Pediatrics in Review_April2011

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Articles

Thrombocytopenia in Infants and Children135Deborah M. Consolini

Corrections151Invasive Meningococcal Disease in Childhood152Anne F. Brayer, Sharon G. Humiston

Cover Art Contest162Index of SuspicionCase 1: Foot Deformities, Asymmetric Calf Muscles, and

Frequent Falls in an 8-year-old Boy

Case 2: Seizures in a 5-month-old Boy Whose MotherRecently Emigrated From Honduras

Case 3: A Gradually Increasing Perianal Mass in aTeenage Girl163

Case 1: Radhika Dhamija, Katherine C. NickelsCase 2: Alexa Calero, Brinda Doraiswamy, Jacob RosenbergCase 3: Sani Haider Kizilbash, Sarah Javed Kizilbash, Roli Agrawal

Visual Diagnosis: Bilateral Posterior Swelling of theKnees in a 12-year-old Boy169Moshe Shapira, Daniela Militianu, Miriam Butnariu

Online-Only ArticleAbstract appears on page 175.

Opioids: Nonmedical Use and Abuse in Older Childrene44William A. Frese, Kimberly Eiden

Cover: The artwork on the cover of thismonth’s issue is by one of the winners ofour 2009 Cover Art Contest, 12-year-oldMichael J of Green Bay, WI. Michael’spediatrician is Gordon Haugan, MD.

contentsPediatrics inReview� Vol.32 No.4 April 2011

Editor-in-Chief: Lawrence F. Nazarian, Rochester, NYAssociate Editors: Tina L. Cheng, Baltimore, MD

Joseph A. Zenel, Sioux Falls, SDEditor, In Brief: Henry M. Adam, Bronx, NYConsulting Editor, In Brief: Janet Serwint, Baltimore, MDEditor, Index of Suspicion: Deepak M. Kamat, Detroit, MIConsulting Editor Online and Multimedia

Projects: Laura Ibsen, Portland, OREditor Emeritus and Founding Editor:

Robert J. Haggerty, Canandaigua, NYManaging Editor: Luann ZanzolaMedical Copy Editor: Deborah K. KuhlmanEditorial Assistants: Kathleen Bernard, Melissa Schroen,

Sydney SutherlandEditorial Office: Department of Pediatrics

University of RochesterSchool of Medicine & Dentistry601 Elmwood Avenue, Box 777Rochester, NY [email protected]

Editorial BoardHugh D. Allen, Columbus, OHMargie Andreae, Ann Arbor, MIRichard Antaya, New Haven, CTDenise Bratcher, Kansas City, MOGeorge R. Buchanan, Dallas, TXBrian Carter, Nashville, TNJoseph Croffie, Indianapolis, INB. Anne Eberhard, New Hyde Park, NYPhilip Fischer, Rochester, MNRani Gereige, Miami, FLLindsey Grossman, Springfield, MAPatricia Hamilton, London, United Kingdom

Jacob Hen, Bridgeport, CTHal B. Jenson, Springfield, MADonald Lewis, Norfolk, VAGregory Liptak, Syracuse, NYSusan Massengill, Charlotte, NCJennifer Miller, Gainesville, FLBlaise Nemeth, Madison, WIRenata Sanders, Baltimore, MDThomas L. Sato, Milwaukee, WISarah E. Shea, Halifax, Nova ScotiaAndrew Sirotnak, Denver, CONancy D. Spector, Philadelphia, PA

Publisher: American Academy of PediatricsMichael J. Held, Director, Division of Scholarly Journals and Professional Periodicals

Pediatrics in Review�Pediatrics in Review�(ISSN 0191-9601) is owned and controlled by the American Academy ofPediatrics. It is published monthly by the American Academy of Pediatrics, 141Northwest Point Blvd., Elk Grove Village, IL 60007-1098Statements and opinions expressed in Pediatrics in Review� are those of the authorsand not necessarily those of the American Academy of Pediatrics or its Committees.Recommendations included in this publication do not indicate an exclusive courseof treatment or serve as a standard of medical care.Subscription price for 2011 for print and online/online only: AAP Fellow $177/$135; Nonmember $222/$172; Allied Health or Resident $165/$111.Institutions call for pricing (866-843-2271). For overseas delivery, add $109.Current single issue price is $10 domestic, $12 international. Replacement issuesmust be claimed within 6 months from the date of issue and are limited to threeper calendar year. Periodicals postage paid at ARLINGTON HEIGHTS,ILLINOIS and at additional mailing offices.© AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved. Printedin USA. No part may be duplicated or reproduced without permission of theAmerican Academy of Pediatrics.POSTMASTER: Send address changes to PEDIATRICS IN REVIEW�, AmericanAcademy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., ElkGrove Village, IL 60007-1098.Pediatrics in ReviewPrint Issue Editorial Board DisclosuresThe American Academy of Pediatrics (AAP) Policy on Disclosure of FinancialRelationships and Resolution of Conflicts of Interest for AAP CME Activities isdesigned to ensure quality, objective, balanced, and scientifically rigorous AAP CMEactivities by identifying and resolving all potential conflicts of interest before theconfirmation of service of those in a position to influence and/or control CME content.All individuals in a position to influence and/or control the content of AAP CMEactivities are required to disclose to the AAP and subsequently to learners that theindividual either has no relevant financial relationships or any financial relationships withthe manufacturer(s) of any commercial product(s) and/or provider(s) of commercialservices discussed in CME activities. Commercial interest is defined as any entityproducing, marketing, reselling or distributing health-care goods or services consumedby, or used on, patients.Each of the editorial board members, reviewers, question writers, PREP CoordinatingCommittee members and staff has disclosed, if applicable, that the CME content he/she edits/writes/reviews may include discussion/reference to generic pharmaceuticals,off-label pharmaceutical use, investigational therapies, brand names, and manufacturers.None of the editors, board members, reviewers, question writers, PREP CoordinatingCommittee members, or staff has any relevant financial relationships to disclose, unlessnoted below. The AAP has taken steps to resolve any potential conflicts of interest.Disclosures● Richard Antaya, MD, FAAP, disclosed that he participates in Astellas Pharma, US,

Inc., clinical trials, speaker bureau and advisory board; and that he participates in theNovartis speaker bureau.

● Athos Bousvaros, MD, MPH, FAAP, disclosed that he has research grants from Merckand UCB; and that he is a paid consultant and on the speaker bureau for Millennium.

● Brian Carter, MD, FAAP, disclosed that he participates in the MedImmune speakerbureau.

● David N. Cornfield, MD, FAAP, disclosed that he has National Institutes ofHealth grants.

● Donald W. Lewis, MD, FAAP, disclosed that he is a consultant for and has aresearch grant from Astra Zeneca and Merck; and that he has research grantsfrom Ortho McNeil, Lilly, Bristol-Myers Squibb, GlaxoSmithKline, andBoehringer Ingelheim Pharmaceutical.

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Pediatrics in Review� is supported, in part, through aneducational grant from Abbott Nutrition, a division ofAbbott Laboratories, Inc.

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DOI: 10.1542/pir.32-4-135 2011;32;135-151 Pediatr. Rev.

Deborah M. Consolini Thrombocytopenia in Infants and Children

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Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned, Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

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Thrombocytopenia in Infants and ChildrenDeborah M. Consolini,

MD*

Author Disclosure

Dr Consolini has

disclosed no financial

relationships relevant

to this article. This

commentary does

contain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

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

1. Explain the relationship between platelet count and bleeding risk.2. State the two basic underlying pathologic mechanisms that may lead to clinically

significant thrombocytopenia.3. Describe the typical presentation and natural history of immune (idiopathic) thrombo-

cytopenic purpura (ITP) in children.4. List the features of the complete blood count and peripheral blood smear that suggest

a serious disorder associated with decreased platelet production.5. Discuss the treatment modalities that have been proven to be effective in raising the

platelet count to a safe level in children who have ITP and are experiencing significantbleeding manifestations.

IntroductionPlatelets are essential for maintaining the integrity of the vascular endothelium andcontrolling hemorrhage from small-vessel injury through the formation of platelet plugs(primary hemostasis). More extensive injury and involvement of larger blood vesselsrequires, in addition to platelets, the participation of the coagulation system to provide afirm, stable, fibrin clot (secondary hemostasis). Thrombocytopenia, defined as a plateletcount of less than 150�103/�L (150�109/L), is the most common cause of defectiveprimary hemostasis that can lead to significant bleeding in children.

Thrombocytopenia should be suspected when a child presents with a history of easybruising or bleeding, particularly mucosal or cutaneous bleeding. However, the mostcommon office presentation of a patient who has isolated thrombocytopenia is the

unexpected discovery of a low platelet count when a com-plete blood count (CBC) is obtained for unrelated reasons.

Thrombocytopenia can be caused by one of two mecha-nisms: decreased production of platelets or increased de-struction or removal of platelets from the circulation. Man-agement of thrombocytopenia should be guided by anunderstanding of its cause and clinical course. The principalmanagement goal in all patients who have thrombocytopeniais to maintain a safe platelet count to prevent significantbleeding. What constitutes a safe platelet count in a specificpatient varies, depending on the cause of the thrombocyto-penia and consideration of all other aspects of hemostasis, aswell as the patient’s expected level of activity.

Platelet Count and Bleeding RiskPlatelets are nonnucleated, cellular fragments produced bythe megakaryocytes of the bone marrow. As the megakaryo-cyte matures, the cytoplasm fragments, and large numbers ofplatelets are released into the circulation. Once released, thelife span of platelets is about 7 to 10 days, after which they areremoved from the circulation by cells of the monocyte-

*Assistant Professor of Pediatrics, Thomas Jefferson University, Philadelphia, PA; Diagnostic Referral Division, A.I. duPontHospital for Children, Wilmington, DE.

Abbreviations

CBC: complete blood countDIC: disseminated intravascular coagulationHIV: human immunodeficiency virusHUS: hemolytic-uremic syndromeICH: intracranial hemorrhageIg: immunoglobulinIGIV: immune globulin intravenousITP: immune thrombocytopenic purpuraKMS: Kasabach-Merritt syndromeMPV: mean platelet volumeNAIT: neonatal alloimmune thrombocytopeniaNEC: necrotizing enterocolitisPBS: peripheral blood smearSLE: systemic lupus erythematosusTTP: thrombotic thrombocytopenic purpuraWAS: Wiscott-Aldrich syndrome

Article hematology

Pediatrics in Review Vol.32 No.4 April 2011 135. Provided by Health Internetwork on April 1, 2011 http://pedsinreview.aappublications.orgDownloaded from


macrophage system. In disorders characterized by in-creased platelet destruction and shortened platelet lifespan, a healthy marrow may increase platelet productionover the basal rate by about tenfold.

Circulating platelets perform many critical hemostaticfunctions. When small blood vessels are transected, plate-lets accumulate at the site of injury, forming a hemostaticplug. Platelet adhesion is initiated by contact with ex-travascular components, such as collagen, and facilitatedby the presence and binding of von Willebrand factor.Secretion of mediators of hemostasis (eg, thromboxane,adenosine 5� diphosphate, serotonin, and histamine)cause firm aggregation via fibrinogen binding and in-crease local vasoconstriction. Platelets also are necessaryfor normal clot retraction. Bleeding risk increases with alow platelet count.

The normal platelet count ranges from 150 to450�103/�L (150 to 450�109/L). The risk of bleed-ing does not increase until the platelet count falls signif-icantly below 100�103/�L (100�109/L) (Fig. 1). (1)A platelet count greater than 50�103/�L (50�109/L)is adequate for hemostasis in most circumstances, andpatients who have mild thrombocytopenia will likelynever be recognized unless a platelet count is obtainedfor other reasons. Patients who have moderate throm-bocytopenia, with platelet counts between 30 and50�103/�L (30 and 50�109/L) are rarely symptom-atic (ie, easy bruising or bleeding), even with significanttrauma. Patients who have persistent platelet countsbetween 10 and 30�103/�L (10 and 30�109/L) are

often asymptomatic with normaleveryday activities but may be atrisk for excessive bleeding withsignificant trauma. Spontaneousbleeding typically does not occurunless platelet counts are less than10�103/�L (10�109/L). Suchpatients commonly have petechiaeand spontaneous bruising, but eventhey may be entirely asymptomatic.In most cases, it appears that theplatelet count must be less than5�103/�L (5�109/L) to causecritical spontaneous bleeding (eg,atraumatic intracranial hemorrhage[ICH]). (1)

Younger circulating platelets arelarger and more hemostaticallyactive. Thus, patients who havedestructive thrombocytopenias ac-companied by a brisk production

and release of younger platelets have less severe bleedingsymptoms than patients who have a similar degree ofthrombocytopenia due to impaired platelet production,resulting in an older circulating population of platelets.

Causes of ThrombocytopeniaThe system used most often to categorize the differentcauses of thrombocytopenia is based on the underlyingpathologic mechanism leading to the thrombocytopenia,that is, either increased destruction or decreased produc-tion of platelets (Table 1).

Increased DestructionDisorders involving increased destruction or removal ofplatelets from the circulation typically result in the ap-pearance of enlarged platelets on the peripheral bloodsmear (PBS), indicating that the bone marrow is pro-ducing new platelets to compensate for the increaseddestruction. In this setting, examination of the bonemarrow generally shows normal or increased numbers ofmegakaryocytes. The destructive mechanisms resultingin thrombocytopenia are:

● Immune-mediated destruction● Platelet activation and consumption● Mechanical platelet destruction● Platelet sequestration and trapping

IMMUNE-MEDIATED DESTRUCTION. The most com-mon cause of thrombocytopenia due to increased de-

Figure 1. Relationship between major bleeding and platelet count. Adapted from SlichterSJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients.Transfus Med Rev. 2004;18:153–167.

hematology thrombocytopenia

136 Pediatrics in Review Vol.32 No.4 April 2011. Provided by Health Internetwork on April 1, 2011 http://pedsinreview.aappublications.orgDownloaded from


struction of platelets in infants and children is animmune-mediated process. Autoantibodies, drug-dependent antibodies, or alloantibodies may mediateplatelet destruction through interaction with plateletmembrane antigens, leading to increased platelet clear-ance from the circulation.

Primary ITP is an acquired immune-mediated disor-der characterized by isolated thrombocytopenia in theabsence of any obvious initiating or underlying cause.(2)(3) Formerly, the abbreviation ITP stood for idio-pathic thrombocytopenic purpura. The new terminologyreflects the current understanding of the immune-

mediated nature of the disease and the absence or mini-mal signs of bleeding in most cases. The platelet countnow used to define cases of ITP is less than 100�103/�L(100�109/L). (2) The term secondary ITP refers toimmune-mediated thrombocytopenias that are due to anunderlying disease or to drug exposure. (2)(3) The dis-tinction between primary and secondary ITP is clinicallyrelevant both in regard to prognosis and treatment.

ITP is the most common immune-mediated throm-bocytopenia in children, with an annual incidence ofsymptomatic cases estimated to be between 3 and 8 casesper 100,000 children. Pediatric patients who developITP usually present between the ages of 2 and 10 years,with a peak incidence at 2 to 5 years. There does notappear to be a significant sex bias in childhood ITP.(4)(5)

The typical case of symptomatic childhood ITP ischaracterized by the sudden appearance of bruising ormucocutaneous bleeding in an otherwise healthy child,often after a preceding viral illness. An increased risk ofITP is also associated with measles, mumps, rubella im-munization, which accounts for perhaps 50% of all ITPcases during the second year after birth. This form of ITPtends to be transient and rarely is the bleeding severe.

The history should reveal no systemic symptoms suchas fever, weight loss, or bone pain. Other than muco-cutaneous bleeding, patients should appear well. Nolymphadenopathy or hepatosplenomegaly should bepresent. If one or more of these findings are present,another diagnosis should be strongly considered. Other-wise, the diagnosis of ITP can be made based on twocriteria: 1) isolated thrombocytopenia with otherwisenormal blood counts and PBS and 2) no clinically appar-ent associated conditions that may cause thrombocyto-penia.

The severity of bleeding symptoms in childhood ITPis proportionate to the degree of thrombocytopenia.Serious bleeding requiring transfusion is uncommon.The presenting platelet count is usually less than20�103/�L (20�109/L). This value probably is due topatients who have higher platelet counts, which are muchless likely to lead to bleeding, never coming to medicalattention. Children who have ITP and platelet countsgreater than 30�103/�L (30�109/L) usually have fewor no symptoms and require no treatment other thanrestriction of activity and avoidance of medications thathave antiplatelet or anticoagulant activity. For thosewhose platelet counts are below 30�103/�L (30�109/L), treatment recommendations are based on the pres-ence and severity of associated bleeding symptoms or therisk thereof. (4)(6)

Table 1. Causes ofThrombocytopeniaIncreased Platelet Destruction

● Immune-mediated–Immune thrombocytopenic purpura–Neonatal alloimmune thrombocytopenia–Neonatal autoimmune thrombocytopenia–Autoimmune diseases–Drug-induced

● Platelet activation/consumption–Disseminated intravascular coagulation–Hemolytic-uremic syndrome–Thrombotic thrombocytopenic purpura–Kasabach-Merritt syndrome–Necrotizing enterocolitis–Thrombosis

● Mechanical platelet destruction● Platelet sequestration

–Chronic liver disease–Type 2B and platelet-type von Willebrand disease–Malaria

Decreased Platelet Production

● Infection● Cyanotic congenital heart disease● Bone marrow failure or infiltrate

–Acute lymphoblastic leukemia and othermalignancies

–Acquired aplastic anemia–Fanconi pancytopenia

● Nutritional deficiencies● Genetically impaired thrombopoiesis

–Thrombocytopenia with absent radii syndrome–Congenital amegakaryocytic thrombocytopenia–Wiskott-Aldrich syndrome–X-linked thrombocytopenia with thalassemia–Giant platelet disorders–Bernard-Soulier syndrome–May-Hegglin/Fechtner/Epstein and Sebastiansyndromes




ITP is now classified by duration into newly diag-nosed, persistent (3- to 12-month duration), andchronic (�12-month duration). (2)(3) Whereas ITP inadults typically has an insidious onset and follows achronic course, ITP in children is usually short-lived,with about two thirds of patients making full and sus-tained recoveries within 6 months of presentation, withor without treatment. (2)(3) Children who have persis-tent or chronic ITP or who manifest any atypical featuresshould be referred to or discussed with a hematologistexperienced in the assessment and treatment of childrenwho have ITP.

Neonatal alloimmune thrombocytopenia (NAIT) isan uncommon syndrome whose estimated incidence inthe general population is 1 in 1,000 to 5,000 births. Thecondition is manifested by an isolated, transient, butpotentially severe thrombocytopenia in the neonate dueto platelet destruction by maternal alloantibodies. NAIToccurs when fetal platelets contain an antigen inheritedfrom the father that the mother lacks. Fetal platelets thatcross the placenta into the maternal circulation triggerthe production of maternal immunoglobulin (Ig) Gantiplatelet antibodies against the foreign antigen. Theseantibodies recross the placenta into the fetal circulationand destroy the body’s platelets, resulting in fetal andneonatal thrombocytopenia (analogous to hemolytic dis-ease of the newborn). In contrast to Rh sensitization,NAIT often develops in the first pregnancy of an at-riskcouple. The most serious complication of NAIT is ICH,which occurs in approximately 10% to 20% of affectednewborns, with up to 50% of these events occurring inutero. (7) The mother of a newborn who has NAIT isasymptomatic, although she may have a history of previ-ously affected pregnancies. Affected newborns typicallypresent with signs consistent with severe thrombocyto-penia, including petechiae, bruising, and bleeding, butare otherwise healthy. Platelet counts are often less than10�103/�L (10�109/L). The platelet count typicallyfalls in the first few days after birth, but then rises over thenext 1 to 4 weeks as the alloantibody concentrationdeclines. In families who have an affected infant, the rateof recurrence is as high as 75% to 90%, and thrombocy-topenia in the second affected child is always as or moresevere than in the first. (7)

Neonatal autoimmune thrombocytopenia also canoccur. This disorder is mediated by maternal antibodiesthat react with both maternal and infant platelets. Thispathologic mechanism occurs in maternal autoimmunedisorders, including ITP and systemic lupus erythemato-sus (SLE). The diagnosis usually is apparent from themother’s medical history and maternal thrombocytope-

nia. Mothers of infants who manifest unexplained neo-natal thrombocytopenia should be investigated for thepresence of an autoimmune disorder because neonatalthrombocytopenia can sometimes be the presenting signof maternal disease. Clinical signs are consistent withisolated thrombocytopenia, as in NAIT.

The risk of severe thrombocytopenia and ICH isgreater in alloimmune than in autoimmune neonatalthrombocytopenia. Ninety percent of infants born tomothers who have ITP have safe (�50�103/�L[50�109/L]) or normal platelet counts. (8) The risk forsevere thrombocytopenia in the infant generally corre-lates with the severity of ITP in the mother. Neonatalthrombocytopenia may be predicted if the mother hashad a splenectomy for treatment of chronic refractoryITP, the mother’s platelet count has been less that50�103/�L (50�109/L) at some time during the preg-nancy, or an older sibling has had neonatal thrombocy-topenia. (8) Platelet counts of infants born to motherswho have ITP often decrease sharply during the firstseveral days after birth. The nadir typically occurs at 2 to5 days of age, and infants should be monitored closelyduring this time. (8)

Autoimmune diseases such as SLE can present inchildhood with isolated immune-mediated thrombocy-topenia, and the true diagnosis may not be apparent for aprolonged period of time. Autoimmune diseases occurmore commonly in older children and have an insidiousonset of symptoms and persistent thrombocytopeniabeyond 6 months from the time of presentation. In-frequently, other autoimmune-mediated cytopeniaspresent coincidentally with thrombocytopenia. In partic-ular, Evans syndrome is characterized by a Coombs(direct antiglobulin test)-positive hemolytic anemia inassociation with immune-mediated thrombocytopenia.Antibody-mediated thrombocytopenia also occurs withantiphospholipid antibody syndrome and autoimmunelymphoproliferative syndrome.

