain and swell-
flex sympathetic dystrophy syndrome, a nerve injury, not necessarily lim- ing significantly.
is a chronic progressive disease char- ited to the distribution of the in-
acterized by severe pain, swelling, jured nerve Prognosis
and changes in the skin. Current un- 2. Evidence at some time of edema, The prognosis is good if the condition
derstanding of this condition is that it changes in skin blood flow, or is treated early, ideally within the first 3

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


index of suspicion

months of onset. Patients may develop estimated to be 1/200,000 children including skin, liver, spleen, lung,
permanent muscle, nerve, and skin younger than 15 years of age. The and bone marrow).
damage if CRPS is not diagnosed name of the disease is derived from
and treated in a timely fashion. the type of cell involved, which is Clinical Presentation
the histiocyte. Normal histiocytes The clinical manifestations depend
originate from pluripotent stem cells, on the site of the lesions and on the
Lessons for the Clinician
which can be found in bone marrow. organs involved. LCH can affect a sin-
• CRPS is a diagnosis that some- Under the influence of various cyto- gle organ or multiple organs. Bone
times is overlooked but should kines, these precursor cells can be involvement, which can be a single
be considered if there is intense committed to becoming specialized lesion or multiple lesions, is observed
and intractable pain, especially in cells, monocytes, which migrate from in 80% of patients. Skull bones are in-
an isolated area the bloodstream to their various tis- volved in 50% of cases. Symptoms
• For most patients, the diagnosis sue sites and differentiate into mac- due to bone involvement are swelling
and treatment are delayed by rophages and dendritic cells. or lumps on the skull, which can be
months and even years Macrophages are found in loose painful. Long-bone involvement can
• Early diagnosis and treatment can connective tissues and some organs cause fractures.
prevent long-term damage, such as (Kupffer cells of the liver), and Cutaneous disease occurs in 50%
muscle atrophy, joint contractures, their main function is phagocytosis. of patients, usually during the first
and possible permanent loss of func- Dendritic cells, which are antigen- months after birth, presenting as
tion of the affected extremity. presenting cells to T and B lympho- papulosquamous, erythematous, pete-
cytes, are known as Langerhans cells chial patches suggestive of eczema or
(Rhina Castillo, MD, Josue Flores,
in the skin. Histiocytosis, with accu- seborrheic dermatitis. Lymph node
MD, Randolf Nunez, MD, Depart-
mulation and infiltration in the af- enlargement is observed in 30% of pa-
ment of Pediatrics, Lincoln Medical
fected tissues, is believed to be due tient, whereas pulmonary involvement
& Mental Health Center, New York,
to dysfunction of lymphocytes and occurs in 20% to 40% of patients. Re-
NY)
cytokines. The Histiocytosis Society spiratory symptoms include cough,
classifies the histiocytic syndromes in- dyspnea, and chest pain due to pneu-
to dendritic cell-related (Langerhans mothorax. Other organs also may
Case 2 Discussion cell histiocytosis and juvenile xanthog- be involved, with hepatic manifesta-
CT scan of the temporal bones revealed ranuloma) and macrophage-related tions that include hepatomegaly with
a destructive soft tissue lesion. The dif- (hemophagocytic lymphohistiocytosis, hypoalbuminemia, increased liver en-
ferential diagnosis included a small familial, or primary and acquired) zymes levels, and clotting factor
round cell tumor, such as neuroblas- disorders. deficiency.
toma, rhabdomyosarcoma, and lym- One century has passed since his- Patients also can present with diar-
phoma or leukemia. Langerhans cell tiocytic disorders were recognized. rhea, gingival hypertrophy, ulcers of
histiocytosis was another consideration. In 1987, the Histiocytosis Society the oral mucosa, and discharge from
The patient was referred to the pedi- adopted the name LCH and defined the ear. Splenic involvement can lead
atric hematologist/oncologist, who the criteria for diagnosis. Langer- to hypersplenism. Both hypersplenism
obtained an MRI of the brain that con- hans refers to Dr Paul Langerhans, and bone marrow involvement can
firmed the findings on CT scan. A skel- who first described these cells in cause anemia and thrombocytopenia.
etal survey showed an additional lytic the skin. In the past, the condition LCH can infiltrate various areas of
lesion of the right humeral epiphysis. was called histiocytosis X, encom- the brain, resulting in cerebellar dys-
Her bone marrow examination yielded passing three clinical conditions: eo- function, seizures, and disruption of
normal results. Findings on biopsy con- sinophilic granuloma (a disease that hypothalamic and pituitary function
firmed the diagnosis of Langerhans cell affects a single part of the body, that can cause diabetes insipidus.
histiocytosis (LCH) of bone. eg, bones); Hand-Schuller-Christian
disease (involving bones, pituitary Diagnosis
The Condition gland causing diabetes insipidus, Laboratory evaluation depends on
LCH is a rare disorder that occurs at and exophthalmos); and Letterer- the extent of the disease suspected
any age but most frequently affects Siwe disease (which affects mainly on the basis of the history and phys-
young children. The incidence is newborns and has systemic involvement, ical findings. The diagnosis is always