Drug-induced thrombocytopenia is a rare cause ofthrombocytopenia in children. Medications begunwithin the past month are more likely to be the cause ofthe thrombocytopenia than medications that have beentaken for longer periods of time. Drug-induced throm-bocytopenia is typically caused by drug-dependent anti-bodies formed against a new antigen on the plateletsurface that is created by drug binding to a plateletsurface protein. Heparin-induced thrombocytopenia,which can be associated with severe thrombosis, is due tothe formation of antibodies against the heparin-plateletfactor 4 complex. The platelet count in heparin-inducedthrombocytopenia is usually only moderately decreased.




Although this condition is more commonly seen inadults, heparin-induced thrombocytopenia has beendescribed in children. Other drugs commonly used inpediatrics that can cause thrombocytopenia include car-bamazepine, phenytoin, valproic acid, trimethoprim/sulfamethoxazole, and vancomycin. Support for the di-agnosis of drug-induced thrombocytopenia is providedby resolution of the thrombocytopenia within approxi-mately 1 week of withdrawal of the offending drug.

PLATELET ACTIVATION AND CONSUMPTION. In pa-tients who experience disseminated intravascular co-agulation (DIC) and the microangiopathic disordershemolytic-uremic syndrome (HUS) and thromboticthrombocytopenic purpura (TTP), thrombocytopeniaoccurs because of systemic platelet activation, aggrega-tion, and consumption (Table 2). More localized plateletactivationandconsumptioncontributestothethrombocy-topenia seen in Kasabach-Merritt syndrome (KMS), ne-crotizing enterocolitis (NEC), and thrombosis in infantsand neonates. In infants who have KMS, thrombocyto-penia results from shortened platelet survival caused bysequestration of platelets and coagulation activa-tion in large vascular malformations of the trunk, extrem-ities, or abdominal viscera. Cutaneous vascular lesionsare noted at birth in approximately 50% of patients.Detection of visceral lesions requires imaging studies. Allpatients have severe thrombocytopenia, hypofibrinogen-emia, elevated fibrin degradation products, and fragmen-tation of red blood cells on PBS.

NEC is a syndrome of gastrointestinal necrosis thatoccurs in 2% to 10% of infants whose birthweights areless than 1,500 g. Thrombocytopenia is a frequent find-ing and can result in significant bleeding. In the earlystages of NEC, declining platelet counts correlate withthe presence of necrotic bowel and worsening disease.The primary mechanism of thrombocytopenia appearsto be platelet destruction, although the destruction isnot caused by laboratory-detectable DIC in most cases.Thrombosis in infants and neonates is often accompa-nied by thrombocytopenia. A thromboembolic disordershould be considered if the thrombocytopenia cannot beexplained by other conditions.

MECHANICAL PLATELET DESTRUCTION. The use of ex-tracorporeal therapies, such as extracorporeal membraneoxygenation, cardiopulmonary bypass, hemodialysis, andapheresis, is associated with mechanical destruction ofplatelets, which may result in thrombocytopenia. Ex-change transfusion also may reduce platelet number byloss in the exchange effluent. Severe ongoing hemor-

rhage requiring rapid and repeated red blood cell trans-fusions may lead to thrombocytopenia due to a “washout” phenomenon.

PLATELET SEQUESTRATION AND TRAPPING. Aboutone third of the platelet mass is normally sequestered inthe spleen at any given time. A greater proportion ofplatelets are sequestered in patients who experience hy-persplenism, reducing the number of circulating plateletsand leading to thrombocytopenia. The survival of plate-lets in persons who have hypersplenism is normal or nearnormal. It is the pooling and unavailability of platelets“trapped” in the spleen that is the problem. Leukopeniaor anemia also may accompany a low platelet countcaused by hypersplenism. Conditions in this categoryinclude:

● Chronic liver disease with portal hypertension andcongestive splenomegaly. Occasionally, isolated throm-bocytopenia may be the initial manifestation of thistype of chronic liver disease. The platelet count istypically in the range of 50 to 100�103/�L (50 to100�103/L) and usually does not represent a clinicallyimportant problem.

● Type 2B and platelet-type von Willebrand disease.Thrombocytopenia in this disorder is caused by in-creased removal of platelets from the circulation. In-creased binding between larger von Willebrand factormultimers and platelets leads to the formation of smallplatelet aggregates that are cleared from the circula-tion, resulting in a lower platelet count.

● Malaria with hypersplenism. This diagnosis should beconsidered in any child who has fever, splenomegaly,thrombocytopenia, and a history of recent travel to anendemic area.

Decreased ProductionImpaired platelet production may be due to loss of bonemarrow space from infiltration, suppression or failure ofcellular elements, or a defect in megakaryocyte develop-ment and differentiation. In this setting, examination ofthe bone marrow generally shows decreases in the num-ber of megakaryocytes. Causes of marrow dysfunctioninclude:

● Infection● Cyanotic heart disease● Bone marrow failure or infiltration● Nutritional deficiencies● Genetic defects




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INFECTION. Thrombocytopenia due to infections notassociated with evidence of DIC is usually caused bybone marrow suppression. In some cases, increased de-struction due to an infection-induced immune-mediatedprocess or splenomegaly and reticuloendothelial hyper-activity may compound the problem of bone marrowsuppression. The most common infectious agents asso-ciated with thrombocytopenia due to bone marrow sup-pression are Epstein-Barr virus, cytomegalovirus, parvo-virus, varicella virus, and rickettsiae. In most cases, thethrombocytopenia is transient, with recovery within aperiod of weeks. Thrombocytopenia is a common find-ing in patients who are infected with the human immu-nodeficiency virus (HIV), in whom both platelet destruc-tion and impaired production appear to play roles indecreasing the platelet count.

CYANOTIC HEART DISEASE. Cyanotic congenital heartdisease is associated with thrombocytopenia. The cause isunclear, but the mechanism appears to involve decreasedproduction of megakaryoctes.

BONE MARROW FAILURE OR INFILTRATION. Throm-bocytopenia associated with anemia and leukopenia (ie,pancytopenia) suggests general bone marrow dysfunc-tion or infiltration. Serious disorders such as leukemia orother malignancy, hemophagocytic lymphohistiocytosis,acquired aplastic anemia, myelodysplasia, and inheritedbone marrow failure syndromes such as Fanconi pancy-topenia syndrome and dyskeratosis congenita can presentwith pancytopenia. General bone marrow dysfunctioncan also be caused by exposure to chemotherapeuticagents or radiation.

Acute lymphoblastic leukemia is the most commonchildhood leukemia. Affected children usually have otherclinical and laboratory findings besides thrombocytope-nia. These manifestations include systemic symptomssuch as fever, bone pain, and weight loss as well ashepatosplenomegaly, lymphadenopathy, leukocytosis,and anemia.

Acquired aplastic anemia is a rare disorder caused byprofound, almost complete bone marrow failure. Specificsymptoms associated with acquired aplastic anemia varybut can include fever, fatigue, dizziness, weakness, head-aches, and episodes of excessive bleeding. Pancytopeniais often seen on presentation. Based on the response ofapproximately 50% of patients to immunosuppressivemedications, including antithymocyte globulin, cyclo-sporine, high-dose corticosteroids, and cyclophosph-amide, most cases are now believed to be due to an

immune-mediated destruction of hematopoietic stemcells.

Fanconi pancytopenia syndrome is a rare autosomalrecessive disorder. The mean age at diagnosis of thepancytopenia is approximately 6 to 9 years, but thecondition may be recognized earlier by characteristiccongenital malformations that are present in 60% to 70%of affected patients. The most common malformationsare hypopigmented macules, cafe-au-lait macules, abnor-malities of the thumbs, microcephaly, and urogenitalabnormalities. Short stature of prenatal onset may also beseen.

NUTRITIONAL DEFICIENCIES. Folate, vitamin B12, andiron deficiencies have been associated with thrombocy-topenia. Folate and vitamin B12 deficiencies impair bonemarrow production, usually resulting in pancytopenia.Iron deficiency, which can cause either thrombocytosisor thrombocytopenia, appears to impair a late stage ofthrombopoiesis. Thrombocytosis and iron deficiencymay be a response to gastrointestinal blood loss.

GENETIC CAUSES OF IMPAIRED THROMBOPOIESIS. Alarge number of rare inherited diseases present withreduced platelet count, and many involve impaired plate-let function as well. These conditions arise from geneticdefects of the megakaryocyte lineage that result in im-paired thrombopoiesis. The consideration of congenitalthrombocytopenia should be greater in patients whohave a prolonged history of asymptomatic abnormalplatelet counts or a family history of thrombocytopenia.Some patients born with congenital thrombocytopeniaare followed for many years with the presumptive diag-nosis of ITP until another family member is discoveredto have a low platelet count. Table 3 outlines the geneticcauses of impaired thrombopoiesis.

Clinical ManifestationsChildren who have thrombocytopenia may be asymp-tomatic or symptomatic. In asymptomatic patients,thrombocytopenia is often detected unexpectedly on aCBC obtained for another clinical issue. Symptomaticpatients generally present with mucosal or cutaneousbleeding.

Mucosal bleeding usually manifests as epistaxis, gin-gival bleeding or extensive oral mucous membranebleeding (“wet purpura”), hematuria, or in postpubertalfemales, excessive menstrual bleeding. The presence of“wet purpura” is widely perceived as a risk factor forpotentially life-threatening hemorrhage.

Cutaneous bleeding usually appears as petechiae or




Tab

le3.

Gene

tic

Caus

esof

Impa

ired

Thro

mbo

poie

sis

Diag

nosi

sIn

herit

ance

Caus

eCl

inic

alFe

atur

esLa

bora

tory

Feat

ures

Prog

nosi

sTr

eatm

ent

Thro

mbo

cyto

peni

aw

ithab

sent

radi

isyn

drom

eVa

riabl

ein

herit

ance

Uncl

ear

gene

ticca

use.

Poss

ible

defe

ctof

meg

akar

yocy

tem

atur

atio

n.Do

esno

tin

volv

eei

ther

thro

mbo

poie

tinor

thro

mbo

poie

tinre

cept

or.

●Se

vere

thro

mbo

cyto

peni

a●

Bila

tera

labs

ent

radi

i●

Nor

mal

thum

bs●

Oth

ersk

elet

al,g

enito

urin

ary,

hear

tan

omal

ies

●Ab

sent

orm

arke

dly

decr

ease

dm

egak

aryo

cyte

s●

Nor

mal

eryt

hroi

dan

dm

yelo

idm

atur

atio

n

Mor

talit

ysi

gnifi

cant

inin

fanc

ydu

eto

intr

acra

nial

hem

orrh

age.

Ifpa

tient

surv

ives

,th

rom

bocy

tope

nia

ofte

nim

prov

esov

erne

xtse

vera

lyea

rs.

●Pl

atel

ettr

ansf

usio

ns

Cong

enita

lam

egak

aryo

cytic

thro

mbo

cyto

peni

aAu

toso

mal

rece

ssiv

eM

utat

ions

inth

rom

bopo

ietin

rece

ptor

gene

,lea

ding

toab

sent

ordy

sfun

ctio

nal

thro

mbo

poie

tinre

cept

ors.

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vere

but

isol

ated

thro

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a●

Abse

ntor

mar

kedl

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crea

sed

meg

akar

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tes

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orm

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oid

and

mye

loid

mat

urat

ion

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enpr

ogre

sses

topa

ncyt

open

iaan

dle

ukem

ictr

ansf

orm

atio

n

●Pl

atel

ettr

ansf

usio

ns●

Bone

mar

row

tran

spla

ntat

ion

Wis

kott

-Ald

rich

synd

rom

eX-

linke

dre

cess

ive

diso

rder

Abno

rmal

gene

onpr

oxim

alar

mof

Xch

rom

osom

een

code

sre

gula

tory

prot

ein

ofly

mph

ocyt

ean

dpl

atel

etfu

nctio

n.

●At

opic

derm

atiti

s●

Thro

mbo

cyto

peni

cpu

rpur

a●

Incr

ease

dsu

scep

tibili

tyto

infe

ctio

ns

●Sm

all(

3to

5fL

)de

fect

ive

plat

elet

s●

Nor

mal

-app

earin

gm

egak

aryo

cyte

s

Surv

ival

beyo

ndte

ens

rare

.In

fect

ions

orbl

eedi

ngar

em

ajor

caus

esof

deat

h.12

%in

cide

nce

offa

tal

mal

igna

ncy.

Sple

nect

omy

may

impr

ove

plat

elet

coun

tbu

tof

ten

com

plic

ated

byov

erw

helm

ing

seps

is/

deat

hGi

ant

plat

elet

diso

rder

s●

Bern

ard-

Soul

ier

synd

rom

e

Auto

som

alre

cess

ive

Dysf

unct

ion/

abse

nce

ofpl

atel

etre

cept

orfo

rvo

nW

illeb

rand

fact

or(G

PIb

-IX

-V)

●Ea

sybr

uisi

ngan

dse

vere

hem

orrh

age

with

trau

ma/

surg

ery

●M

acro

thro

mbo

cyto

peni

a,se

vere

plat

elet

dysf

unct

ion

Blee

ding

tend

ency

lifel

ong

For

both

Bern

ard-

Soul

ier,

MYH

9RD:

Desm

opre

ssin

acet

ate

may

shor

ten

blee

ding

time.

Plat

elet

tran

sfus

ions

for

surg

ery/

seve

rebl

eedi

ng.

Bern

ard-

Soul

ier

patie

nts

may

deve

lop

antip

late

let

antib

odie

sbe

caus

eof

GPIb

-IX-

Von

tran

sfus

edpl

atel

ets.

●M

YH9-

rela

ted

dise

ase

(MYH

9RD)

Auto

som

aldo

min

ant

Non

mus

cle

myo

sin

heav

ych

ain

gene

(MYH

9)m

utat

ions

●Bl

eedi

ng,n

ephr

itis,

hear

ing

loss

,cat

arac

ts.E

pste

in,

Fech

tner

,Seb

astia

nsy

ndro

me

orM

ay-H

eggl

inan

omal

ypr

evio

usly

diag

nose

dba

sed

onsp

ecifi

ccl

inic

alfin

ding

sat

pres

enta

tion

but

now

rega

rded

ason

edi

sord

er.

●M

acro

thro

mbo

cyto

peni

a,le

ukoc

yte

incl

usio

ns,

hem

atur

ia,p

rote

inur

ia

Prog

ress

ive

high

-fre

quen

cyse

nsor

ineu

ralh

earin

glo

ss,

glom

erul

onep

hriti

san

dca

tara

cts

may

deve

lop

anyt

ime

betw

een

infa

ncy

and

adul

thoo

d.




superficial ecchymoses. Patients who have thrombocyto-penia may also have persistent, profuse bleeding fromsuperficial cuts. Petechiae, the pinhead-sized, red, flat,discrete lesions caused by extravasation of red cells fromskin capillaries and often occurring in crops in dependentareas, are highly characteristic of decreased platelet num-ber or function. Petechiae are nontender and do notblanch under pressure. They are asymptomatic and notpalpable and should be distinguished from small telangi-ectasias and vasculitic (palpable) purpura. Purpura de-scribes purplish discolorations of the skin due to thepresence of confluent petechiae. Ecchymoses are non-tender areas of bleeding into the skin that are typicallysmall, multiple, and superficial and can develop withoutnoticeable trauma. Ecchymoses often have a variety ofcolors due to the presence of extravasated blood (red orpurple) and the ongoing breakdown of heme pigment inthe extravasated blood by skin macrophages (green, yel-low, or brown).

This pattern of bleeding differs from that of patientswho have disorders of coagulation factors, such as hemo-philia. Patients who have thrombocytopenia tend to haveless deep bleeding into muscles or joints, more bleedingafter minor cuts, less delayed bleeding, and less postsur-gical bleeding. In addition, patients who have coagula-tion factor disorders tend not to have petechiae. Al-though rare, bleeding into the central nervous system isthe most common cause of death due to thrombocyto-penia. When such bleeding occurs, it is often preceded bya history of head trauma.

EvaluationA thorough history and physical examination and judi-cious use of laboratory testing can lead to the appropriatediagnosis in most patients (Fig. 2). Patients should bequestioned about past and current bleeding symptoms,including bruising with little or no trauma, nosebleeds,blood in the urine or stool, gum bleeding, bleeding withsurgical or dental procedures, or excessive menstrualbleeding. Duration and onset of the bleeding symptomsmay help determine whether the cause is acquired orcongenital. If thrombocytopenia is due to an acquiredcause, the onset of symptoms may be linked to a specifictrigger (eg, infection). Congenital thrombocytopeniashould be considered in patients who have a prolongedhistory of asymptomatic abnormal platelet counts or afamily history of thrombocytopenia.

In children who have suspected or known thrombo-cytopenia, the skin, gingivae, and oral cavity should beexamined carefully for evidence of bleeding. In hospital-ized patients, careful examination for bleeding should be

performed at the site of indwelling catheters, drains, andincisions or areas of previous trauma. Table 4 lists the“red flags” in the history and physical examination ofchildren who have thrombocytopenia that should lead toconsideration of diagnoses other than ITP.

Laboratory EvaluationThe laboratory evaluation of thrombocytopenia beginswith a CBC and evaluation of the PBS. Although a dyingskill for most general practitioners, the ability to assessthe PBS accurately is invaluable in the evaluation ofchildren who have thrombocytopenia or other hemato-logic abnormalities. Consultation with a hematopatholo-gist or experienced laboratory technologist may be use-ful.

The CBC should be examined closely for the plateletcount and mean platelet volume (MPV) as well as forevidence of any other cytopenias (anemia or leukopenia).A platelet count that does not make sense clinicallyshould be confirmed before undertaking extensive eval-uation to be sure that thrombocytopenia exists and thefinding is not due to artifact or laboratory error. Spuriousthrombocytopenia can be caused by improper collectionor inadequate anticoagulation of the blood sample, re-sulting in platelet clumps that are counted as leukocytesby automated cell counters. Once thrombocytopeniahas been confirmed, an MPV that is significantly higherthan normal suggests one of the macrothrombocyto-penia syndromes. A mildly elevated MPV is consistentwith a destructive cause. A low MPV is typically seen inpatients who have Wiscott-Aldrich syndrome (WAS)gene mutations.

The PBS should be examined to estimate the plateletnumber (1 platelet/high power field�platelet count of�10�103/�L [10�109/L]), determine the plateletmorphology and the presence or absence of plateletclumping, and assess whether there are associated whiteand red blood cell changes. Large platelets suggest eitheran ongoing platelet destructive process leading to theproduction of younger and larger platelets or the pres-ence of a congenital macrothrombocytopenia syndrome.Small platelets in the appropriate clinical setting suggestWAS. The presence of schistocytes suggests a micro-angiopathic process such as DIC, HUS, or TTP. Sphero-cytes suggest autoimmune hemolytic anemia coupledwith immune-mediated thrombocytopenia (Evans syn-drome).

Other tests may be useful in determining the cause ofthe thrombocytopenia but are generally performed basedon suggestive findings from the initial history and phys-ical examination and laboratory testing. A positive direct




Coombs test suggests an autoimmune process in a pa-tient who has evidence of hemolysis as well as spherocyteson the PBS. For patients who have persistant or chronicITP, antinuclear antibody, serum immunoglobulins(IgG, IgA, IgM), and antiphospholipid antibodiesshould be considered. Fibrin degradation products andfibrinogen measurements are useful to diagnose intravas-cular coagulation.

If the PBS results are consistent with a microangio-pathic process, additional tests should be considered,including serum lactate dehydrogenase and creatinine toassess for HUS or TTP. HIV testing should be consid-ered because thrombocytopenia may be the initial diseasemanifestation in as many as 10% of patients who haveHIV infection. If clinical suspicion or local prevalence ishigh, tests to identify hepatitis C viral infection or Heli-cobacter pylori infection should also be considered.

Screening tests for inherited disorders associated withthrombocytopenia should be considered in patients whoexperience chronic thrombocytopenia, especially in thepresence of short stature or other congenital anomalies.

Platelet antibodies can be detected by a variety ofassays. Although many of these assays have high sensitiv-ity, they lack specificity and are not indicated or per-formed routinely to confirm the diagnosis of acute ITP inchildren.

A bone marrow examination is not necessary in mostcases of isolated unexplained thrombocytopenia in chil-dren. In general, a bone marrow examination is indicatedwhen clinical signs or symptoms suggest either marrowinfiltration or failure. These findings include pancytope-nia; the presence of blasts on the PBS; and the presenceof systemic symptoms such as fever, fatigue, weight loss,or bone pain. A bone marrow examination also is indi-

Figure 2. Diagnostic algorithm for thrombocytopenia. CAMT�congenital amegakaryocytic thrombocytopenia, DIC�disseminatedintravascular coagulation, HUS�hemolytic-uremic syndrome, TAR�thrombocytopenia with absent radii syndrome, TTP�thromboticthrombocytopenic purpura, WAS�Wiscott-Aldrich syndrome.




cated for unexplained, chronic, stable thrombocytope-nia, even when the presumed diagnosis is ITP, or if thesubsequent clinical course is inconsistent with the naturalhistory of ITP because of the development of new clinicalsigns or symptoms or laboratory abnormalities.