Pediatrics in Review Vol.34 No.2 February 2013 97


index of suspicion

made on cytologic examination. Re- that 15% to 20% of patients achieve resection of her bony lesions. She
gardless of the clinical severity, the spontaneous regression when they has responded well to therapy.
histopathology of LCH generally is have localized disease.
uniform. An electron microscopic Chemotherapy is recommended for
finding of racquet-shaped bodies multisystem disease. A number of com- Lessons for the Clinician
(Birbeck granules) in the cells labeled binations of chemotherapeutic ag-
• Because of its diverse clinical pre-
with anti-CD1a antibodies confirms ents, including vinblastine, vincristine,
sentations, the differential diagno-
the pathologic diagnosis. and 6-mercaptopurine as well as cor-
sis of LCH can be extensive.
CT and MRI imaging are used to ticosteroids, are used for treating
• Timely intervention may decrease
determine the extent of organ system multisystem disease. Radiation ther-
morbidity and mortality and thus
involvement and can help in staging apy is effective for localized disease.
improve prognosis.
the disease. Myeloablative therapy followed by
bone marrow transplantation has been (Alfredo Torralbas, MD, Doctors Medical
Treatment and Prognosis tried in patients with refractory disease. Center & Miami Children Hospital,
Progress has been made in under- Long-term follow-up by a team of Miami, FL)
standing the pathogenetic mecha- individuals with experience in man-
nisms of LCH, which has helped to aging patients with LCH is critical,
Reference
design effective therapy. The goal of because there is a significant risk of Merskey H, Bogduk N, eds. International
therapy is to relieve clinical symptoms developing late complications of Association for the Study of Pain. Classi-
and prevent complications. Multidisci- the disease or adverse effects of treat- fication of Chronic Pain: Descriptions of
plinary care is essential for all patients. ment. The extent of organ involvement Chronic Pain Syndromes and Definitions
of Pain Terms. Seattle, WA: IASP Press;
For single-system disease, observation and the rapidity of the response to
1994
or local therapy only is recommended, chemotherapy correlate with the
including topical corticosteroids for prognosis. To view Suggested Reading lists
skin lesions and curettage if there is lo- This patient received a chemo- for these cases, visit http://pedsinreview.
calized bone involvement. This rec- therapeutic regimen which includ- aappublications.org and click on
ommendation is based on the fact ed vinblastine and prednisone after 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

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


visual diagnosis

A 3½-year-old Boy With Sickle


b-Thalassemia and a Groin Mass
Aditi Bagchi, MD,* Ashraf Elnawawi, MD,†
Swayam Sadanandan, MD‡