TreatmentManagement of thrombocytopenia in an individual pa-tient should be guided by an understanding of its causeand predicted clinical course. Correction of the causemay not be possible (eg, congenital thrombocytopenias)or may not be necessary (eg, mild-to-moderate ITP).The principal management goal in all patients who havethrombocytopenia is to maintain a safe platelet count toprevent significant bleeding, not to achieve a normalplatelet count. What constitutes a safe platelet count in aparticular patient varies, depending on the cause of thethrombocytopenia and consideration of all other aspectsof hemostasis. For patients who have significant bleedingsymptoms, treatment is essential. Asymptomatic or min-imally symptomatic thrombocytopenia may be treated ifthe thrombocytopenia is severe or the perceived risk ofbleeding is great.

Activity RestrictionsWhen moderate-to-severe thrombocytopenia is recog-nized, implementing reasonable precautions to minimizebleeding risk is recommended. These steps includetrauma precautions (eg, avoidance of contact sports anduse of a helmet while cycling) and avoidance of medica-tions that have antiplatelet or anticoagulant activity (in-cluding aspirin-containing preparations, ibuprofen, andother nonsteroidal anti-inflammatory drugs).

Invasive ProceduresA platelet count greater than 50�103/�L (50�109/L)provides safety for most invasive procedures. If the risksof potentially serious bleeding are believed to be severe,a platelet count of greater than 100�103/�L (100�109/L) is often required by surgeons or anesthesiolo-gists. For common minor procedures, such as toothextractions, a platelet count of 30 to 50�103/�L(50�109/L) often is sufficient. (1) For patients whohave lower platelet counts, some measure to increase theplatelet count immediately before the procedure may berequired. A short course of corticosteroids (prednisone2 mg/kg per day for 1 week) or a single dose of immuneglobulin intravenous (IGIV) (1 g/kg) is often sufficientto increase the platelet count acutely for proceduralhemostasis. Platelet transfusions can be used in urgentsituations. Although platelet survival in the circulation of

patients who have destructive thrombocytopenias maynot be normal, platelet transfusion nearly always providesprompt, satisfactory hemostasis, even if only for a shortduration.

Emergency Management of Critical BleedingPatients who have severe thrombocytopenia and criticalbleeding require immediate transfusion of platelets re-gardless of the cause of the thrombocytopenia. ICH isthe most serious consequence of severe thrombocyto-penia. Early diagnostic imaging should be consideredfor patients who have severe thrombocytopenia andneurologic signs or symptoms to identify ICH. Forpatients who have unstable or progressive ICH, emer-gency craniotomy may be necessary. For patients whohave ITP with life-threatening bleeding, in addition toplatelets, adjunctive treatment with high doses of corti-costeroid (intravenous methylprednisolone 30 mg/kg

Table 4. Red Flags Suggesting aDiagnosis Other Than ImmuneThrombocytopenic PurpuraHistory

● Fever● Bone pain● Weight loss● Fatigue● Recent history of infections or vaccinations● Past medical history of diseases associated with

thrombocytopenia (eg, autoimmune disorders,cirrhosis)

● Dietary history suggestive of iron, vitamin B12, orfolate deficiency

● Exposure to medications known to be associatedwith thrombocytopenia

● Travel history to an endemic area for malaria

Physical Examination

● Lymphadenopathy● Splenomegaly● Joint swelling● Short stature● Limb defects, including radial agenesis and thumb

abnormalities● Cataracts● Sensorineural hearing loss● Oral leukoplakia● Dystrophic nails● Eczema in male patient● Frequent infections● Superficial hemangiomas




Tab

le5.

Init

ialT

reat

men

tfo

rN

ewly

Diag

nose

dIm

mun

eTh

rom

bocy

tope

nic

Purp

ura

(ITP)

Wit

hSi

gnifi

cant

Blee

ding

orRi

skof

Blee

ding

Trea

tmen

tM

echa

nism

ofAc

tion

Resp

onse

Rate

Toxi

citie

sCo

mm

ents

Cort

icos

tero

ids

Dosi

ngva

ries

from

pred

niso

ne2

mg/

kgpe

rda

yor

ally

for

2to

4w

eeks

tohi

gh-d

ose

met

hylp

redn

isol

one

30m

g/kg

per

day

(max

imum

,1g)

intr

aven

ousl

yfo

r3

to7

days

●Re

duce

san

tibod

ypr

oduc

tion

●Re

duce

sre

ticul

oend

othe

lial

syst

emph

agoc

ytos

isof

antib

ody-

coat

edpl

atel

ets

●Im

prov

esva

scul

arin

tegr

ity●

Impr

oves

plat

elet

prod

uctio

n

Upto

75%

achi

eve

plat

elet

resp

onse

,dep

endi

ngon

dose

;res

pons

eto

ther

apy

usua

llyw

ithin

2to

7da

ys

●Be

havi

oral

chan

ges

●Sl

eep

dist

urba

nce

●In

crea

sed

appe

tite

●W

eigh

tga

in●

Gast

ritis

/gas

troi

ntes

tinal

hem

orrh

age

●Im

mun

osup

pres

sion

●Po

orlin

ear

grow

th

●N

ocu

rativ

ebe

nefit

know

n●

Oft

en,a

drop

inpl

atel

etco

unt

afte

rst

eroi

dsdi

scon

tinue

d●

Repe

ated

cour

ses

may

bene

cess

ary

ifsi

gnifi

cant

blee

ding

sym

ptom

spe

rsis

tor

recu

rIm

mun

eGl

obul

inIn

trav

enou

s(IG

IV)

Sing

ledo

se1

g/kg

Unkn

own

and

likel

ym

ultif

acto

rial.

Theo

ries

incl

ude:

●Re

ticul

oend

othe

lials

yste

mbl

ocka

de/in

hibi

tion

●Au

toan

tibod

yne

utra

lizat

ion

byan

ti-id

ioty

pean

tibod

ies

●In

crea

sed

auto

antib

ody

clea

ranc

edu

eto

com

petit

ive

inhi

bitio

nof

imm

unog

lobu

linFc

rece

ptor

>80

%ac

hiev

epl

atel

etre

spon

se;r

espo

nse

toth

erap

yus

ually

with

in24

hour

s

●N

ause

a/vo

miti

ng●

Seve

rehe

adac

he●

Feve

r●

Chill

s●

Mor

epr

onou

nced

inol

der

patie

nts

●N

ocu

rativ

ebe

nefit

know

n●

30%

have

sign

ifica

ntdr

opin

plat

elet

coun

tin

2to

6w

eeks

●IG

IVap

pear

sto

impr

ove

plat

elet

coun

tsm

ore

relia

bly

than

cort

icos

tero

ids

orno

trea

tmen

t.So

me

expe

rts

belie

veth

atin

patie

nts

who

fail

tosh

owan

ypl

atel

etris

ew

ithIG

IV,t

hedi

agno

sis

ofIT

Psh

ould

bere

cons

ider

edan

dbo

nem

arro

was

sess

men

tst

rong

lyco

nsid

ered

Anti-

Rho(

D)im

mun

egl

obul

inSi

ngle

dose

50to

75�

g/kg

Spec

ific

red

bloo

dce

llan

tibod

ies

coat

red

bloo

dce

lls,w

hich

are

then

take

nup

byth

ere

ticul

oend

othe

lial

syst

emin

plac

eof

antib

ody-

coat

edpl

atel

ets

50%

to77

%ac

hiev

epl

atel

etre

spon

se,d

epen

ding

ondo

se;u

pto

50%

resp

ond

with

in24

hour

s

●H

emol

ysis

(can

bese

vere

)●

Diss

emin

ated

intr

avas

cula

rco

agul

atio

n●

Rena

lfai

lure

(rar

e)●

Hea

dach

e,fe

ver,

chill

sle

ssco

mm

onth

anw

ithIG

IV

●W

ithhi

gher

dose

s,is

com

para

ble

toIG

IV●

Onl

yef

fect

ive

inch

ildre

nw

hoar

eRh

o(D)

-pos

itive

.Sho

uld

only

begi

ven

ifhe

mog

lobi

n>

10g/

dL(1

00g/

L)an

dCo

ombs

-neg

ativ

e.Tr

eate

dpa

tient

sm

ust

bew

atch

edfo

rpr

esen

cean

dse

quel

aeof

sign

ifica

nthe

mol

ysis

.IGI

Vis

gene

rally

pref

erre

d.




Tab

le6.

Trea

tmen

tO

ptio

nsfo

rCh

ildre

nW

hoH

ave

Refr

acto

ryIm

mun

eTh

rom

bocy

tope

nic

Purp

ura

Wit

hSi

gnifi

cant

Blee

ding

Sym

ptom

sTr

eatm

ent

Mec

hani

smof

Actio

nRe

spon

seRa

teTo

xici

ties

Com

men

ts

Sple

nect

omy

Redu

ces

dest

ruct

ion

ofbo

thau

tolo

gous

and

tran

sfus

edpl

atel

ets

Usua

llyra

ises

the

plat

elet

coun

tw

ithin

hour

s;60

%to

70%

achi

eve

ape

rman

ent

rem

issi

on

●In

trao

pera

tive

blee

ding

●Li

fe-t

hrea

teni

ngin

fect

ions

Even

thos

eno

tde

mon

stra

ting

rise

inpl

atel

etco

unt

may

bem

ore

resp

onsi

veto

prev

ious

lyfa

iled

med

ical

ther

apie

s.H

igh-

dose

met

hylp

redn

isol

one

30m

g/kg

per

day

(max

imum

,1g)

for

3da

ysfo

llow

edby

20m

g/kg

per

day

for

4da

ys

●Re

duce

san

tibod

ypr

oduc

tion

●Re

duce

sre

ticul

oend

othe

lial

syst

emph

agoc

ytos

isof

antib

ody-

coat

edpl

atel

ets

●Im

prov

esva

scul

arin

tegr

ity●

Impr

oves

plat

elet

prod

uctio

n

>60

%to

100%

achi

eve

plat

elet

resp

onse

;re

spon

seto

ther

apy

usua

llyw

ithin

2to

7da

ys

●Be

havi

oral

chan

ges

●In

crea

sed

appe

tite

●Ga

strit

is/g

astr

oint

estin

alhe

mor

rhag

e●

Imm

unos

uppr

essi

on●

Poor

linea

rgr

owth

●De

crea

sed

bone

min

eral

izat

ion

Ifre

peat

edco

urse

sne

cess

ary,

alte

rnat

ive

ther

apie

ssh

ould

beco

nsid

ered

.

Sing

leor

com

bina

tion

regi

men

s:cy

clos

porin

A,az

athi

oprin

e,vi

ncris

tine,

cycl

opho

spha

mid

e,da

nazo

l�

pred

niso

ne,i

mm

une

glob

ulin

intr

aven

ous

(IGIV

)

Imm

unos

uppr

essi

onvi

acy

toto

xic

effe

cts

�70

%ac

hiev

epl

atel

etre

spon

se;r

espo

nse

toth

erap

yva

ries

but

gene

rally

days

tom

onth

s

Usua

ladv

erse

effe

cts

ofin

divi

dual

agen

tsEx

perie

nce

inch

ildre

nlim

ited.

Ritu

xim

ab37

5m

g/m

2pe

rdo

sein

trav

enou

sly

wee

kly

for

4w

eeks

Not

com

plet

ely

defin

ed.

Poss

ibly

,sou

rce

ofpa

thog

enic

antib

odie

s(B

lym

phoc

ytes

)re

mov

edby

sele

ctiv

ede

stru

ctio

nof

CD20

-pos

itive

cells

,re

sulti

ngin

decr

ease

dan

tibod

ypr

oduc

tion.

Atle

ast

30%

com

plet

ere

spon

sera

tela

stin

gan

aver

age

of13

mon

ths;

resp

onse

isus

ually

prom

pt(1

to2

wee

ks)

but

may

take

upto

8w

eeks

.Del

aym

aybe

resu

ltof

time

need

edto

clea

rci

rcul

atin

gpa

thog

enic

antib

odie

s.

Usua

llyw

ellt

oler

ated

with

man

agea

ble

infu

sion

-re

late

dad

vers

eef

fect

s.H

ypog

amm

aglo

bulin

emia

isin

freq

uent

.IGI

V40

0m

g/kg

ever

y3

to4

wee

ksm

aybe

adm

inis

tere

dto

mai

ntai

nno

rmal

conc

entr

atio

ns.

Prog

ress

ive

mul

tifoc

alle

ukoe

ncep

halo

path

yha

sbe

enre

port

ed,b

utca

usal

rela

tions

hip

not

confi

rmed

.

Ifth

rom

bocy

tope

nia

recu

rs,

seco

ndco

urse

appe

ars

tobe

safe

and

effe

ctiv

e.

Thro

mbo

poie

tinre

cept

orag

onis

tsRo

mip

lost

im1

to10

�g/

kgsu

bcut

aneo

usly

wee

kly

Eltr

ombo

pag

25to

75m

gor

ally

daily

Rom

iplo

stim

,asu

bcut

aneo

usth

rom

bopo

iesi

s-st

imul

atin

gFc

pept

ide

fusi

onpr

otei

n,an

del

trom

bopa

g,an

oral

lyac

tive,

nonp

eptid

eth

rom

bopo

ietin

rece

ptor

agon

ist,

act

byst

imul

atin

gpl

atel

etpr

oduc

tion.

Ashi

ghas

80%

inad

ult

patie

nts.

Stud

ies

inch

ildre

nex

trem

ely

limite

d.Us

ecu

rren

tlyre

stric

ted

tore

frac

tory

patie

nts

who

have

sign

ifica

ntbl

eedi

ngsy

mpt

oms.

●Th

rom

bosi

s●

Incr

ease

dco

ncen

trat

ions

ofbo

nem

arro

wre

ticul

in

No

effe

cton

unde

rlyin

gpa

thol

ogic

mec

hani

sm,a

ndre

boun

dth

rom

bocy

tope

nia

whe

ndr

ugs

are

stop

ped

isco

mm

on.U

sed

toke

eppl

atel

ets

insa

fera

nge

(50

to20

0�10

3/�

L[5

0to

200�

109/L

]).V

ery

expe

nsiv

e,an

dlo

ng-t

erm

expe

rienc

elim

ited.




up to 1 g/day for 3 days) and a single dose of IGIV(1 g/kg) is also appropriate. Emergency splenectomymay be considered in cases of refractory ITP accompa-nied by life-threatening hemorrhage.

Thrombocytopenia Associated With OtherCytopenias

Patients who have pancytopenia with systemic symptomsor significant findings on examination should be evalu-ated carefully in a timely manner because they are atincreased risk for a serious disorder that may requireurgent intervention. Consultation with a pediatric hema-tologist should be strongly considered. Treatment of theidentified underlying primary disorder guides subse-quent management. For such patients, maintenance of asafe platelet count may be only a small part of the overalltreatment plan.

Isolated ThrombocytopeniaThe most likely diagnosis in an otherwise healthy childwho has isolated thrombocytopenia is ITP. Most patientsdo not have serious bleeding (including those whoseplatelet counts are �10�103/�L [10�109/L]). ICH isextremely rare, with an incidence of 0.1% to 0.5%. Al-though treatments for childhood ITP may reduce theseverity and duration of the initial thrombocytopenicepisode and presumably the risk of bleeding, they do notappear to affect the eventual recovery rate. Up to twothirds of children who have ITP recover within 6 monthsof presentation with or without treatment. (3)(5)

Most experts agree that pharmacologic interventionis not generally needed for children who have mild-to-moderate thrombocytopenia (platelet counts �30�103/�L] 30�109/L]) because they are unlikely to haveserious bleeding. Exceptions to this policy include chil-dren who have concomitant or preexisting conditionsthat increase their risk for severe bleeding and childrenundergoing procedures likely to include blood loss. (6)

For patients whose platelet counts are less than30�103/�L (30�109/L), treatment recommendationsare based on the presence and severity of associatedbleeding or the risk thereof. Although there is no definedmeans to predict which children who have ITP will sufferfrom an ICH, retinal hemorrhages and extensive muco-sal bleeding or “wet purpura” have been reported toprecede and possibly predict spontaneous ICH. (4)Thus, any individual who has ITP and actual or obviouspotential for significant bleeding requires immediatetreatment, regardless of the platelet count.

When therapy is indicated, the primary treatmentoptions for the newly diagnosed patient are corticoste-

roids, IGIV, and anti-Rho(D) immune globulin (Table5). Several studies have shown that the duration ofsymptomatic thrombocytopenia is shortened by any ofthese three interventions compared with no treatment.All ITP therapies are temporizing interventions intendedfor rapid reversal of a real or perceived risk for significanthemorrhage. They do not need to be continued untilnormal platelet counts are reached. Therapy is targetedto increase the platelet count above a threshold (usually�20�103/�L [20�109/L]) that stops bleeding oreliminates the risk of serious bleeding. (6) Platelet trans-fusions are indicated in patients who have ITP only inthe setting of life-threatening bleeding, such as ICH.Because of accelerated platelet destruction in ITP, plate-let transfusions result in a relatively limited rise in theplatelet count of very short duration (measured in hoursor even minutes) that may be adequate for the immediatehemostasis required in the setting of ICH but otherwiseis of no benefit.

Almost all children who develop ITP are treated in theambulatory setting. Patients who require pharmacologicintervention with IGIV or high-dose intravenous corti-costeroids are usually hospitalized for an average of 1 to3 days. Platelet counts are monitored once or twiceweekly, depending on the clinical situation and severityof the thrombocytopenia. When recovery of plateletcounts is detected, the interval between platelet countassessment may be lengthened. Monitoring should con-tinue until the platelet count has returned to normal andis stable.

Approximately 20% to 30% of children who presentwith ITP eventually develop chronic ITP, defined aspersistent thrombocytopenia beyond 12 months fromthe time of presentation. Patients who have chronic ITPare usually clinically indistinguishable from those whohave acute ITP at presentation. Children younger than10 years of age are more likely to have remissions thanolder patients. Children whose bleeding manifestationslast more than 14 days are substantially more likely todevelop chronic ITP.

All children who have persistent (3 to 12 months) orchronic (�12 months) ITP should have their cases re-viewed and managed by a pediatric hematologist. Indi-viduals who have chronic ITP should undergo evaluationthat includes bone marrow examination to exclude othercauses of thrombocytopenia. In chronic ITP, plateletcounts tend to range between 20 and 75�103/�L(20 and 75�109/L); consequently, many patients re-quire no or only intermittent treatment for episodes ofsignificant bleeding or increased risk of bleeding.

A small percentage of pediatric patients who have ITP




and significant hemorrhagic symptoms demonstrate re-sistance to both corticosteroids and IGIV. Managementof such so-called refractory ITP is difficult (Table 6).

Pulse intermittent high-dose corticosteroids and sple-nectomy have been the mainstays of treatment in thesesituations, although not without significant risks. Newertreatment modalities that may be useful include ritux-imab, a chimeric anti-CD20 monoclonal antibody, andthe thrombopoietin receptor agonists romiplostim andeltrombopag, although studies of these agents in chil-dren are limited (9)(10)(11) and not approved by theUnited States Food and Drug Administration for chil-dren younger than 18 years. The recent use of thrombo-poietin receptor agonists reflects a new paradigm in thetreatment of ITP, with the focus not on reducing plateletconsumption through immune modulation or suppres-sion but on increasing platelet production.

References1. Slichter SJ. Relationship between platelet count and bleedingrisk in thrombocytopenic patients. Transfus Med Rev. 2004;18:153–1672. Rodeghiero F, Stasi R, Gemsheimer T, et al. Standardization ofterminology, definitions and outcome criteria in immune thrombo-cytopenic purpura of adults and children: report from an interna-tional working group. Blood. 2009;113:2386–23933. Provan D, Stasi R, Newland A, et al. International consensusreport on the investigation and management of primary immunethrombocytopenia. Blood. 2010;115:168–1864. Medeiros D, Buchanan GR. Current controversies in the man-agement of idiopathic thrombocytopenic purpura during child-hood. Pediatr Clin North Am. 1996;43:757–7725. Kuhne T, Buchanan GR, Zimmerman S, et al. A prospectivecomparative study of 2540 infants and children with newly diag-nosed idiopathic thrombocytopenic purpura (ITP) from the In-tercontinental Childhood ITP Study Group. J Pediatr. 2003;143:605–6086. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombo-cytopenic purpura: a practice guideline developed by explicitmethods for the American Society of Hematology. Blood. 1996;88:3–407. Bussel JB, Zabusky MR, Berkowitz RL, et al. Fetal alloimmunethrombocytopenia. N Engl J Med. 1997;337:22–268. Payne SD, Resnik R, Moore TR, et al. Maternal characteristicsand risk of severe neonatal thrombocytopenia and intracranial hem-orrhage in pregnancies complicated by autoimmune thrombocyto-penia. Am J Obstet Gynecol. 1997;177:149–1559. Wang J, Wiley JM, Luddy R, et al. Chronic immune thrombo-cytopenic purpura in children: assessment of rituximab treatment.J Pediatr. 2005;146:217–22110. Bennett CM, Rogers ZR, Kinnamon DD, et al. Prospectivephase I/II study of rituximab in childhood and adolescentchronic immune thrombocytopenic purpura. Blood. 2006;107:2639–264211. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy oflong-term treatment with romiplostim in thrombocytopenic pa-tients with chronic ITP. Blood. 2009;113:2161–2171

Summary• Thrombocytopenia should be suspected in any child

presenting with a history of easy bruising orbleeding or petechiae, but it also may present as anincidental finding in an asymptomatic individual.

• Thrombocytopenia may be caused by either increaseddestruction or removal of platelets from thecirculation or decreased production of platelets.

• Destructive mechanisms resulting inthrombocytopenia include immune-mediateddestruction, platelet activation and consumption,mechanical platelet destruction, and plateletsequestration or trapping.

• Impaired platelet production may be due to bonemarrow infiltration, suppression, or failure or defectsin megakaryocyte development and differentiation.

• A thorough history and physical examination andjudicious use of laboratory testing can lead to theappropriate diagnosis in most patients who havethrombocytopenia.

• Childhood ITP generally presents with the suddenappearance of bruising, bleeding, or petechiae in anotherwise healthy child.

• The diagnosis of ITP can be made using two criteria:1) isolated thrombocytopenia with otherwise normalblood counts and peripheral blood smear and 2) noclinically apparent associated conditions that maycause thrombocytopenia.

• Further evaluation, including bone marrowassessment, should be considered in patients whohave atypical clinical or laboratory features atpresentation; thrombocytopenia lasting more than 6months; or a subsequent clinical course that isinconsistent with the natural history of ITP,including failure to respond to usually effectivetherapies.

• Management of thrombocytopenia should be guidedby an understanding of its cause and clinical course,with the principal goal in all patients being tomaintain a safe platelet count to prevent significantbleeding.

• For childhood ITP, pharmacologic intervention,including corticosteroids, IGIV, and anti-Rho(D)immune globulin, has been shown to raise theplatelet count more quickly than no therapy and isrecommended for children who have or at risk forsevere or life-threatening bleeding, based on strongevidence.

• ITP in children usually is short-lived, with at leasttwo thirds of patients making a full and sustainedrecovery within 6 months of presentation, with orwithout treatment.




PIR QuizQuiz also available online at http://pedsinreview.aappublications.org.

1. A 4-year-old boy is brought to the office with a 3-week history of bruising. He has had no othercomplaints. He has mild bruising but no petechiae and no mucosal bleeding. His physical examinationfindings are otherwise normal. Laboratory results include a white blood cell count of 8.4�103/�L(8.4�109/L), hemoglobin of 13.4 g/dL (134 g/L), and platelet count of 31�103/�L (31�109/L). The mostappropriate management is:

A. High-dose intravenous corticosteroids.B. Intravenous anti-D.C. Intravenous gamma globulin.D. Observation.E. Oral corticosteroids.

2. A 4-year-old girl presents with a 5-week history of bruising but is otherwise well. On physical examination,the only abnormal finding is increased bruising and scattered petechiae. Her platelet count is 29�103/�L(29�109/L), hemoglobin is 9.5 g/dL (95 g/L), and white blood cell count is 2.1�103/�L (2.1�109/L). Themost appropriate next step is to:

A. Administer antibiotics.B. Observe the child.C. Obtain antiplatelet antibodies.D. Obtain Ebstein-Barr virus titers.E. Perform a bone marrow aspiration.

3. An 18-month-old girl has a blood count performed at a health supervision visit. The child is well and herphysical examination findings are normal. The laboratory calls because the platelet count is 1�103/�L(1�109/L). The hemoglobin is 13.5 g/dL (135 g/L), white blood cell count is 7.6�103/�L (7.6�109/L), andabsolute neutrophil count is 3.9x103/�L (3.9�109/L). The most appropriate next step is to:

A. Measure immunoglobulins, antinuclear antibody, and antiphospholipid antibodies.B. Measure prothrombin and partial thromboplastin times.C. Perform a bone marrow aspiration.D. Refer to a pediatric hematologist.E. Repeat the platelet count.

4. A 6-year-old boy who has known chronic immune thrombocytopenic purpura is involved in a motor vehicleaccident and arrives in the emergency department unresponsive. Emergency computed tomography scan ofthe head reveals a large subdural hematoma. The child’s blood type is A-negative. The platelet count is1�103/�L (1�109/L). You administer a platelet transfusion and high doses of intravenousmethylprednisolone and begin intravenous gamma globulin. During the emergency craniotomy, it is difficultto control the bleeding. The most appropriate next therapy is:

A. Anti-D immune globulin.B. Cyclophosphamide.C. Emergency splenectomy.D. Plasmapheresis.E. Rituximab (anti-CD 20 monoclonal antibody).




CorrectionsThe caption for Figure 2 in the article entitled “Focus on Diagnosis: Urine Electrolytes” inthe February issue of the journal (Pediatr Rev. 2011;32:65–68) is incorrect. The correctcaption should read, “A graphic illustration of a positive urine anion gap, with the numberof unmeasured anions exceeding the number of unmeasured cations. When this situationoccurs in the context of metabolic acidosis, it is consistent with renal tubular acidosis,indicating an impaired ability to excrete protons in the urine as ammonium.” We regret theerror.

The caption for Figure 1 in the article entitled “Sacral Dimples” in the March issue ofthe journal (Pediatr Rev. 2011;32:109–114) is incorrect. The correct caption should read,“Solitary dimple whose location is greater than 2.5 cm above the anus indicated the needfor further evaluation. . . .” We regret the error.

5. A 7-year-old girl presents with a 3-day history of bruising and an episode of epistaxis lasting 30 minutes.On physical examination, the only abnormalities are scleral icterus, widespread bruising, and cutaneous aswell as mucosal petechiae. Laboratory results include a platelet count of 3�103/�L (3�109/L), hemoglobinof 7.8 g/dL (78 g/L), white blood cell count of 12.9�103/�L (12.9�109/L), absolute neutrophil count of8.8�103/�L (8.8�109/L), and mean corpuscular volume of 86 fL. Urinalysis is negative for red blood cells.The most appropriate next study is:

A. Antiplatelet antibodies.B. Bone marrow aspirate.C. Direct antiglobulin (Coombs) test.D. Flow cytometry on peripheral blood.E. Serum blood urea nitrogen and creatinine assessment.





Deborah M. Consolini Thrombocytopenia in Infants and Children

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Anne F. Brayer and Sharon G. Humiston Invasive Meningococcal Disease in Childhood







Invasive Meningococcal Disease in ChildhoodAnne F. Brayer, MD,*

Sharon G. Humiston, MD,

MPH*

Author Disclosure

Drs Brayer and

Humiston have

disclosed no financial



commentary does not


of an unapproved/


commercial

product/device.


1. Describe the epidemiology of meningococcal disease, including predisposing host andenvironmental factors.

2. Recognize early and key clinical features of meningococcal meningitis and severemeningococcal sepsis.

3. Know current treatment guidelines for invasive meningococcal disease.4. Identify the most common complications and prognosis for meningococcal disease.5. Be familiar with current vaccination recommendations in the United States.

IntroductionNeisseria meningitidis remains a serious bacterial threat to the well-being of children. Sincethe introduction of immunization against Haemophilus influenzae and Streptococcus pneu-moniae, the risk of serious illness from these organisms has decreased sharply amongimmunized children, and it is hoped that widespread use of meningococcal conjugatevaccine will lead to the same outcome. The meningococcus causes a variety of diseaseentities, but this review focuses primarily on its two major manifestations: severe menin-gococcal septicemia (SMS), sometimes confusingly called “meningococcemia,” and me-ningococcal meningitis (MM).

EpidemiologyPrevalence

Annually, meningococcal disease has affected as many as 3,000 people in the United States.Although outbreaks of illness tend to receive major media attention, fewer than 5% of casesoccur during outbreaks. The prevalence of the asymptomatic carrier state varies from lessthan 2% in children younger than 2 years of age to as high as 10% to 40% amongadolescents and young adults. The highest carrier prevalence is among those living in closequarters, such as college students and military recruits.

Based on data from the United States Active Bacterial Core Surveillance sites, theestimated average annual incidence of meningococcal disease is 0.53 cases per 100,000population, with the annual incidence decreasing from 0.92 per 100,000 population in1998 to 0.33 cases per 100,000 population in 2007. Incidence rates are highest in infantsyounger than 1 year of age (5.38 cases per 100,000 population), decline steadily through

late school age, and rise again in adolescence. There has beenseasonal variation in incidence, with peaks in late winter andspring.

CausesFactors related to the organism, host, and environmentdetermine which individual becomes ill with a particularorganism. The causative agent is the aerobic gram-negativediplococcus N meningitidis, which is a natural commensalorganism living in the nasopharynx of humans, its only host.Its immunologically relevant components are its outer mem-brane and the polysaccharide capsule. The membrane isthe site of the lipopolysaccharide molecule, the endotoxin

*Associate Professor of Pediatrics and Emergency Medicine, Department of Emergency Medicine and Pediatrics, University ofRochester, Rochester, NY.

Abbreviations

ACIP: Advisory Committee on ImmunizationPractices

CSF: cerebrospinal fluidICP: intracranial pressureMCV4: meningococcal conjugate vaccineMM: meningococcal meningitisSMS: severe meningococcal septicemiaWBC: white blood cell

Article infectious diseases



that triggers the immune response. Capsular polysaccha-ride composition varies, and it is on this basis that the 13distinctive serogroups of the organism are identified.Virtually all invasive disease is caused by meningococci inone of five serogroups: A, B, C, Y, and W-135. Groups B,C, and Y cause the bulk of disease in North America.Micropilli, or fimbriae on the outer surface of the cap-sule, are the basis for adhesion to the nasopharyngealepithelium. Most commonly, adhesion leads to coloni-zation and is an immunizing event for the host, produc-ing asymptomatic carriage. Systemic infection occurs infewer than 1% of asymptomatic carriers when changes inthe mucosal barrier or host immune factors permitbloodstream invasion.

Predisposing Conditions: The HostChildren younger than 2 years of age have a nearlyfivefold greater risk of contracting meningococcal diseasethan the general adult population. Defects in the hostdefense mechanisms, both congenital and acquired, pre-dispose to bacterial invasion. Acute viral respiratory in-fections are believed to be predisposing factors. Becauseinvasion by the organism triggers a response from virtu-ally every branch of the host immune system, mostimmunodeficiency states increase disease risk. The com-plement system is of major importance in host defenseagainst invasion, and the presence of a complementdeficiency is an important risk factor.

Risk Factors: The EnvironmentEnvironmental factors that affect individual risk of inva-sive disease can be divided into those that promoteperson-to-person spread of the organism and those thataffect the function of the nasopharyngeal mucosal bar-rier. Crowded living conditions (eg, residential camps,college dormitories, military barracks) predispose totransmission of the organism. The rate of secondaryinfection among household contacts is up to 800 timesthat in the general population. Transmission occurs byshort-range exposure (eg, droplet aerosolization or di-rect contact with secretions); effective transmission re-quires close person-to-person contact.

Both active and passive exposure to tobacco smokegreatly increase the risk of illness through disruption ofthe mucosal barrier and by a variety of immunosuppres-sive effects. Tobacco smoke also contributes to increasedtransmission of the organism by increasing productionof respiratory droplets. Asymptomatic carriage rates aresubstantially higher among smokers. Children who areexposed to smoke have a relative risk 3.5 to 7.5 times thatof the general population. There appears to be a positive

dose-response relationship between passive smoke expo-sure and risk. Child care attendance actually may reducethe risk of invasive disease among children who live withsmokers, possibly by reducing the amount of time thechild spends in close contact with asymptomatic carriers.

PathophysiologyMechanism of Disease Process

Infection with N meningitidis produces a variety of dis-ease manifestations, but the two most common anddevastating are MM and SMS. There are two criticalevents in the pathogenesis of meningococcal disease:penetration of the organism through the nasopharyngealmucosa and replication in the bloodstream. Once pene-tration occurs, the response to replication defines thecourse. If replication is rapid and overwhelms host de-fenses, SMS is the result. If replication can be held inpartial check by immune mechanisms, localizing diseasesuch as meningitis or other suppurative complicationsdevelop. Why some individuals develop SMS while oth-ers develop MM is unclear.

COLONIZATION AND INVASION. Following exposure,the organism colonizes the host nasopharynx. N menin-gitidis produces virulence factors, including the polysac-charide capsule and its associated structures that promoteadhesion to mucosal cells, proteases that destroy hostsecretory (immunoglobulin A) antibodies, and mucosalciliary inhibitors. Hosts who have fully functioning im-mune systems typically destroy the organism shortly afterexposure or establish an asymptomatic carrier state. Ineither case, humoral immunity is produced. In hostswho have impaired mucosal barriers (eg, those who haveacute viral illnesses) or are immunocompromised, inva-sion through the mucosa, survival in the bloodstream,and rapid multiplication of the organism set the stage forsevere disease.

Until the maturation of an individual’s ability tomount an immune response (after the first postnatalyear), the innate immune system, particularly comple-ment, provides the primary defense against N meningi-tidis. This mechanism explains the high peak of inci-dence during late infancy, as passive immunity providedby maternal antibody subsides. Acquisition of bothantibody- and cell-mediated immunity occurs through-out childhood, accounting for the drop in disease inci-dence during that period.

THE INFLAMMATORY RESPONSE AND MICROVASCU-LAR INJURY. The host inflammatory immune responsethat follows penetration of primary defenses is intimately

infectious diseases meningococcal disease



involved in the pathogenesis and clinical manifesta-tions of meningococcal disease. The host immune/inflammatory response leads to phagocytosis and activa-tion of pro-inflammatory cytokine pathways. The resultof the activation of the inflammatory cascade is an assaulton the host’s own capillary endothelium. The immune-mediated microvascular injury produces the four generalmanifestations of disease caused by meningococcal infec-tion: capillary leak, vasomotor instability, disordered co-agulation, and myocardial dysfunction. These pathologicmechanisms, in turn, account for the various organ andsystem failures.

Specific Organ Systems InvolvedThe specific result of immune-mediated microvascularinjury is impairment and ultimately failure of most of themajor organ systems.

Myocardial function is impaired in SMS, with de-creased stroke volume resulting in diminished cardiacoutput. In children, diminished stroke volume can becompensated for transiently by increased heart rate, buttachycardia causes increased metabolic demand. Myocar-dial ischemia with elevated cardiac troponin concentra-tions ensues. Impaired myocyte contractility likely resultsfrom numerous factors, including hypoxia, acidosis, andelectrolyte disturbances. Impaired contractility also cor-relates with elevated cytokine and nitrous oxide concen-trations.

Central nervous system impairment occurs by twodistinct mechanisms, either or both of which may bepresent. In MM, inflammatory changes to vascular per-meability and the blood-brain barrier, as well as poly-morphonuclear infiltrates, produce the clinical picture ofmeningitis and direct inflammation of brain. Increasedcerebrospinal fluid (CSF) production and decreased re-absorption, along with cerebral edema, produce rapidlyelevated intracranial pressure (ICP). These changes re-sult in diminished consciousness, confusion, and ulti-mately respiratory compromise if brain herniation oc-curs. By contrast, patients who have SMS and are inrapidly progressive shock experience reduced perfusion,tissue acidosis, and ultimately cerebral infarction, end-organ effects similar to those produced in other bodysystems.

The characteristic evolving rash of meningococcaldisease is the result of damage to capillaries and theendothelium of small end-arteries. Vasculitis, with ex-travasation of red blood cells (and viable organisms) fromleaking capillaries, produces the initial petechial exan-them. With progression, micro- and macroscopicthrombi form in end-arteries and arterioles, producing

varying degrees of ischemia and, ultimately, necrosis andgangrenous changes.

Other organs that are notably affected by microvascu-lar injury and its consequences include the lungs, wherecapillary leak and infiltration with neutrophils produceboth intra-alveolar fluid and thickening of the pulmonaryinterstitium. These changes lead to initial tachypnea,followed by frank respiratory failure with pulmonaryedema.

Renal blood flow suffers during SMS, in direct pro-portion to the degree of shock. Oliguria or anuria mayfollow, and in severe cases, permanent kidney damagefrom acute tubular necrosis may occur.

Splanchnic blood flow is reduced and thrombi form-ing in the mesenteric or gastric distributions can producesubmucosal ischemia and hemorrhage similar to thatseen on the skin; some patients may complain of severeabdominal pain. In rare cases, the lesions may erode andform ulcers.

Vascular injury also contributes to hepatocellulardamage, infarction, and hemorrhage of the adrenalglands (Waterhouse-Friderichsen syndrome) and virtu-ally every other organ and system.

Clinical AspectsThe term “meningococcemia” can be confusing, al-though it is still widely used. SMS expresses the systemicmanifestations of the organism reproducing in the bloodand differentiates this rapidly progressive septic statefrom localized (although still serious) disease. Onlyabout 50% of patients who develop meningococcal bac-teremia (ie, whose blood cultures grow the organism)actually have isolated meningitis (purulent inflammationof the meninges); 10% to 15% have SMS alone; and 40%typically have a mixed picture. Too often, clinicians asso-ciate petechiae only with meningitis and waste valuabletime diagnosing and managing it, while the real culprit,fulminant sepsis, progresses rapidly.

SMSSMS is characterized by sudden onset, rapid progression,and an absence of localizing findings. The presentation isusually more severe than in meningitis or other manifes-tations and the case fatality rate is high (40% to 50%).Most patients who develop SMS have no known immu-nocompromise.

PRESENTING SYMPTOMS AND PHYSICAL FINDINGS.Meningococcal septicemia begins with an acute onset ofhigh fever, shaking chills, and myalgias that may beexpressed as extremity or back pain, particularly in ado-




lescents. Patients presenting with these symptoms beforethe onset of rash may be misdiagnosed as having “viralsyndrome” and discharged.

Within 6 hours, however, patients who have SMSinvariably deteriorate rapidly. The rash that develops mayinitially resemble a viral exanthem, although it is moreclassically petechial. The rash often becomes hemor-rhagic and may coalesce to form widespread purpuriclesions. Purpura fulminans, aggressive spread of purpurato large areas with ischemic necrosis, may develop. Pa-tients who have purpura fulminans are likely to havesudden drops in blood pressure and acute adrenal hem-orrhage (Waterhouse-Friderichsen syndrome).

VITAL SIGNS. Patients who have early SMS can pres-ent with normal blood pressure and warm extremities.Especially in young children, tachycardia may be the solesign of impending disaster. Falling blood pressure is a latesign. Vital sign abnormalities (eg, elevated heart rate andtemperature, widened pulse pressure) may be subtle.Altered mental status of any degree may signal poor brainperfusion.

CLINICAL CLUES FOR EARLY DIAGNOSIS. One reasonthat mortality rates from meningococcus infection havebeen difficult to decrease is that early diagnosis andtreatment continue to evade clinicians. Yung and Mc-Donald (see http://www.mja.com.au/public/issues/178_03_030203/yun10460_fm.html) have summarizedearly clinical clues:

● Patient age, contact with a person who has meningo-coccal disease

● Concern level of the presenting adult● Physical signs and symptoms, especially if the illness

evolves rapidly:– Rash: Any rash appearing in the context of a sud-

den febrile illness should raise concern. Unlikeviral syndromes that have a several-day prodromebefore development of the rash, the meningococ-cal rash is typically present within 24 hours of anysymptomatology. Clinicians should be aware thatthe first petechiae may be intraoral or conjunctivalor be hidden in skinfolds and that the early rashmay not be petechial.

– True rigors (ie, prolonged [10 to 20 minutes]shaking chill that cannot be stopped voluntarily)

– Severe pain in the neck, back, or extremities, whichmay manifest in younger children as refusal to walk

– Vomiting, especially in association with headacheor abdominal pain, in the absence of diarrhea

Most pediatricians see many children who have thesesymptoms, and most such children have a simple viralsyndrome. However, the presence of several of thesefindings in a previously well patient, coupled with a rapidprogression, should trigger alarm. Yung’s review sug-gests that fever and a petechial or hemorrhagic rash isalways SMS until proven otherwise. Further, althoughno single finding is an indication for immediate treat-ment, clinicians should always give serious considerationto meningococcal disease when one or more of the signsare present. When in doubt, clinicians should refer pa-tients for aggressive fluid management and early admin-istration of antibiotics.

MMIn the 50% of patients who have meningitis caused by Nmeningitidis but do not have fulminant sepsis, signs andsymptoms are those of typical bacterial meningitis. Thesepatients are (or have been) bacteremic, and progressionto SMS is an ever-present possibility.

PRESENTING SYMPTOMS AND PHYSICAL FINDINGS.Patients who have MM usually have a 1- to 3-day non-specific prodrome resembling viral illness, with low-grade fever and upper respiratory tract symptoms. Signsand symptoms in MM include:

● Vital signs: In MM, rising ICP may produce the Cush-ing triad (bradycardia, hypertension, and respiratorydepression). This picture contrasts with that seen inSMS patients, who tend to exhibit tachycardia andeventually hypotension.

● Meningismus: In patients older than 3 years, the classicsigns of Kernig and Brudzinski may be elicited,* butthese signs rely on a cooperative patient who has near-normal mental status. Infants and toddlers who haveMM may not have classic signs of meningeal inflamma-tion. Children who are verbal may complain of wors-ening headache with neck flexion.