Presentation
A 3½-year-old boy with a history of sickle b-thalassemia
presents to the hematology/oncology clinic for evalua-
tion of a mass in his left groin. The child’s mother had
noted a small lump in his left inguinal region 2 years
ago. At that time, the pediatrician recommended observ-
ing the lump and monitoring any progression. Subse-
quently, 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.
Figure 1. Computed tomography scan reveals a well-circum- He was prescribed a 5-day course of oral antibiotics
scribed soft tissue mass in the left groin, w3 cm 3 4 cm in for a presumed local infection. However, there was
cross-sectional dimension. no significant 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
Author Disclosure habits. There is no history of trauma.
Drs Bagchi, Elnawawi, and Sadanandan have disclosed no The child was born at term after an uncomplicated
financial relationships relevant to this article. This
pregnancy and delivery, but newborn screening indicated
sickle cell disease. On further evaluation, his mother was
commentary does not contain discussion of unapproved/
found to have b-thalassemia trait and his father had sickle
investigative use of a commercial product/device. 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 docu-
mented bacteremia. He has not had any vaso-occlusive cri-
ses. 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 en-
larged 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-defined 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 firm, 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 findings are normal.
Laboratory examination shows a hemoglobin level of
8.8 g/dL (11.0–15.6 g/dL), white blood cell count of
8.5  103/mL (4.0–12.0  103/mL), and platelet count
348  103/mL (130–400  103/mL). Mean corpuscular
volume is 76 fL (78.0–95.0 fL), and reticulocyte count
is 4% (1%–2%). Lactate dehydrogenase concentration
is 376 U/L (125–243 U/L). Serum electrolyte levels
and liver function test results are normal. Epstein-Barr vi-
rus titers are negative. Hemoglobin electrophoresis
shows 4.1% (0%–4.0%) hemoglobin A2, 34.3% hemoglo-
bin F (0%–5%), and 61.6% hemoglobin S (0%).
Figure 2. Computed tomography scan reveals a few punctate
Based on physical and laboratory findings, the patient
calcifications (arrow) within the mass.
is suspected of having either a sclerotic lymph node mass,
a calcified hematoma, a myoma, a lymph node mass with
fibrotic changes, a benign testicular tumor, or a rare fi- staining with antibodies against factor XIIIa. CD34 anti-
broid tumor such as a calcifying fibrosing pseudotumor body staining also showed endothelial cells and localized
or spindle cell tumor. fibroblasts. These findings were consistent with a calcify-
To further distinguish the mass, a computed tomog- ing fibrous pseudotumor (CFP).
raphy scan is performed. A well-circumscribed soft tissue
mass, w3 cm  4 cm in cross-sectional dimension (Fig 1)
shows a few punctate calcifications (Fig 2). The left testis
is normal. Based on the computed tomography scan find-
ings, 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, firm, and ad-
herent, but separable from the testicle and the scrotum.
The mass also adheres to the floor 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.

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 infil-
trated by spindle cells arranged in an irregular fascicular
pattern. Dense hyalinized collagen was marked by in-
flammatory infiltration, primarily by lymphocytes and
plasma cells (Fig 4). Eosinophils, neutrophils, and mast
cells were present in variable numbers. Calcifications
were dystrophic, ossifying, or psammomatous (Fig 5).
No necrosis, atypia, or mitoses were noted. Immunohis-
tochemically, the spindle cells showed diffuse cytoplasmic Figure 3. A biopsy is performed on the left-sided groin mass.