● Mental status: Patients’ mental status may range fromnormal to obtunded. They may be lethargic or irrita-ble.

● Other neurologic signs: Adolescent patients may de-velop sudden and severe headache, often with photo-phobia. Younger infants may demonstrate a bulgingfontanelle.

● Skin: A petechial rash is sometimes present. Centrally

*The Kernig sign is present when the supine patient with the thigh flexed ontothe abdomen complains of pain on passive extension of the leg. The bestknown of Brudzinski’s five meningeal signs is produced in the supine patientwhen passive neck flexion produces spontaneous flexion of the hips and knees.




mediated vasospasm may lead to decreased peripheralperfusion.

● Gastrointestinal complaints: Nausea and vomiting arecommon.

● Myalgias: Muscle aches and especially back pain arecommon.

DIAGNOSTIC STUDIES. In the case of fulminant menin-gococcal disease, laboratory test results may return toolate or may fall within normal ranges early in a precipitouscourse to be of any value. Blood cultures obtained whenintravenous access is obtained are helpful, but cliniciansshould not delay antibiotics or fluids for the sake ofcultures or other testing.

Culture of the organism from a normally sterile site isthe gold standard for bacteriologic diagnosis, but be-cause of appropriate early administration of antibiotics,cultures may be falsely negative. When CSF is available,Gram stain is highly sensitive and specific and continuesto be a fast and accurate test. Antigen detection assays ofCSF, but not serum or urine, are of some use but havehigh false-negative rates. Polymerase chain reaction anal-ysis of blood specimens has promise but is neither widelyavailable nor timely. If the patient’s condition and timepermit, a Gram stain and culture of aspirates from theedges of purpuric lesions may be diagnostic.

Detection of MeningitisA lumbar puncture should always be deferred if thepatient has signs of airway problems, shock, elevatedICP, or coagulopathy, until the patient has been fullystabilized. When obtained, CSF should be sent for com-plete blood count and differential white blood cell(WBC) count, total protein concentration, and glucoseassessment. WBC counts are elevated in most patientswho have meningitis, although when disease is severeand rapidly progressive, CSF WBC counts are low oreven normal; this finding is a negative prognostic sign. Insuch patients, markedly low glucose and elevated proteinvalues are associated with the diagnosis of meningitis;these ancillary tests add little information when they areonly mildly abnormal. A negative lumbar puncture resultis an ominous, not a reassuring finding in patients whohave meningococcal sepsis.

Immune and Metabolic DeterminationsBlood laboratory tests in patients who have SMS or MMare useful less for diagnostic purposes than for followingthe degree of immune response and metabolic injury.A complete blood count may be difficult to interpret.Because of the rapid progress of SMS, the WBC count

may be normal. A very low WBC count suggests over-whelming sepsis, as does the presence of toxic granula-tions. The hematocrit also may be low, normal, or high,depending on the stage of progression and the patient’svolume status. The platelet count may be the fastestmeans of learning about the extent to which the patienthas disseminated intravascular coagulation, although thecount may be normal early in the course. Other coagu-lation parameters should be determined through the useof standard measures, and products of fibrinolysis, fibrindimmers, or fibrins split products should be monitored.

Standard metabolic panels are used to detect abnor-malities in electrolytes and acid-base status. Arterialblood gas determination may be useful, particularly afterfluid resuscitation, as an indirect measure of pulmonaryextracellular fluid. Elevated serum lactate correlates wellwith other measures of rapidly advancing sepsis and maybe rapidly available.

Differential DiagnosisMeningococcal disease may be confused with “viral syn-drome,” influenza, upper respiratory tract infections, andother causes of abdominal pain. In the patient who hasearly MM or other localizing disease, other invasivebacterial infections enter the differential diagnosis. Inevaluating the patient who develops rash, cliniciansshould consider viral causes such as enteroviruses (insummer), parvovirus, human herpesvirus 6, and rickett-sial diseases (particularly when headache is present).

ManagementInitial Stabilization and Treatment (Table 1)

The first step in managing meningococcal clinical syn-dromes is to recognize them and be prepared to treatearly and aggressively. Patients suspected of having me-ningococcal infections should be referred for evaluationin an emergency care facility and preferably transportedvia emergency medical services to allow for prompt de-livery of intravenous fluids and airway management. Vitalsigns should be monitored frequently throughout thisphase.

FLUIDS. Patients should be given large isotonic fluidboluses (20 mL/kg) over the first 5 minutes, using eithermanual “push” with a large-volume syringe on a three-way stopcock or a high-volume infusion pump. Giving60 to 100 mL/kg in the first hour is associated withimproved survival. Altered mental status may result ei-ther from shock or meningitis with associated elevationsin ICP.




VASOACTIVE AGENTS. Once a patient has received atleast 60 mL/kg of fluid, consideration should be given tostarting an inotropic/vasoactive agent such as dopamineor dobutamine. Starting these drugs sooner is of ques-tionable value; they work best when the intravascularfluid volume has been maximized. In most cases of SMS,initial fluid boluses alone are insufficient to produce morethan transient stabilization. This fact highlights the im-portance of transfer to a facility that can provide ongoingintensive care.

AIRWAY MANAGEMENT. Although most patientswho have meningococcal disease, even those who haveSMS, present with spontaneous respirations, delivery oflarge intravenous fluid volumes may lead to pulmonaryedema. Once circulatory status has been optimized withfluid and inotrope use, early elective intubation is recom-mended.

ANTIBIOTICS. N meningitidis remains sensitive topenicillin, and if the diagnosis is certain, penicillin iseffective treatment for both SMS and MM. Usually thecause of sepsis or meningitis is not certain early in the

treatment course, so broad-spectrum antibiotics effectiveagainst N meningitidis and other potential pathogens areindicated (eg, ceftriaxone, cefotaxime, vancomycin).

CORTICOSTEROIDS. Children who have SMS havelower overall cortisol and higher corticotrophin concen-trations than do those who have meningitis only; thisdeficiency is associated with more profound and refrac-tory shock. Physiologic doses (1 mg/kg intravenouslyevery 6 hours) of hydrocortisone may be beneficial inchildren who have SMS and respond poorly to vasopres-sors. High-dose corticosteroids or dexamethasone havenot been shown to be effective for treating septic shock.For MM, high-dose or high-potency corticosteroidshave not been adequately studied, but experience withpneumococcal and H influenzae disease suggests theirefficacy. In these latter conditions, dexamethasone ad-ministered early in the course reduces opening pressure,lowers concentrations of inflammatory mediators in theCSF, and reduces hearing loss and other neurologicsequelae. Most authorities recommend dexamethasoneadministration when MM is suspected.

Table 1. Initial Treatment and Stabilization of a Patient Who HasMeningococcal DiseaseAirway, Breathing, Circulation (ABCs)

As soon as the diagnosis of meningococcal disease is suspected, assure the ABCs:● Assure a protected airway.● Supply high-flow oxygen by 100% nonrebreather mask.● Secure large-bore intravenous (IV) access, ideally at least two lines.

Deliver IV Fluids and Antibiotics

● Use the first IV line for large volumes of isotonic crystalloid or colloid and IV antibiotics.● Place an intraosseous line if unable to place peripheral lines promptly.

Avoid Delays

● If a blood culture can be obtained from the initial access site, send it, but do not delay antibiotics for the sake ofcultures.

● Do not perform a lumbar puncture in a patient suspected of having meningococcal disease until airway/ breathing,access, and antibiotics are assured.

● Administer antibiotics immediately after initial fluid resuscitation in any suspected case of meningococcal disease.● Prehospital antibiotic use has been shown to reduce case fatality rate, so administer before transport if possible.● Use a third-generation cephalosporin if there is a history of anaphylaxis to penicillin.● Many individuals and institutions continue to worry about the “sudden release of endotoxin” following initial antibiotic

treatment. This concern should not be used as a rationale for delaying antibiotics until arrival at definitive care.

Transport

● Generally it is best to use at least basic life support-level transport with IV access and isotonic saline running, unless todo so would cause significant delay.

● Be sure that the airway will remain stable during transport.




Admission and Transfer ConsiderationsAll patients who have known or suspected meningococ-cal disease must be admitted to a hospital that has in-tensive care capabilities. When such admission requirestransport, the patient must adequately stabilized beforetransport.

Hospital Care (Table 2)Children who require airway management, show signsof increased ICP, or are in a persistent state of shock afterinitial fluid resuscitation require care in a pediatric inten-sive care unit. Other children may be cared for on ageneral pediatric unit. All patients must be closely mon-itored for end-organ malfunction, including pulmonaryedema, myocardial dysfunction, gastrointestinal edemaor ischemia, and renal insufficiency. Metabolic derange-ments (electrolyte disturbances, acidosis) and hemato-logic complications (thrombocytopenia, coagulation dis-orders) are not uncommon and may require treatment.Children manifesting extensive purpura should be mon-itored for progressive necrosis and compartment syn-drome. Consultation with plastic or orthopedic surgeonsmay be necessary.

A total of 5 to 7 days of intravenous antibiotic cover-age is generally sufficient (Table 3). Patients treated withpenicillin also require treatment with oral rifampin toeradicate the nasopharyngeal carriage state. Childrenshould be considered contagious and require isolationwith droplet precautions for 24 hours after initiation ofantibiotic coverage (including rifampin).

Cutting-edge TherapiesHuman bacterial permeability-increasing protein, natu-rally produced in neutrophils, binds endotoxin and hasbactericidal effects. Early trials using the recombinantform of this protein showed reduced mortality and im-proved functional outcome. Interfering with the sepsiscascade further down the line by modifying the sequenceleading to coagulopathy has shown some benefit, but notwithout significant risks of exacerbation of bleeding.

Table 2. Hospital CareMetabolic Derangement

Look for and correct abnormalities of:● Glucose● Potassium● Calcium● Magnesium● pH (correct metabolic acidosis if severe [arterial pH

<7.10])

Adequate Ventilation

Provide adequate ventilation to avoid central nervoussystem acidosis; severe acidosis is itself an indicationfor early and elective intubation.

Transfusions

● Administer red blood cells to patients who haveanemia

● Administer fresh frozen plasma early in response tolaboratory findings of abnormal coagulation

● Platelet transfusions may be necessary, althoughthe consumption rate in early stages is so highthat this procedure can be futile

Monitor Pressures

Although it should never be an early priority, a Swann-Ganz catheter can provide a wealth of informationabout central venous and pulmonary capillary wedgepressure as well as cardiac output.

Table 3. Treatment Regimens for Invasive Meningococcal DiseaseAntibiotic Dosing for Meningitis (5 to 7 Days) Comments

Ceftriaxone 100 mg/kg per day IV in one or two divideddoses; maximum, 4 g/day

May be used in patients who havenonanaphylaxis penicillin allergy

Cefotaxime 225 to 300 mg/kg per day IV in three orfour divided doses; maximum, 12 g/day

May be used in patients with nonanaphylaxispenicillin allergy

Penicillin G* 250,000 to 300,000 U/kg per day IV;maximum, 24 million U/day, in four or sixdivided doses

Use when sensitivity to penicillin is known

Chloramphenicol* 75 to 100 mg/kg per day IV; maximum dose,2 to 4 g/day, in four divided doses

Use in patients who have penicillin allergywith anaphylaxis

*Patients treated with antibiotics other than third-generation cephalosporins should also receive chemoprophylaxis to eradicate nasopharyngeal carriage.IV�intravenous




PrognosisThe mortality rate for SMS approaches 50%, while thatfor MM alone is approximately 10%. A hallmark study byStiehm and Damrosch (1) identified the following fac-tors as predictors of poor outcome:

● Presence of petechiae for less than 12 hours beforemedical presentation

● Presence of shock (systolic blood pressure, �70 mmHg)

● Absence of meningitis (�20 WBC/mm3) in CSF● Blood leukocyte count normal or low (�10,000

WBC/mm3)● Erythrocyte sedimentation rate normal or low

(�10 mm/hour)

Infections with serogroup C appear to be associatedwith a higher mortality. Most children who survive inva-sive meningococcal disease make a full recovery. Com-mon sequelae (occurring in 10% to 20% survivors) in-clude hearing loss, brain damage, renal failure, and limbamputation. All children who survive SMS or MMshould be tested for hearing impairment.

PreventionVaccines

In comparison with pure polysaccharide vaccines, conju-gate vaccines tend to be more effective, have longerduration of immunity, and produce herd immunitythrough eradication of asymptomatic carriage. For thesereasons, development of meningococcal conjugate vac-cine (MCV4) offering protection against four capsulargroups (A, C, Y, and W-135) may be a great break-through in preventing meningococcal disease in theUnited States. MCV4 is routinely recommended at 11 to12 years of age; unvaccinated adolescents through 18years of age should receive a dose at the earliest oppor-

tunity. Vaccination is also recommended (2) for personsages 2 to 55 years who are at increased risk for meningo-coccal disease, including those who have:

● Problems with immunity to N meningitidis (personswho have terminal complement component deficien-cies or anatomic or functional asplenia). The AdvisoryCommittee on Immunization Practices (ACIP) rec-ommends that persons who have human immunodefi-ciency virus infection be vaccinated.

● Increased exposure (microbiologists routinely exposedto isolates of N meningitidis and travelers to or resi-dents of countries in which N meningitidis meningitisis hyperendemic or epidemic).

● Risk due to living conditions or behavior (militaryrecruits, college freshmen living in dormitories).

Although MCV4 is licensed for children as young as 2years of age, it is not routinely recommended for healthychildren ages 2 to 10 years. MCV4 is neither licensednor recommended for use in the age group that has thehighest incidence of meningococcal disease: infants.A meningococcal vaccine for United States infants iscurrently under investigation. (3)

Common symptoms following receipt of MCV4 in-clude local pain, headache, and fatigue. MCV4 can beadministered concomitantly with other vaccines, includ-ing tetanus-diphtheria or tetanus-diphtheria-acellularpertussis. Meningococcal vaccine is contraindicated forpersons who have had an allergic reaction to a previousdose of vaccine or any vaccine component. A personalhistory of Guillain-Barre syndrome is listed as a contra-indication in the MCV4-D package insert; the MCV4-CRM package insert indicates that data are insufficient toassess the risk. The ACIP’s 2011 General Recommenda-tions do not include this as either a precaution or con-traindication.

Table 4. Chemoprophylaxis Regimens for High-risk ContactsTreatment Dosage Duration CommentsRifampin Drug of choice for most patients

<1 month 5 mg/kg every 12 hours 2 days Not recommended for pregnant women; may interferewith medications (anticoagulants, oral contraceptives,anticonvulsants)

>1 month 10 mg/kg (maximum, 600 mg)orally every 12 hours

2 days

Ceftriaxone<15 years 125 mg intramuscularly Single dose>15 years 250 mg intramuscularly Single dose

Ciprofloxacin>1 month 20 mg/kg (maximum, 500 mg)

orallySingle dose Not recommended for pregnant women, for routine use

in those <18 years of age, or in communities thathave reported fluoroquinolone-resistant strains ofN meningitidis

Azithromycin 10 mg/kg (maximum, 500 mg) Single dose Not recommended routinely




RevaccinationPersons who received MCV4 at ages 11 through 12 yearsshould receive a one-time booster at age 16 years. Per-sons who received their first dose at ages 13 through 15years should receive a one-time booster at ages 16through 18 years. For details on revaccinating high-riskchildren, please refer to the most recent “RecommendedImmunization Schedule for Persons Aged 7 Through 18Years–United States,” available at the Centers for DiseaseControl and Prevention website: http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm.

For an excellent list of Internet links to parent andclinician resources on meningococcal vaccination, pleasesee http://immunize.org/mening/#resources.

Treatment of Contacts (Table 4)Household contacts of patients who have meningococcaldisease should be treated to eradicate nasopharyngealcarriage of the organism. Those who have child carecontact and those who have direct exposure to an indexcase’s oral secretions (such as personnel providingmouth-to-mouth resuscitation) during the 7 days beforethe onset of illness also require chemoprophylaxis. Ri-

fampin, ciprofloxacin, azithromycin, or ceftriaxoneshould be used for contacts.

References1. Stiehm ER, Damrosch DS. Factors in the prognosis of menin-gococcal infection. J Pediatr. 1966;68:457–4672. Centers for Disease Control and Prevention. Updated recom-mendation from the Advisory Committee on Immunization Prac-tices (ACIP) for revaccination of persons at prolonged increased riskfor meningococcal disease. MMWR Morbid Mortal Wkly Rep.2009;58:1042–10433. Marchant CD, Miller JM, Marshall GS, et al. Randomized trialto assess immunogenicity and safety of Haemophilus influenzae typeb and Neisseria meningitidis serogroups C and Y-tetanus toxoidconjugate vaccine in infants. Pediatr Infect Dis J. 2010;29:48–524. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseriameningitidis disease epidemiology in the United States,1998–2007: implications for prevention of meningococcal disease.Clin Infect Dis. 2010;50:184–1915. Welch SB, Nadel S. Treatment of meningococcal infection. ArchDis Child. 2003;88:608–6146. Yung AP, McDonald MI. Early clinical clues to meningococcae-mia. Med J Aust. 2003;178:134–1377. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningi-tis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196–22108. Thompson MJ, Ninis N, Perera R, et al. Clinical recognition ofmeningococcal disease in children and adolescents. Lancet. 2006;367:397–4039. Pathan N, Faust SN, Levin M. Pathophysiology of meningococ-cal meningitis and septicaemia. Arch Dis Child. 2003;88:601–60710. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, HughesJM. Meningococcal disease. N Engl J Med. 2001;344:1378–138811. Centers for Disease Control and Prevention. Prevention andcontrol of meningococcal disease: recommendations of the Advi-sory Committee on Immunization Practices (ACIP). MMWR Re-comm Rep. 2005;54(No. RR-7)12. Centers for Disease Control and Prevention. Recommenda-tion from the Advisory Committee on Immunization Practices(ACIP) for use of quadrivalent meningococcal conjugate vaccine(MCV4) in children aged 2–10 years at increased risk for invasivemeningococcal disease. MMWR Morbid Mortal Wkly Rep. 2007;56:1265–126613. Centers for Disease Control and Prevention. Revised recom-mendations of the Advisory Committee on Immunization Practicesto vaccinate all persons aged 11–18 years with meningococcalconjugate vaccine. MMWR Morbid Mortal Wkly Rep. 2007;56:794–79514. Schaffner W, Harrison LH, Kaplan SL, et al. Reducing theImpact of Meningococcal Disease in Adolescents and Young Adults.Bethesda, MD: National Foundation for Infectious Diseases;2005. Accessed January 2011 at: http://www.nfid.org/_old1/pdf/meningococcalepid.pdf15. Kaplan SL, Schutze GE, Leake JA, et al. Multicenter surveil-lance of invasive meningococcal infections in children. Pediatrics.2006;118:e979–e984

Summary• Based on strong surveillance data, (4) the incidence

of invasive meningococcal disease has decreased inthe past decade. Children younger than 2 years ofage remain at highest risk.

• Based on multiple clinical studies and consensus,(5)(6)(7)(8)(9) N meningitidis produces a variety ofdisease manifestations, but the two most commonand devastating are MM and SMS. Because thesemanifestations present subtly and progress rapidly,clinicians still must be watchful for patients whomight be developing meningococcal disease and treatthem aggressively.

• Based on multiple research studies, (5)(7)(10)despite improved understanding of meningococcaldisease, no intervention has proved more effective atreducing morbidity and mortality than penicillin andthe aggressive management of shock.

• Based on surveillance data and clinical research,(4)(11)(12)(13)(14)(15) it seems likely thatprevention through routine vaccination shouldsignificantly diminish disease burden, and ameningococcal vaccine may soon be licensed for useduring infancy.




PIR QuizQuiz also available online at http://pedsinreview.aappublications.org.

6. In an infectious disease seminar for medical students, you are addressing the risk factors that increase thelikelihood that transmission from carriers will result in meningococcal disease. You correctly state thatamong the following groups, the risk of disease is highest among:

A. Healthy schoolchildren.B. Healthy nonsmoking adults.C. Household contacts of an index case.D. Toddlers in child care centers.E. Vaccinated students living in college dormitories.

7. While taking a weekend call, you receive a call from the mother of a previously healthy, fully immunized14-month-old boy who has had cold symptoms for the past 2 days. Late this morning, he developed atemperature of 40.0°C, malaise, and discomfort, and she now sees raised red spots scattered over histrunk. He is alert and interactive but very fussy. The most appropriate next step is to:

A. Arrange for him to be seen in the office first thing tomorrow morning.B. Call in a prescription for high-dose oral amoxicillin.C. Immediately arrange to transfer him to the nearest emergency department.D. Order a complete blood count and differential count.E. Recommend an antipyretic and close observation at home.

8. A previously healthy adolescent arrives by ambulance to your emergency department. He has become veryill over the past few hours. A quick physical examination reveals fever, tachycardia, a stiff neck, andwidely scattered petechiae. He is also becoming progressively more obtunded. You establish an intravenousline, draw a blood culture, order electrolyte assessment and a complete blood count, and administer afluid bolus. The most appropriate next step is to:

A. Administer intravenous ceftriaxone.B. Obtain a chest radiograph.C. Order a computed tomography scan of the head.D. Perform a Gram stain on an aspirate of a purpuric lesion.E. Perform a lumbar puncture.

9. A 2-year-old boy is diagnosed with meningococcal meningitis. Intravenous penicillin was administered onadmission, droplet precautions were begun immediately, and he received oral rifampin the next morning.No special resuscitative procedures were ever required. To reduce the risk of secondary cases, prophylaxiswith oral rifampin is necessary for:

A. Grandparents who live out of state and visited him in the hospital.B. His companions in child care.C. Laboratory personnel who drew blood samples.D. Nurses who delivered routine bedside care.E. Physicians who examined the patient.

10. Meningococcal conjugate vaccine is routinely recommended:

A. At age 4 to 5 years.B. At the earliest opportunity between 11 and 18 years.C. At 12 months.D. For all infants at birth.E. For children of all ages who have cellular immune deficiencies.





Anne F. Brayer and Sharon G. Humiston Invasive Meningococcal Disease in Childhood




c_disordershttp://pedsinreview.aappublications.org/cgi/collection/neurologi

Neurologic Disorders _diseaseshttp://pedsinreview.aappublications.org/cgi/collection/infectious

Infectious Diseasesfollowing collection(s): This article, along with others on similar topics, appears in the






http://pedsinreview.aappublications.org/cgi/collection/infectious_diseases

http://pedsinreview.aappublications.org/cgi/collection/neurologic_disorders




DOI: 10.1542/pir.32-4-162 2011;32;162 Pediatr. Rev.

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Moshe Shapira, Daniela Militianu and Miriam Butnariu Visual Diagnosis: Bilateral Posterior Swelling of the Knees in a 12-year-old Boy







Bilateral Posterior Swelling of theKnees in a 12-year-old Boy

Author Disclosure

Drs Shapira, Militianu, and Butnariu have disclosed no

financial relationships relevant to this case. This

commentary does not contain a discussion of an

unapproved/investigative use of a commercial

product/device.

Moshe Shapira, MD,* Daniela Militianu, MD,†

Miriam Butnariu, MD§

PresentationA 12-year-old boy presents with a 2-month history ofmild bilateral posterior knee discomfort and fullness,especially on the left side. The swelling does not restrictwalking or weight bearing. There is no history of recentfever, rash, anorexia, weight loss, bleeding disorder, orany other joint pain or swelling. The only finding of noteon his past medical history is a fall 19 months ago that didnot cause a sprain or fracture to the lower limbs.

Physical examination shows a well-appearing boywhose vital signs are normal for age. Inspection andpalpation of the posteromedial aspect of both kneesreveals bilateral swelling, with the left side larger than theright (Fig. 1). However, there is no evidence of kneejoint effusion or limited range of motion, lower extrem-ity erythema, warmth, or edema. The remainder of thephysical examination findings are within normal param-eters. A complete blood cell count, erythrocyte sedimen-tation rate, C-reactive protein, and blood chemistrypanel and urinalysis yield normal results. Ultrasonogra-phy of the posterior knees confirms the suspected clinicaldiagnosis.

*Maccabi Health Services, Nave-Sha’anan Clinic, Haifa, Israel.†The Department of Medical Imaging, MRI Unit, Rambam Health Care Campus,Technion Rappaport Faculty of Medicine and Research Institute, Haifa, Israel.§The Pediatric Orthopedic Unit, The Bnai-Zion Medical Center, TechnionRappaport Faculty of Medicine and Research Institute, Haifa, Israel.

Figure 1. Bilateral swelling of the posterior aspect of theknees, with the left side larger than the right.

visual diagnosis



Diagnosis: Bilateral Popliteal Cysts(Baker Cyst)Ultrasonography of the posterior aspect of the kneesrevealed fluid-filled formations measuring 5.3�1.6 cmon the left and 2.35�1.34 cm on the right (Fig. 2),confirming the clinical diagnosis of bilateral poplitealcysts.

A popliteal synovial cyst is a fluid-filled mass in thepopliteal fossa resulting from extrusion of joint fluid intothe gastrocnemius-semimembranosus bursa through aweak portion of the posteromedial capsule of the kneebetween the medial head of gastrocnemius and the semi-membranosus tendon. (1)(2) Adams first reported suchcysts in 1840, and Baker described their occurrence inthe presence of intra-articular disease in 1877.

Cause and IncidencePopliteal cysts are classified into primary cysts, in whichbursa distension does not communicate with the jointspace and no knee effusion or intra-articular pathology ispresent, and secondary cysts, in which there is commu-nication between the bursa and the knee joint withintra-articular pathology. (1)(2)

Primary cysts typically are seen in children, usuallyappearing before 15 years of age, especially in boys, andfrequently presenting after trauma to the lower limbs.A secondary cyst is common in adults and rare in chil-dren. Secondary cysts develop after intra-articular diseaseoccurs, such as meniscal tears, anterior cruciate ligamentinsufficiencies, degenerative cartilage lesions, rheumatoidarthritis, pyogenic arthritis, or pigmented villonodularsynovitis. (1)(3)

De Maeseneer and associates, (3) in a retrospectivestudy of 393 children undergoing magnetic resonanceimaging (MRI) of the knee, found that the prevalence ofpopliteal cysts is 6.3%, which is significantly lower thanthat reported in adults (19%). Seil and colleagues, (4) ina prospective ultrasonographic study, found a prevalenceof 2.4%, but their study included a relatively smallernumber of pediatric patients compared with the previousstudy. Popliteal cysts are noted in 61% of children whohave juvenile idiopathic arthritis (JIA). (5)

Clinical Manifestations andAssociated Pathology

Primary popliteal cysts in children are usually an inciden-tal finding, appearing as a painless mass in the poplitealfossa between the medial head of the gastrocnemius andthe semimembranosus tendon. Sometimes a poplitealcyst appears after direct trauma to the popliteal fossa. Themechanism for cyst development after direct trauma isunclear, (3) although it is speculated that in small chil-dren, the action of swinging the legs against the frontedge of the chair while sitting causes repeated injury tothe popliteal fossa, leading to inflammation and subse-quent distension of the bursa. (5)(6)

O’Connor and coworkers (7) described 14 childrenwho had popliteal cysts confirmed by ultrasonography.The mean age at presentation was 6 years (range, 2.5 to11 years). Most of the children were boys (10/14), andin only one case were the cysts bilateral. Clinical andultrasonographic confirmation of complete resolutionwas documented in 54% of the children, with a meantime of 28.6 months (range, 10 to 50 months). In 46% ofthe children, ultrasonography confirmed the persistenceof the cyst without subsequent enlargement or othersymptoms.

Another study of 75 children (47 boys) whose meanage was 6.5 years (range, 2 to 12 years) found bilateralcysts in only 8% (6/75). (8) The cysts disappeared afteran average of 1 year, 11 months (from 3 weeks to 7 years)and at an average age of 8.5 years (range, 3 to 17 years).The bilateral cysts disappeared at approximately thesame time. Those patients who had persistent cysts had

Figure 2. Ultrasonography demonstrating the right poplitealcyst.

visual diagnosis



no other symptoms, and the cysts decreased in size aftera mean of 1 to 8 years, between ages 8 and 14 years. Theauthors concluded that primary synovial cysts disappearbefore 18 years of age and that there is no relationbetween the age at which a cyst is detected and the timeit takes to disappear.

Popliteal cysts can be associated with other conditions(Table). Rodriguez and associates (9) first described theoccurrence of a ruptured popliteal cyst with diffusion ofblood into the calf muscles after trauma to the knees in a71⁄2-year-old boy who had hemophilia A. An unusual caseof synovial sarcoma arising within a popliteal cyst hasbeen described in a 13-year-old girl presenting withbilateral popliteal cysts. (10) Bilateral popliteal cysts weredescribed as the presenting symptom of a paraneoplasticsyndrome in a young adult in whom gastric lymphomaultimately was diagnosed. (11)

Popliteal cysts have been associated with some infec-tious diseases, especially Lyme disease, but also withbrucellosis, tuberculosis, candidiasis, and aspergillosis.(12) In one case report of a 13-year-old boy who hadLyme disease, the popliteal cysts were bilateral. (13)

Secondary popliteal cysts are rare in children, but theydo occur. A symptomatic popliteal cyst has been reportedin an 11-year-old girl who had an underlying intra-articular chondral lesion. (14) Secondary popliteal cystshave also been reported in children who have osteochon-dritis dissecans of the knee (3) and in children who havepigmented villonodular synovitis (PVS), which is a be-nign proliferative disease of the synovium that affectsjoints, bursae, and tendon sheaths.

PVS is rare in children and occurs most commonlyin the knee joint (80%) but can appear in other joints(hip, shoulder, ankle, and fingers). Signs and symptomsinclude intermittent joint pain, swelling, tenderness,limited range of motion, and sometimes a palpable mass.

Two forms of macroscopic PVS have been described: adiffuse type affecting the entire synovial surface of ajoint, bursa, or tendon sheath and a rare focal, localizedtype presenting as a pedunculated nodule within thesynovium. (15) Multifocal joint involvement has beendescribed, especially in children.

A case of PVS was noted in a 9-year-old boy whopresented with popliteal cyst and chronic arthritis of theleft knee. (16) Meehan and Daftari (17) described an-other case of PVS presenting as unilateral popliteal cyst ina 10-year-old boy. PVS was suspected after ultrasonog-raphy revealed a multiseptate mass and MRI delineateda well-circumscribed, multiseptate, cystic mass in themedial aspect of the popliteal fossa with a small effusionin the joint. An excisional biopsy confirmed the diag-nosis. MRI is the imaging method of choice for diagnos-ing PVS because it best demonstrates synovial effusion,hyperplastic synovitis, and hemosiderin deposits by lowsignal on T1- and T2-weighted sequences. (15)

Treatment for the diffuse form of PVS is total syno-vectomy, and open or arthroscopic excision of the nod-ule is undertaken for the localized form of PVS.

Children who have JIA have a high incidence ofsecondary cysts, especially during periods of disease ac-tivity as well as when experiencing the systemic form ofJIA. In such cases, the cysts may manifest atypical exten-sion into the surrounding tissue. Synovial cysts alsocan appear in other uncommon locations, such as theshoulder, elbow, hip, and ankle. (2) Because of the highprevalence of synovial cysts in patients who have inflam-matory arthritis, it is important to rule out JIA in childrenwho present with a single or multiple synovial cysts,especially if the cyst is enlarging and long-standing. JIAshould be suspected if repeated ultrasonography findsevidence of joint effusion, synovial thickening, or cystchanges, all of which are possible manifestations of JIA.

Differential DiagnosisThe differential diagnosis of popliteal cysts includes vas-cular lesions (popliteal vein varix), ganglion cysts, othertypes of synovial cysts, parameniscal cysts, and lesionsthat mimic cysts, such as synovial chondromatosis. (6)Benign or malignant soft-tissue tumors also should beconsidered, especially if the popliteal swelling is locatedin a lateral position rather than a medial one or if ini-tial ultrasonography indicates pathology other than asimple popliteal cyst that is located specifically betweenthe medial head of the gastrocnemius and the semi-membranosus tendon. Bogumill and associates (18) de-scribed three adult patients who presented with malig-nant lesions masquerading as popliteal cysts that finally

Table. Medical ConditionsAssociated With PoplitealCysts in Children• Trauma• Inflammation (juvenile idiopathic arthritis)• Infections (especially Lyme disease)• Hematologic (hemophilia A)• Orthopedic (chondral lesions, osteochondritis

dissecans)• Proliferative (synovial sarcoma, pigmented

villonodular synovitis)

visual diagnosis



were diagnosed as fibrosarcoma, synovial cell sarcoma,and malignant fibrous histiocytoma. In such cases, if theclinical and initial laboratory investigation suggests asolid rather than a cystic lesion or even a lesion that hassolid components, although mostly cystic, a prompt re-ferral to a pediatric orthopedic surgeon is required.

ImagingUltrasonography is the preferred initial noninvasive toolto confirm a fluid-filled structure and identify its relationto surrounding muscles, tendons, nerves, and vessels.Ultrasonography also can demonstrate synovial hyper-

trophy and internal septations as well as complicationssuch as synovial rupture or internal hemorrhage. (2)

MRI is indicated if the mass is not cystic or beforesurgical intervention because it better demonstrates sizeand relation to the surrounding anatomic structures andcan detect the existence of intra-articular pathology bet-ter. (2)(4)

TreatmentBecause spontaneous resolution is expected for popli-teal cysts in children, conservative treatment is recom-mended, with follow-up examinations until cyst disappear-ance. Figure 3 displays an algorithm for evaluating a popli-teal cyst. Surgical intervention is recommended for thosechildren in whom the popliteal cyst progressively enlarges,causing pain, restriction of activity, or limitation of kneemotion. Surgical removal is also indicated for patients whohave ruptured cysts and cysts that have an atypical appear-Figure 3. Algorithm for evaluating a popliteal cyst.

Figure 4. Sagittal MRI of left knee demonstrating poplitealcyst.

visual diagnosis



ance on MRI. (6)(19) The postoperative recurrence rate is42% to 50%, (6)(16) but a new modified surgical methodperformed on nine children whose mean age was 5.7 yearsshowed no recurrences after a mean follow-up period of 8.3years (range, 5.6 to 12.1 years). (19)

Patient CourseBecause the patient had no other general symptomsor joint complaints, he was observed for 8 months. Hecontinued to have no other symptoms or joint com-plaints, but repeated examinations revealed persistentbilateral cysts and a clinical impression of further enlarge-ment of the cysts, with the left greater than the right.

A second ultrasonographic evaluation demonstratedpersistence of both cysts, without enlargement on the rightside and with a slight enlargement on the left. The cysts didnot have any septations, lobulations, or internal hemor-rhage and had no signs of rupture. Because the cysts werepersistent and enlarging, a pediatric orthopedic surgeonand a pediatric rheumatologist were consulted. Rheumato-logic examination and specific laboratory tests ruled out aconnective tissue disease. The pediatric orthopedic surgeonrecommended MRI of both knees to exclude any intra-articular disease before making any further decisions regard-ing treatment of the cysts.

MRI confirmed the ultrasonographic findings ofbilateral popliteal cysts that had lengths of 8.3 and4.8 cm, widths of 3.0 and 2.3 cm, and depths of 1.4 and1.0 cm in the left and right knee, respectively, withoutany intra-articular pathology (Figs. 4 and 5).

Based on the symptoms, physical examination find-ings, blood test results, ultrasonography, and MRI, thepatient was diagnosed as having unusual posttraumaticbilateral popliteal cysts, a unique appearance becausemost popliteal cysts are unilateral. Taking into consider-ation the natural history of popliteal cysts, with sponta-neous disappearance in most cases and the relatively highpostoperative recurrence rates, a conservative, observa-tional approach was taken.

SummaryMost popliteal cysts in children are primary and unilat-eral, appearing mostly in boys, sometimes after trauma,with a prevalence of 6.3%. Bilateral cysts have a frequencyof 7% to 8%, and some of these cysts have been describedin association with other conditions such as infectiousdiseases, especially Lyme disease, and neoplasia. Second-ary cysts occur mostly in adults, but they do occur rarelyin children. Popliteal cysts are common in children whohave inflammatory arthritis. Rheumatologic evaluationand MRI studies are recommended for children whohave persistent or enlarging cysts. Ultrasonography is theinitial imaging tool of choice to detect popliteal cysts;MRI is the modality of choice for determining intra-articular pathology and the need for surgery. In this case,bilateral popliteal cysts appeared after trauma.

The prognosis for popliteal cysts usually is good be-cause spontaneous disappearance is expected. Ortho-pedic follow-up evaluation is recommended for persis-tent and enlarging cysts, and prompt referral is indicatedif initial ultrasonography shows pathology other than asimple popliteal cyst. Surgery is reserved for enlargingpopliteal cysts causing enough pain to restrict the child’severyday activity, cysts that limit the knee’s range ofmotion, ruptured cysts, and cysts that have an atypicalappearance on MRI.

References1. Fritschy D, Fasel J, Imbert JC, Bianchi S, Verdonk R, Wirth CJ.The popliteal cyst. Knee Surg Sports Traumatol Arthrosc. 2006;14:623–6282. Roth J, Scheer I, Kraft S, Keitzer R, Riebel T. Uncommonsynovial cysts in children. Eur J Pediatr. 2006;165:178–1813. De Maeseneer M, Debaere C, Desprechins B, Osteaux M.Popliteal cysts in children: prevalence, appearance and associatedfindings at MR imaging. Pediatr Radiol. 1999;29:605–6094. Seil R, Rupp S, Jochum P, Schofer O, Mischo B. Prevalence ofpopliteal cysts in children. Arch Orthop Trauma Surg. 1999;119:73–755. Szer IS, Klein-Gitelman M, DeNardo BA. Ultrasonography inthe study of prevalence and clinical evolution of popliteal cysts inchildren with knee effusions. J Rheumatol. 1992;19:458–4626. Lang IM, Hughes DG, Williamson JB, Gough SGW. MRI

Figure 5. Axial MRI of left knee demonstrating popliteal cyst.

visual diagnosis



appearance of popliteal cysts in childhood. Pediatr Radiol. 1997;27:130–1327. O’Connor D, Clarke NMP, Hegarty SE, Fairhurst JJ. Thenatural history of popliteal cysts in children: an ultrasound study.Knee. 1998;5:249–2518. De Greef I, Molenaers G, Fabry G. Popliteal cysts in children: aretrospective study of 62 cases. Acta Orthoped Belg. 1998;64:180–1839. Rodriguez V, Haughnessy WJ, Schmidt KA, Slaby JA, GilchristGS, Pruthi RK. Haemorrhage into a popliteal cyst: an unusualcomplication of haemophilia A. Haemophilia. 2002;8:725–72810. Ayoub KB, Davies AM, Mangham DC, Grimer RJ, TwistonDavies CW. Synovial sarcoma arising in association with a poplitealcyst. Skeletal Radiol. 2000;29:713–71611. Shapira A, Peshin J, Lin E, Gordin A, Mendel F, Herness D.Bilateral Baker’s cyst as the presenting symptom of paraneoplasticsyndrome. Arch Orthop Trauma Surg. 1988;107:385–38712. Magee TH, Segal LS, Ostrov B, Groh B, Vanderhave KL.Lyme disease presenting as popliteal cyst in children. J PediatrOrthop. 2006;26:725–727

13. Nicholls T. Bilateral Baker’s cysts. Pediatr Infect Dis J. 2003;22:837, 851–85214. Seil R, Rupp S, Kohn D. Popliteal cyst accompanied by anintra-articular cartilage lesion in a child. Arch Orthop Trauma Surg.1999;119:476–47715. Tavanger SM, Ghafouri M. Multifocal pigmented villonodularsynovitis in a child. Singapore Med J. 2005;46:193–19516. Rosenberg, Kohler R, Chau E, Bouvier R, Pouillaude JM,David L. La synovite villonodulaire et pigmentee. Formed dif-fuse ET formed localize chez L’Enfant. Arch Pediatr. 2001;8:381–38417. Meehan PL, Daftari D. Pigmented villonodular synovitis pre-senting as a popliteal cyst in a child. J Bone Joint Surg Am. 1994;76:593–59518. Bogumill GP, Bruno PD, Barrick EF. Malignant lesions mas-querading as popliteal cysts. A report of three cases. J Bone JointSurg Am. 1981;63:474–47719. Chen JC, Lu CC, Lu YM, et al. A modified surgical method fortreating Baker’s cyst in children. Knee. 2008;15:9–14

visual diagnosis




Moshe Shapira, Daniela Militianu and Miriam Butnariu Visual Diagnosis: Bilateral Posterior Swelling of the Knees in a 12-year-old Boy




keletal_disordershttp://pedsinreview.aappublications.org/cgi/collection/musculos

Musculoskeletal Disordersfollowing collection(s): This article, along with others on similar topics, appears in the






http://pedsinreview.aappublications.org/cgi/collection/musculoskeletal_disorders





Rosenberg, Sani Haider Kizilbash, Sarah Javed Kizilbash and Roli Agrawal Radhika Dhamija, Katherine C. Nickels, Alexa Calero, Brinda Doraiswamy, Jacob

Increasing Perianal Mass in a Teenage GirlWhose Mother Recently Emigrated From Honduras • Case 3: A GraduallyFrequent Falls in an 8-year-old Boy • Case 2: Seizures in a 5-month-old Boy

Index of Suspicion • Case 1: Foot Deformities, Asymmetric Calf Muscles, and







The reader is encouraged to writepossible diagnoses for each case beforeturning to the discussion.

The editors and staff of Pediatrics in

Review find themselves in the

fortunate position of having too

many submissions for the Index of

Suspicion column. Our publication

slots for Index of Suspicion are filled

through 2013. Because we do not

think it is fair to delay publication

longer than that, we have decided

not to accept new cases for the

present. We will make an

announcement in Pediatrics in

Review when we resume accepting

new cases. We apologize for having

to take this step, but we wish to be

fair to all authors. We are grateful

for your interest in the journal.

Author Disclosure

Drs Dhamija, Nickels, Calero,

Doraiswamy, Rosenberg, Kizilbash,

and Agrawal have disclosed no

financial relationships relevant to

these cases. This commentary does

not contain a discussion of an

unapproved/investigative use of a

commercial product/device.