e6 Pediatrics in Review Vol.34 No.2 February 2013


visual diagnosis

The etiology and pathogenesis of this recently de-


scribed distinctive lesion remain unclear. These lesions
are thought to be reactive, without evidence of any spe-
cific cytogenetic abnormality. A possible relationship with
other pseudotumors, such as nodular fasciitis or inflam-
matory myofibroblastic tumor (IMT), has been proposed.
IMT describes a spindle cell tumor with a variable inflam-
matory component; its cause is unknown. In a recent pub-
lication, CFP was proposed to a burned out or late
sclerosing IMT. However, there are no convincing mor-
phologic or immunophenotypic features that would sup-
port the classification 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
Figure 4. Microscopy reveals the presence of plasma cells
by a proliferation of fibroblastic spindle cells embedded
(arrows) within dense hyalinized matrix.
in a dense stroma showing variable degrees of mineral-
ization and inflammation. Stromal calcification may be
Discussion
psammomatous or dystrophic in appearance. The amount
CFP is a rare benign lesion, first described in 1988 under
of inflammation is variable; but, in all cases, the inflamma-
the name of “childhood fibrous tumor with psammoma
tory cells are primarily plasma cells and, to a lesser extent,
bodies.” (The descriptive term “psammoma” refers to
lymphocytes. Occasionally, eosinophils and mast cells with
a round collection of calcium.) A series of ten cases
rare reactive giant cells appear. Identification of the spindle
was reported in 1993, and the term “calcifying fibrous
cells in CFP is achieved by diffuse cytoplasmic staining by
pseudotumor” was used for the first time. Initial reports
antibodies against factor XIIIa and the protein vimentin;
suggested that these lesions occurred mainly in young
there may be some focal staining for the glycoprotein
children. However, CFP occurs in almost all age groups.
CD68.
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
Differential Diagnosis
CFP can present with inflammatory or infectious clinical
case reports of multiple tumors occurring at the same
features. CFP should be distinguished pathologically
time. CFP can appear in the soft tissues of the trunk,
from fibrous inflammatory lesions, fibromatosis, other
limbs, peritoneum, epididymis, neck, pleura, chest wall,
spindle cell neoplasms, and IMT. In general, IMT has
and mediastinum.
a higher incidence than CFP and tends to occur in the
retroperitoneal region. Histologically, IMT can vary from
hyalinized, hypocellular area to areas with florid fibroblas-
tic proliferations that may suggest sarcomas. Calcifica-
tions are rarely seen.

Management
Gross total surgical excision is the standard treatment
for CFP. Repeat surgical excision is indicated for tumor
recurrence.

Abbreviations:
CFP: calcifying fibrous pseudotumor
Figure 5. Microscopy reveals dystrophic calcification (1), IMT: inflammatory myofibroblastic tumor
dense collagen matrix (2), and psammoma bodies (3).

Pediatrics in Review Vol.34 No.2 February 2013 e7


visual diagnosis

Prognosis has an excellent prognosis, surgical resection is the treat-


CFP has an excellent prognosis. Recurrence is rare and ment, and further intervention is unnecessary.
usually displays the same morphology as the initial tumor.
Suggested Reading
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The child was discharged from the hospital 3 days after presenting with acute peritonitis: case report with immunohis-
tochemical study and review of literature. Int J Surg Pathol.
the surgical excision. He continues to go to the hematol-
2001;9(3):249–253
ogy/oncology clinic for his sickle cell disease and so far Hill KA, Gonzalez-Crussi F, Chou PM. Calcifying fibrous pseudo-
has shown no evidence of tumor recurrence. tumor versus inflammatory myofibroblastic tumor: a histological
comparison. Mod Pathol. 2001;14(8):784–790
Jain A, Maheshwari V, Alam K, Jain V. Calcifying fibrous pseudo-
Summary tumor of peritoneum. J Postgrad Med. 2007;53(3):189–190
A benign, slowly progressive, nontender mass in children Nascimento AF, Ruiz R, Hornick JL, Fletcher CDM. Calcifying
should raise the possibility of CFP or IMT. Punctate cal- fibrous ‘pseudotumor’: clinicopathologic study of 15 cases and
cifications within the mass are a unique feature of CFP. analysis of its relationship to inflammatory myofibroblastic
tumor. Int J Surg Pathol. 2002;10(3):189–196
The diagnosis can be confirmed by histology that shows Van Dorpe J, Ectors N, Geboes K, D’Hoore A, Sciot R. Is calcifying
a dense hyalinized matrix, spindle cells, psammoma bod- fibrous pseudotumor a late sclerosing stage of inflammatory
ies, and the absence of markers for smooth muscles. CFP myofibroblastic tumor? Am J Surg Pathol. 1999;23(3):329–335

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