Case 1: Foot Deformities, Asymmetric Calf Muscles,and Frequent Falls in an 8-year-old Boy

Case 2: Seizures in a 5-month-old Boy WhoseMother Recently Emigrated From Honduras

Case 3: A Gradually Increasing Perianal Mass in aTeenage Girl

Case 1 PresentationAn 8-year-old boy presents with pro-gressive bilateral foot deformities andasymmetric calf muscles of 1 year’sduration. He states that he tires easilyand falls frequently. He denies anypain, paresthesias, and bowel or blad-der complaints. He attained his mo-tor and social developmental mile-stones on time, although he hadspeech delay. During his speech eval-uation, he was found to have bilateralhearing loss. His maternal grandfa-ther developed gait difficulties earlyin life and became wheelchair-bound. In addition, he had foot de-formities and thin legs. The boy’sparents are asymptomatic.

The boy’s heart rate is 100 beats/min, respiratory rate is 16 breaths/min, blood pressure is 85/64 mmHg, and head circumference is52 cm. He is nondysmorphic. Neu-rologic examination reveals a normalmental status and normal cranialnerves II through XII, except fornerve VIII. He has normal strengthin his upper extremities, but there isweakness of his ankle dorsiflexors bi-laterally. This weakness is demon-strated again in gait testing becausehe is unable to walk on his heels,although he can walk on his tiptoes.The deep tendon reflexes are absentin his lower extremities but normal inhis upper extremities. His touch,temperature, and pain sensations arenormal, but vibration and positionsenses are absent in both feet. He hasobvious atrophy of his left calf mus-cles compared with the right as wellas hammer toes and high arches. The

rest of the examination findings arenormal.

Radiographs of his feet show pescavus deformity bilaterally. Addi-tional evaluation reveals the diagno-sis.

Case 2 PresentationA 5-month-old boy presents to theED 3 hours after a shaking episodethat lasted approximately 3 minutesand consisted of shaking of all ex-tremities, generalized pallor, andperioral cyanosis. He does not havesigns of upper respiratory tract infec-tion, fever, or diarrhea; has no historyof trauma; and does not take medica-tion. He is developmentally appro-priate for age. He was born at termvia vaginal delivery to a previouslyhealthy 25-year-old woman. Prenatallaboratory evaluation yielded nor-mal results. His birthweight was 8 lb13 oz (75th percentile), head cir-cumference was 35.5 cm (50th per-centile), and length was 52 cm (75thpercentile).

Physical examination reveals anawake and active boy. His temperatureis 37.0°C, heart rate is 138 beats/min,blood pressure is 100/64 mm Hg, andrespiratory rate is 40 breaths/min. Hishead circumference is 42 cm (25th to50th percentile) and his pupils are re-active to light. He has pectus excava-tum. There is slight increase in hismuscle tone, and his deep-tendon re-flexes are brisk. The remainder of theexamination findings are normal.

Laboratory evaluation shows aWBC count of 19.0�103/�L

index of suspicion



(19.0�109/L) with a normal differ-ential count, Hgb of 10.6 g/dL(106 g/L), Hct of 31% (0.31), andplatelet count of 394�103/�L(394�109/L). His AST concentra-tion is 167 U/L (normal, �40 U/L), ALT is 68 U/L (normal,�45 U/L), and alkaline phosphataseis 215 U/L (normal, 16 to 500 U/L). Serum electrolyte values and uri-nalysis results are normal. Brain CT(Fig. 1) and MRI show bilateralasymmetric thalamic calcifications aswell as a calcification in the rightfrontal lobe. Electroencephalogra-phy appears normal. Additional his-tory and laboratory evaluation revealthe cause of his seizure.

Case 3 PresentationA 15-year-old girl presents to thehospital with a 4-month history ofprogressively increasing perianalswelling and pain. There is no dis-charge from the swelling. She deniesfever or weight loss. She was treated2 months ago with a 10-day course ofcephalexin without response, and

this therapy was followed by threeincision and drainage procedures.Review of records shows that al-though large amounts of necrotic fatand old clots were removed eachtime, no frank purulence was noted.Culture-directed antibiotics were ad-ministered following each proce-dure, but her symptoms did not re-solve. Her past medical history isotherwise unremarkable.

Physical examination reveals anindurated and tender area 10 cm indiameter in her perianal region.There is no erythema, warmth, ordischarge, nor is there clinically sig-nificant lymphadenopathy. The restof her examination findings are unre-markable. Initial laboratory results,including CBC and serum electrolytevalues, are within normal limits forher age. Additional evaluation leadsto a definitive diagnosis.

Case 1 DiscussionElectromyography (EMG) and nerveconduction velocity (NCV) studiesshowed evidence of a predominantlyaxonal, fiber length-dependent, sen-sorimotor polyneuropathy. Auto-nomic reflex testing showed length-

dependent postganglionic sympatheticsudomotor (nerves that stimulatesweat glands) impairment. These testresults, in addition to the family historyof neuropathy in the grandfather, ledto the clinical diagnosis of Charcot-Marie-Tooth (CMT) disease. Genetictesting for CMT disease was per-formed, and a variant not previouslyreported was detected in the SH3TC2gene. Results of a serum vitamin Eassessment and peroxisomal panelcomprising very long-chain fatty acids,phytanic acid, and pristanic acid werenormal. Genetic testing was not per-formed on his parents.

Differential DiagnosisNeurologic examination helps to lo-calize a pathologic lesion either in thecentral or peripheral nervous system.Muscle atrophy with weakness andabsent tendon reflexes suggests a le-sion in the peripheral neuromuscularsystem, which includes the anteriorhorn cell, peripheral nerve, neuro-muscular junction, and muscle. An-terior horn cell disorders present withsymmetric weakness and atrophy (spi-nal muscle atrophy) without sensorychanges. Primary peripheral nerve dis-orders present with atrophy, weakness,and loss of tendon reflexes with orwithout sensory involvement. Neuro-muscular junction problems presentwith fatigue-related, fluctuating weak-ness, primarily in the bulbar (facial, oc-ular, oropharyngeal) regions. Primarymuscle problems present with sym-metric weakness, with or without atro-phy, and reduced tendon reflexes pro-portional to the degree of weakness.EMG and NCV studies and nerve ormuscle biopsy can aid further in thediagnosis, but genetic testing is impor-tant in making the definitive diagnosis.

The differential diagnosis ofchronic peripheral neuropathy pre-senting in childhood includes CMTdisease, vitamin E deficiency, andneuropathies caused by heavy metals

Frequently Used Abbreviations

ALT: alanine aminotransferaseAST: aspartate aminotransferaseBUN: blood urea nitrogenCBC: complete blood countCNS: central nervous systemCSF: cerebrospinal fluidCT: computed tomographyECG: electrocardiographyED: emergency departmentEEG: electroencephalographyESR: erythrocyte sedimentation rateGI: gastrointestinalGU: genitourinaryHct: hematocritHgb: hemoglobinMRI: magnetic resonance imagingWBC: white blood cell

Figure 1. CT scan of brain showing bi-lateral asymmetric thalamic calcifica-tions.

index of suspicion



and chemotherapeutic agents as wellas rare metabolic conditions such asperoxisomal disorders (Refsum dis-ease). Lesions involving the caudaequina, such as tethered cord, canmimic hereditary sensory motor neu-ropathy but generally have bowel orbladder involvement.

The ConditionCMT disease is one of the most com-mon inherited neuromuscular disor-ders and, according to the NationalInstitutes of Health, affects approxi-mately 1 in 2,500 people in theUnited States. The disorder is causedby mutations in the genes that pro-duce proteins involved in the struc-ture and function of either the pe-ripheral nerve axon or the myelinsheath. At least 20 different types ofmutations have been reported. CMTdisease has five different classifica-tions, with subtypes based on themutation, mode of inheritance, andassociated phenotype. Most formsare autosomal dominant. Becausethe genetic defect has variable pen-etrance, it is not uncommon to iden-tify asymptomatic parents after thediagnosis is established in their child.

The disease is named for the threephysicians who first described it in1886: Jean-Martin Charcot andPierre Marie in Paris, France, andHoward Henry Tooth in Cam-bridge, England. CMT disease is alsoknown as hereditary motor and sen-sory neuropathy.

The symptoms of CMT diseaseoften start in the second decade, al-though they start in early childhoodin some families. Both mild and se-vere phenotypes exist. The neuropa-thy tends to worsen progressivelyover time, affects both motor andsensory nerves, and sometimes caninvolve autonomic nerves. A typicalfeature is weakness of the foot andlower leg muscles, which may resultin foot drop and a high-stepped gait

with frequent falls. Foot deformities,such as high arches, hammer toes,and an inverted “champagne bottle”appearance of the lower extremities,are characteristic and caused byweakness and atrophy of the muscles.Later in the course, hand musclesmay be involved. One form of CMTdisease caused by the mutation in thePMP22 gene is associated with sen-sorineural deafness, although this pa-tient did not have that mutation.

CMT disease can be diagnosed inthe appropriate clinical setting withadditional studies such as EMG andNCV. Nerve biopsy may be per-formed to distinguish it from otherneuropathies, and mutation analysiscan be performed to identify the sub-type.

ManagementManagement of CMT requires amultidisciplinary team approach in-volving physical therapy, occupa-tional therapy, and in selected cases,orthopedic surgery. Because pain canbe debilitating in some patients, paincontrol is crucial. Although longevityis not affected, the quality of life canbe severely affected, depending onthe type of mutation.

This patient elected to undergosurgery for the foot deformities andbegan physical therapy. The progres-sive nature of the disease has beenexplained to the family. At this time,the boy is fully mobile but has fre-quent falls. He will be re-evaluatedevery year in the neurology clinic.

Lessons for the Clinicians

● CMT disease is a common heredi-tary neuropathy that can presentwith foot deformities and gait dis-turbances.

● Family history, along with EMGand NCV studies, help to establishthe diagnosis.

● Genetic tests for this condition areavailable commercially.

(Radhika Dhamija, MB, BS,Katherine C. Nickels, MD, Division ofChild and Adolescent Neurology,Mayo Clinic, Rochester, MN)

Case 2 DiscussionFurther questioning revealed thatthe boy’s mother had emigrated byland from Honduras to the UnitedStates during her third trimester ofpregnancy. The possibility of con-genital viral infection (encephalitis)was considered due to the presenceof intracranial calcifications and sei-zures. Laboratory evaluation re-vealed that the boy’s Toxoplasmaimmunoglobulin G (IgG) titer waselevated at 5.43 mg/dL and thequalitative IgM antibody assay waspositive. The findings were con-firmed by an independent researchinstitute. The Toxoplasma serologyshowed dye test titers of 1 to 64,000,an IgA titer of more than 11 mg/dLby enzyme-linked immunosorbentassay, and a positive IgM titer by theimmunosorbent agglutination test.The dye test measures primarily IgGantibodies against Toxoplasma, andany titer is considered positive. CSFanalysis revealed 44 WBCs, proteinconcentration of 329 mg/dL, andglucose of 62 mg/dL. Laboratorytests on the mother confirmed acuteToxoplasma infection. Thus, congen-ital toxoplasmosis was diagnosed.Results of hearing and retinal exami-nation in the infant were normal, andhe was treated with pyrimethamine,sulfadiazine, and leucovorin (folinicacid). He is growing and developingnormally.

Differential DiagnosisInfections with Toxoplasma, cyto-megalovirus (CMV), herpes simplexvirus, rubella, and lymphocytic cho-

index of suspicion



riomeningitis (LCM) virus were con-sidered. These infections can causecongenital infection with variable in-volvement of the liver, eyes, hearing,hematopoietic system, and centralnervous system. Infants infected withCMV frequently have periventricularnecrosis and calcifications along withmicrocephaly. Toxoplasmosis leadsto more diffuse calcifications andusually hydrocephalous. Calcifica-tions also are seen in parvovirus andLCM virus infections. Rubella andherpes are most likely to cause exten-sive cerebral cortical calcifications.Features such as microcephaly anddiffuse brain calcifications also are as-sociated with Aicardi–Goutier syn-drome, a familial disorder that in-cludes CSF lymphocytosis.

The OrganismT gondii is an obligate intracellularparasite. Infection usually is asymp-tomatic in children and adults, butserious disease can occur in the set-ting of a congenital infection. Infec-tion of pregnant women can becaused by ingestion of oocysts(sporozoites) after handling contam-inated soil, cat litter, water, or food;by ingestion of cysts (bradyzoites) inundercooked meat; or as tachyzoitesvia blood product transfusion. Theincubation period ranges from 10 to23 days after the ingestion of cystsand from 5 to 20 days after the inges-tion of oocysts. Placental transmis-sion usually occurs following a pri-mary maternal infection.

The risk of transmission varieswith the baby’s gestational age at thetime of maternal infection. Thetransmission rate is approximately15% for the first trimester, 30% forthe second trimester, and 60% for thethird trimester. Congenital disease ismore severe when infection is ac-quired in the first trimester.

Clinical ManifestationsIt is estimated that 2,400 to 4,000cases of congenital toxoplasmosis oc-cur in the United States each year.About 80% of newborns who havecongenital toxoplasmosis are asymp-tomatic. Late sequelae of fetal infec-tion are chorioretinitis, hydrocepha-lus, and intracranial calcifications.Calcifications due to T gondii usuallyare located in the basal ganglia andare predictive of cognitive and audi-tory defects later in childhood. Hy-drocephalus incidence peaks at 6months of age and is associated withpermanent neurologic sequelae.

Disseminated infection in early in-fancy, which occurs in one third ofpatients, can result in anemia, sei-zures, deafness, visual impairment,fever, growth retardation, jaundice,lymphadenopathy, maculopapularrash, microcephaly, spasticity, nervepalsies, hepatosplenomegaly, throm-bocytopenia, and petechiae. Chil-dren who have disseminated infec-tion may appear very similar to the“blueberry muffin” babies who havecongenital rubella and congenitalCMV infection.

Eye involvement is the most char-acteristic feature of all forms of con-genital T gondii infection. Disease isseen in the macula, and active diseasecauses vitreitis. During childhood,the most common ophthalmologicpresentation is strabismus, but neweye lesions may occur through thethird decade of life or even later. Upto 80% of affected children developlearning or visual disabilities in earlychildhood.

Diagnosis and TreatmentInitial evaluation for congenital tox-oplasmosis should include neuro-logic assessment, ocular examina-tion, hearing screen, head CT scan,CSF analysis, CBC, and liver func-tion tests. Maternal infection is diag-nosed by the Sabin-Feldman dye test,

which makes use of the uptake ofmethylene blue by the organism. Ifthe mother is infected, fetal infectioncan be confirmed using polymerasechain reaction amplification of theB1 gene of T gondii in amniotic fluid.

Congenital infection is diagnosedin the newborn by testing forToxoplasma-specific IgM and IgAantibodies because they do not crossthe placenta and are not likely to beabsorbed from human milk. Fetal in-fection can be prevented by treat-ment of maternal infection withspiramycin.

Treatment for congenital toxo-plasmosis is with pyrimethamine(1 mg/kg daily for 2 to 6 months, then1 mg/kg every other day to complete1 year of therapy), sulfadiazine(100 mg/kg twice a day for 1 year),and folinic acid (10 mg three times perweek, with dose increased as needed),which prevents the hematologic toxic-ity from pyrimethamine, a folic acidantagonist. If therapy is required dur-ing pregnancy, spiramycin is used.

Follow-up evaluations includeCBC to monitor for drug toxicity, pe-riodic head circumference measure-ments to monitor for hydrocephalus,neurodevelopmental assessments,ophthalmologic and hearing evalua-tions, and serum Toxoplasma IgG andIgM titers.

Lessons for the Clinician

● Parasitic disorders should be in-cluded in the differential diagnosisof seizures in immigrants from en-demic countries.

● A detailed history can provide cluesto the cause of seizures duringinfancy.

● Emigration from developing coun-tries, especially from CentralAmerica, where more virulent par-asites predominate, is a major riskfactor for acquisition of toxoplas-mosis.

index of suspicion



● Early diagnosis and treatment ofcongenital toxoplasmosis may pre-vent late neurologic sequelae.

(Alexa Calero, MD, Brinda Do-raiswamy, MD, Nassau UniversityMedical Center, East Meadow, NY;Jacob Rosenberg, MD, Vaughan Pedi-atric Clinic, Woodbridge, Ontario,Canada)

Case 3 DiscussionMost often, recurrent abscesses in theperianal region are due to incompletedrainage, adjacent pockets of un-drained purulence, and undiagnosedfistulae. However, underlying condi-tions such as diabetes mellitus, im-munosuppression (acquired immunedeficiency syndrome, chronic steroiduse, and chemotherapy), inflammatorybowel disease, perianal hidradenitissuppurativa, and malignancy also maycause recurrent abscesses.

For this patient, a diagnosis of un-derlying Crohn disease was enter-tained at the time of presentation.However, both esophagogastroduo-denoscopy and colonoscopy provednondiagnostic. To investigate further,a CT scan of the pelvis was obtained

that revealed a 13.5�13.0�11.0-cmlobulated perirectal soft-tissue masswith peripheral necrosis and posteriorextension involving the left gluteal re-gion (Figs. 2, 3, 4). Consequently, abiopsy of the perirectal mass was per-formed that showed nests of smallround blue tumor cells separated bybands of connective tissue. Some ofthese nests mimicked alveolar spaces.Immunohistochemistry was stronglypositive for desmin, muscle-specific ac-tin, and myogenin. Thus, alveolarrhabdomyosarcoma was diagnosed.

Chest CT scan and bilateral bonemarrow biopsies were negative formetastatic disease. MRI of the girl’sabdomen and pelvis showed en-larged lymph nodes in the left ingui-nal and left iliac chains as well as theperiaortic and interaortocaval re-gions. Vaginal invasion also was sus-pected. Radionuclide bone scanningfollowed by an MRI of her shouldersuggested metastatic disease to theright proximal humerus along withsome soft-tissue involvement in theglenohumeral joint.

Chemotherapy with vincristine,actinomycin D, and cyclophosph-amide (VAC regimen) was initiated,followed by radiation to the perirec-tal mass and shoulder. However, ap-

proximately 2 years later, she devel-oped metastases to the bone marrow,metastatic lesions in the epiduralspace of the thoracolumbar spineleading to spinal cord compression,diffuse osseous metastatic disease,and orbital metastases. She died 31months after diagnosis.

The ConditionRhabdomyosarcomas are the mostcommon pediatric tumors, yet only350 new cases of rhabdomyosarcomaare diagnosed each year in the UnitedStates. Among the four major histo-logic subtypes, alveolar rhabdomyo-sarcomas are uncommon and have arelatively poor prognosis. They usuallyaffect adolescents and young adults,but they may affect individuals of anyage. Usually, rhabdomyosarcomas de-velop sporadically and without specificrisk factors. However, associationshave been found with familial cancersyndromes such as neurofibromatosis,Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and Costellosyndrome.

Although rhabdomyosarcomascan occur at any anatomic site, theypresent most commonly in the headand neck (35% to 40%), genitouri-nary tract (25%), and extremities

Figure 2. CT scan of pelvis shows a largesoft-tissue mass in perirectal region.

Figure 3. CT scan of pelvis shows thatthe mass extends from the ischiorectalfossa to the perineum.

Figure 4. CT scan of pelvis shows massinfiltrating the pelvic floor muscles, al-though there is no involvement of ad-ductor, hamstring, or gluteal muscles.

index of suspicion



(20%), and 50% to 75% of extremityrhabdomyosarcomas are of the alve-olar subtype. Rhabdomyosarcomasusually present as rapidly growing,nontender masses, occasionally withoverlying skin erythema. They mayappear to be fungating when theyarise in external locations such as theconjunctiva and vagina. Often, rhab-domyosarcomas of the trunk and ex-tremities are first noticed aftertrauma and are regarded initially ashematomas. Symptoms of rhab-domyosarcomas are diverse, hetero-geneous, and nonspecific. The lesionmay or may not be painful. Symp-toms and signs result from mass for-mation and the displacement, ob-struction, infiltration, or destructionof adjacent structures. Despite fre-quent delays in diagnosis, the diseaseusually is localized at the time of di-agnosis. However, metastasis to thelungs, bones, and bone marrow doesoccur and may present with pain, re-spiratory distress, and symptomatichypercalcemia.

DiagnosisCT scan or MRI is essential to deter-mine the location, size, anatomicboundaries, and invasiveness of theprimary tumor. A minimal metastaticevaluation should involve a chest CTscan, radionuclide bone scan, and bi-lateral bone marrow aspiration andbiopsy. Regional lymph nodes alsoshould be imaged and sampled, espe-cially for rhabdomyosarcomas of thegenitourinary tract and extremities.Positron emission tomography usu-ally is not used for staging.

An adequate tissue biopsy of theprimary tumor is crucial for diagno-sis. Cytology from fine-needle aspira-

tion never suffices. Rhabdomyosar-comas are one of the small roundblue cell tumors that need to be dis-tinguished from Ewing sarcoma,neuroblastoma, and non-Hodgkinlymphoma. Light microscopic iden-tification of rhabdomyoblasts is es-sential for diagnosis. Electron mi-croscopy and immunohistochemicalstaining (for polyclonal desmin,muscle-specific actin, and myogenin)also are useful in detecting evidenceof myogenic differentiation. Most al-veolar rhabdomyosarcomas can bespecifically identified by the uniquePAX3-FKHR and PAX7-FKHRgene fusions.

ManagementComplete resection, with marginsnegative for tumor, should be con-ducted, although total removal maynot be possible due to functional orcosmetic morbidity. All patients whohave rhabdomyosarcoma are pre-sumed to have subclinical micro-metastatic disease on presentation.VAC is the gold standard chemo-therapy regimen for rhabdomyosar-coma. In low-risk patients, cyclo-phosphamide can be omitted safelyfrom the regimen. Low risk is definedas localized tumors that have embry-onal histology, localized diseasecompletely resected (at any site), to-tal gross resection with evidence ofonly regional spread (at any site), orincomplete resection with gross re-sidual disease at a favorable site (theorbit, nonparameningeal head andneck locations, genitourinary system[excluding bladder and prostate],and the biliary tract).

Radiotherapy also is extremelyimportant for achieving local control

in patients who have microscopic orgross residual disease after resection.Alveolar rhabdomyosarcomas are anexception in that affected patientsshould undergo radiotherapy evenafter complete resection.

With multimodal therapy, pro-longed disease-free survival isachieved in 80% to 90% of patientswho have completely resected tu-mors and about 70% of patientswhose tumors are resected incom-pletely.

Lessons for the Clinician

● Rhabdomyosarcomas are uncom-mon soft-tissue tumors that candevelop at virtually any anatomicsite and can present with multipledifferent symptom complexes.

● The possibility of rhabdomyosar-coma should be considered when ateenager presents with a swelling ormass of long duration.

● Alveolar rhabdomyosarcomas havea poor prognosis and must be diag-nosed early and treated aggres-sively to minimize morbidity andmortality.

● A malignancy should be consid-ered whenever there is an unex-plained mass anywhere in the body.

(Sani Haider Kizilbash, MD, Wil-liam Beaumont Hospital, Royal Oak,MI; Sarah Javed Kizilbash, MD, RoliAgrawal, MD, Children’s Hospital ofMichigan, Detroit, MI)

To view Suggested Reading listsfor these cases, visit pedsinreview.aappublications.org and click on In-dex of Suspicion.

index of suspicion




Rosenberg, Sani Haider Kizilbash, Sarah Javed Kizilbash and Roli Agrawal Radhika Dhamija, Katherine C. Nickels, Alexa Calero, Brinda Doraiswamy, Jacob

Increasing Perianal Mass in a Teenage GirlWhose Mother Recently Emigrated From Honduras • Case 3: A GraduallyFrequent Falls in an 8-year-old Boy • Case 2: Seizures in a 5-month-old Boy

Index of Suspicion • Case 1: Foot Deformities, Asymmetric Calf Muscles, and



Supplementary Material

/DC1http://pedsinreview.aappublications.org/cgi/content/full/32/4/163Supplementary material can be found at:


of_blood_neoplasmshttp://pedsinreview.aappublications.org/cgi/collection/disorders_

Disorders of Blood/Neoplasms born_infanthttp://pedsinreview.aappublications.org/cgi/collection/fetus_new

Fetus and Newborn Infant c_disordershttp://pedsinreview.aappublications.org/cgi/collection/neurologi

Neurologic Disorders keletal_disordershttp://pedsinreview.aappublications.org/cgi/collection/musculos

Musculoskeletal Disorders _diseaseshttp://pedsinreview.aappublications.org/cgi/collection/infectious

Infectious Diseases dysmorphologyhttp://pedsinreview.aappublications.org/cgi/collection/genetics_

Genetics/Dysmorphology _medicine_gynecologyhttp://pedsinreview.aappublications.org/cgi/collection/adolescent

Adolescent Medicine/Gynecologyfollowing collection(s): This article, along with others on similar topics, appears in the






http://pedsinreview.aappublications.org/cgi/content/full/32/4/163/DC1

http://pedsinreview.aappublications.org/cgi/collection/adolescent_medicine_gynecology

http://pedsinreview.aappublications.org/cgi/collection/genetics_dysmorphology

http://pedsinreview.aappublications.org/cgi/collection/infectious_diseases

http://pedsinreview.aappublications.org/cgi/collection/musculoskeletal_disorders

http://pedsinreview.aappublications.org/cgi/collection/neurologic_disorders

http://pedsinreview.aappublications.org/cgi/collection/fetus_newborn_infant

http://pedsinreview.aappublications.org/cgi/collection/disorders_of_blood_neoplasms




DOI: 10.1542/pir.32-4-e44 2011;32;e44-e52 Pediatr. Rev.

William A. Frese and Kimberly Eiden Opioids: Nonmedical Use and Abuse in Older Children

http://pedsinreview.aappublications.org/cgi/content/full/32/4/e44located on the World Wide Web at:




http://pedsinreview.aappublications.org/cgi/content/full/32/4/e44


Opioids: Nonmedical Use and Abuse in Older ChildrenWilliam A. Frese, MD,*

Kimberly Eiden, APN†

Author Disclosure

Dr Frese and Ms

Eiden have disclosed

no financial



commentary does not


of an unapproved/


commercial

product/device.


1. Characterize the prevalence of overall pediatric opioid use, both medical andnonmedical.

2. Identify demographic and clinical characteristics associated with pediatric nonmedicalopioid use.

3. Discuss abuse and dependence comorbidities associated with pediatric nonmedical useof opioids.

4. Describe the pediatrician’s role in prevention and screening for pediatric nonmedicalprescription opioid use.

5. Explain opioid overdose management.

IntroductionAlone or in combination with other pain management modalities, the use of opioids can bea mainstay of adequate analgesia. However, increased prescribing and availability of opioidmedications correlate with overall medication abuse and misuse rates. Prescription drugnonmedical use is second only to marijuana as the most common form of newly initiatedillicit drug use (Fig. 1). (1) Surveys among adolescent populations similarly support a highincidence of nonmedical opioid medication use. (1)(2) Nonmedical opioid use ratesamong 12- to 17-year-old children have stabilized (Fig. 2), (3) but the overall prevalenceof such inappropriate use may prompt pediatricians to consider decreasing opioid prescrib-ing and potentially undertreat pain in an attempt to reduce the abuse of these medications.Pediatricians must be knowledgeable about the prevalence of pediatric nonmedical opioiduse, its pattern, and appropriate prevention strategies. This article reviews the nonmedicaluse of prescription opioids in the pediatric population. The characteristics of such usage areincorporated into prevention, screening, and management strategies.

DefinitionsTo appreciate the characteristics of opioid use, it is essential to understand basic nomen-clature. Terminology describing the pharmacology and clinical diagnoses associated withopioids and their nonmedical use frequently is used inconsistently and incorrectly, result-ing in stigmatization and undertreatment of pain. Table 1 reviews definitions for opiate,narcotic, and opioid and selected opioid use and abuse definitions. Opioid is the preferreddefinition for referencing this class of analgesic medications. (4)(5)

EpidemiologyPrevalence

Cross-sectional studies of diverse pediatric populations indicate that opioid medicationsare the most widely prescribed among studied scheduled medications (opioids, stimulants,sedatives, anxiolytics, and sleep medications). (8)(10)(11) Almost half (46% to 48%) ofchildren ages 10 to 18 years report using an opioid during their lifetimes for variousmedical and nonmedical purposes. (11)(12)

Although most children use opioids for medical reasons only, (8)(10)(11)(12) opioidmedications also comprise the most common medication class that children take fornonmedical purposes. (8)(10)(11) Medical users are eight to ten times more likely to

*Assistant Professor, Department of Pediatrics, Medical College of Wisconsin and Children’s Research Institute, Milwaukee, WI.Formerly Department of Pediatrics, Advocate Hope Children’s Hospital, Oak Lawn, IL.†Department of Pediatrics, Advocate Hope Children’s Hospital, Oak Lawn, IL.

Article substance abuse

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report lifetime and past-year nonmedical opioid usage,respectively. (12) Because medical and nonmedical opi-oid use overlap, nonmedical use behaviors may bemasked and make diagnosis difficult. Ranges of 2.7% to3.8% (2)(3) of surveyed children, ages 12 to 17 years,engage in past-month nonmedical opioid use, compris-ing the second highest population group using opioidsfor nonmedical reasons (Fig. 2). A higher percentage ofpediatric respondents (7% to 12%) identify themselves aspast-year nonmedical opioid users. (2)(8)(9)(10) Life-time nonmedical opioid prevalence is highest, rangingfrom almost 10% to 18% of all children, ages 12 to 18years. (2)(11)(12)(13)

However, these increasing prevalence patterns overtime do not equate to consistent usage; more than 50% ofsurveyed 12th graders report fewer than five occasions oflifetime nonmedical opioid use. (2) Similarly, 82% ofrespondents from a different study reported less thanweekly or no past-year nonmedical opioid use. (13) Thepreviously cited prevalence and usage rates suggest thatnonmedical opioid use is inconsistent, yet increases overa lifetime. Anticipatory counseling regarding nonmedicalopioid use, therefore, should focus both at regular inter-vals and during other identified “high-risk” periodsthrough adolescence.

Compared with prescription opioids, lifetime preva-lence of heroin abuse is less common, ranging between1.2% and 1.4% among adolescents. (2) Prevalence ofillicit, designer fentanyl analogs (china white, Mexicanbrown, tango & cash) usage among children is unknown.

DemographicsCertain demographic characteris-tics listed in Table 2 are signifi-cantly associated with pediatricnonmedical opioid use and can as-sist the pediatrician in screening.

Clinical AspectsUse Motivations

Sixty-nine percent of pediatric re-spondents report pain control forconditions such as migraine head-aches or menstrual cramps as thesole reason to engage in nonmedi-cal opioid use. (8) Most pediatricnonmedical opioid use, therefore,may more appropriately be classi-fied as self-medication or opioidmisuse. This misuse pattern ex-plains why most pediatric nonmed-ical users identify themselves as

both medical and nonmedical users. Nonmedical usersreport taking opioids to aid sleep (15.7%) as the secondmost common motive, (8) which possibly indicates atransitional motivation to more concerning, abusive be-haviors. Only a minority (11%) of pediatric nonmedicalopioid users endorse using opioids solely to “get high.”(8) Similarly, fewer than 10% of nonmedical opioid userscite motivations such as “helps decrease anxiety, coun-teracts other drugs, safer than street drugs, experimenta-

Figure 1. Specific drug employed when initiating illicit drug use among initiates of illicitdrugs ages 12 years or older in the past year. Reproduced with permission from ResultsFrom the 2008 National Survey on Drug Use and Health: National Findings. (1)

Figure 2. Nonmedical use of prescription pain relievers in thepast month by age group: percentages, 2002 to 2007. Repro-duced with permission from The NSHUD Report: Trends inNonmedical Use of Prescription Pain Relievers: 2002 to 2007. (3)

substance abuse opioids

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tion, and because I’m addicted” fortheir nonmedical use. (8) Al-though males still report pain re-lief as the most common motiva-tion for nonmedical opioid use,the other abuse motivations aresignificantly associated with malescompared with females. (8) Un-derstanding motivations behindpediatric nonmedical opioid use isimportant because most pediatricnonmedical opioid users may haveunrecognized and inadequatelytreated pain that should be ad-dressed and may require more ag-gressive analgesic treatment regi-mens.

Diversion BehaviorsOpioid diversion among pediatricnonmedical users is common andfollows sex and age associations. Af-ter allergy medications, opioidmedications are the second mostcommonly loaned and borrowedprescription medications by chil-dren aged 12 to 17 years (14) andcomprise one of the most com-monly diverted class of scheduledmedications. (10) Twenty-five per-cent of older children report givingaway their opioid prescriptions, and10% report trading opioid medica-tions. (10) Recent medical users areespecially likely to contribute to di-version; 64% report being ap-proached to give, trade, or loan opi-oid medications within the past yearof receiving an opioid prescription.(10) Most pediatric nonmedicalopioid users obtain opioid medica-tions for free from well-knownsources, such as family (34%) andfriends (17%). (12) Girls are morelikely than boys to divert pain med-ications, and older children aremore likely to divert opioids thanyounger children. (14)

One consequence of such diversion behaviors is that75% of children report borrowing medications in place ofmaking an appointment with a health-care practitioner

(HCP). (14) Moreover, 32% still sought a HCP aftertaking borrowed medications, but 41% did not informthe HCP about borrowing the medication during the

Table 1. DefinitionsPharmacologic Terms

● Opiates: Natural alkaloids and their semisynthetic compounds derived from theopium poppy. Examples of natural opiates include morphine and codeine.Semisynthetic opiates include hydrocodone, oxycodone, hydromorphone, andheroin.

● Narcotic: A predominantly legal term that refers to a wide range of substances,not limited to opioids, that are characterized by their analgesic effects, abilityto alter mood, and potential for abuse. The United States Drug EnforcementAgency classifies opioids and cocaine together as narcotics. (6) Due to thisbroad classification, the World Health Organization recommends that “narcotic”be replaced with more specific terminology (eg, “opioid”). (7)

● Opioid: Opiates and fully synthetic compounds and naturally producedendorphins that bind to opiate receptors. Examples of fully synthetic opioidsinclude methadone, fentanyl, and tramadol.

Psychiatric Terms

● Medical Use: The compliant use of a medication at the dose, frequency,treatment interval, and purpose intended by the prescriber.

● Misuse: Noncompliant use of a prescribed medication with the purposeintended by the prescriber; however, the medication is taken at differentdosages, frequencies, or intervals than instructed by the prescriber. (8)

● Nonmedical Use: The noncompliant or illegal use of prescription medication bysomeone without a doctor’s prescription for the experience or feeling caused bythe medication. (1)

● Abuse: Recurrent substance use causing significant impairment or distress thathas at least one of the following characteristics: failure to fulfill majorobligations, use in hazardous scenarios, social or interpersonal problems causedby the substance, substance-related legal problems.

● Subthreshold Dependence: Some characteristics of dependence endorsedwithout meeting all necessary DSM-IV criteria for a dependence diagnosis. Usedin research contexts. (9)

● Physical Dependence: Substance use causing significant impairment or distressthat contains criterion 1 or 2 as part of at least three of the following criteria:1) Presence of tolerance.2) Presence of withdrawal.3) Substance is taken in larger amounts or periods than planned.4) There is a wish to control or cut down substance use.5) There is a great deal of time spent obtaining or recovering from the

substance’s effect.6) Substance use replaces or reduces social, occupational, and recreational

activities.7) Substance use is continued despite awareness of persistent or recurring

physical or psychological problems caused by the substance.Physical dependence can occur with both medical and nonmedical use.

● Addiction: A maladaptive state of periodic and chronic intoxication associated withstrong physical and psychological dependence requiring maintenance of a certainlevel of intake for function. Addicts are driven by a compulsion to use a substancerepeatedly despite disastrous consequences and attempts to control use.

DSM-IV�Diagnostic and Statistical Manual of Mental Disorders. 4th ed.




visit. (14) Patients and families must be reminded of theinherent medical risks, potential masking of symptoms,and inappropriate delay in seeking timely treatment as-sociated with opioid diversion.

Abuse and Dependence AssociationsAlthough most pediatric nonmedical opioid users reportpain relief as the reason for opioid use, a significantminority endorse more concerning abuse and addic-tion motives. Pediatric nonmedical opioid use accord-ingly demonstrates a higher prevalence of opioid abuse

and dependence diagnoses. Thirty-five percent of past-year nonmedical users meet criteria for abuse, sub-threshold dependence, or dependence diagnoses ver-sus 1.1% of a baseline population (9), and stands incontrast to the percentage of pediatric nonmedicalusers who report pain control as the sole motivation(69%) and are at decreased risk for substance abuse. (8)Table 3 describes characteristics and specific Diagnos-tic and Statistical Manual of Mental Disorders, 4th edcriteria significantly associated with pediatric opioidabuse and dependence. Of note, 66% of respondents inthe abuse group reported some symptoms of depen-dence and 58% of respondents in the dependencegroup reported symptoms of abuse, indicating symp-tom commonality. (9) This overlap has led to furtherstudies suggesting that abuse and dependence shouldbe combined as one clinical diagnosis for pediatricnonmedical users, rather than be considered two clin-ically distinct diagnoses. (9)(15)

Table 2. Demographic VariablesRelated to PediatricNonmedical Opioid UseSex

● Females are up to two times more likely to reportlifetime nonmedical opioid use than males. (12)

Age

● Nonmedical opioid use increases with age, asindicated by lifetime prevalence by age asfollows: (13)–4.9% among ages 12 to 13 years–8.0% among ages 14 to 15 years–16.4% among ages 16 to 17 years

● The average age for first-time nonmedical opioid useis 13.3 years. (13)

Race

● Nonmedical opioid use is highest among whites,nonwhite Hispanics, children of mixed racialancestry, and Native American/Alaskan populations.

● Nonmedical opioid use among African Americanchildren is less than that of whites in most studies.

● Asian race is associated with the lowest nonmedicalopioid use prevalence.

Education

● Nonmedical opioid prevalence is higher amongschool dropouts.

● Children who have no college plans report a higherprevalence of nonmedical opioid use compared tothose who plan to attend college.

Health Indicators

● Children who have higher nonmedical opioid useprevalence rates report the following:–Perceived poor-to-fair health.–A past-year hospitalization.–Three or more past-year emergency departmentvisits.

Table 3. CharacteristicsSignificantly Associated withPediatric Opioid Abuse andDependenceClinical Characteristics

● Abuse–Poor/fair health status–Nonstudent status

● Dependence–Female sex–Polypharmacy (>3 drug opioid products)–Illicit drug dealing

● Common to abuse and dependence–Weekly nonmedical opioid use–History of major depressive episode(s)–Past-year alcohol use disorder

Specific DSM-IV Diagnostic Criteria

● Abuse–Hazardous use–Role interference

● Dependence–Withdrawal–Giving up activities–Continued use despite having physical/psychologicalproblems

–Tolerance–Salience

Modified from Wu et al. (9)




Nonmedical opioid use also correlates positively withincreased substance abuse beyond opioids, such as higheralcohol, marijuana, and inhalant use at younger ages,compared with nonusers. Nonmedical opioid users aremore than eight times more likely than nonusers toengage in other underage and illicit drug use (medicalusers: odds ratio�1.5). (12) Nonmedical users are alsomore likely to use multiple substances. (11)(12)(13)However, when nonmedical opioid users are divided into“self-medication” versus “other reasons” for nonmedicalusage, scores are significantly lower for the self-treatmentgroup. (8) This difference supports previous assertionsthat there appear to be two distinct groups of nonmedicalusers: those who use opioids for self-medication/misusepurposes and those who use opioids for abuse/experimentation purposes.

Clinical PresentationOpioids interact with �1, �2, �, and � opioid receptorspredominantly located in nervous and gastrointestinaltissues. The �1 receptor is notably responsible for bothanalgesia and dependence symptoms. The � receptor alsoproduces analgesia as well as sedation. The �2 receptorproduces common adverse effects. Most opioid medica-tions affect several receptors, acting as agonists, antago-nists, or mixed agonists/antagonists.

Opioids overall increase parasympathetic and decreasesympathetic activity. Table 4 lists select clinical symp-toms and signs observed in opioid ingestion and over-dose. Symptom severity is generally dose- and tolerance-related. (16) Most prescription opioids are taken orally(crushed or whole) and produce symptoms for 3 to6 hours, with the exception of methadone, whose effectsmay last as long as 48 hours. Heroin acts within shortertime periods, producing euphoria in less than 5 to30 minutes (intravenous and inhaled routes, respec-tively), with effects generally lasting less than 1 hour.Designer fentanyl analogs are taken for effects and byroutes similar to heroin, yet are significantly more potent.Meperidine analogs have been known to cause irrevers-ible Parkinson-like symptoms.

The combination of coma, respiratory depression, andpinpoint pupils suggests opioid overdose. Patients com-monly are profoundly stuporous or comatose, promptingassociated airway and aspiration concerns. Adverse respira-tory and neurologic symptoms are the most life-threateningconsequences that may be observed up to 24 hours afteroverdose. Central respiratory depression causes decreasedrespiratory rate and tidal volume, which leads to cerebralhypoxia/ischemia. Noncardiogenic pulmonary edema also

may result, manifesting as crackles on auscultation and pink,foamy secretions. Common cardiovascular effects include

Table 4. Select Symptoms andSigns Associated With OpioidIngestion and OverdoseNervous System

● Analgesia● Depressed consciousness

–Light somnolence to coma● Alteration of affect

–Euphoria to dysphoria● Central respiratory depression

–Mild depression to apnea● Miosis (mydriasis with cerebral ischemia)● Generalized seizures● Reflex suppression

–Impaired gag response (comatose states)–Cough suppression–Reduced deep tendon reflexes

Respiratory

● Noncardiogenic pulmonary edema● Respiratory acidosis● Bronchospasm● Aspiration (comatose states)

Cardiovascular

● Bradycardia● Arrhythmias● Orthostatic hypotension

Gastrointestinal

● Nausea● Emesis● Ileus● Constipation

Musculoskeletal

● Relaxed muscular tone to rigidity● Rhabdomyolysis

Dermatologic

● Flushing● Pruritus

Urinary

● Decreased urine formation● Urinary retention

Endocrinologic

● Decreased catecholamine release● Increased antidiuretic hormone secretion

Modified from Brunton (4) and Tobias. (16)




bradycardia and orthostatic hypotension, resulting fromcombined increased parasympathetic tone and histamine-related vasodilation. Arrhythmias may develop beyond bra-dycardia if an excitable automatic focus exists.

PreventionPrevention of pediatric nonmedical opioid use encom-passes both primary and secondary prevention strategies.Pediatricians are in a unique position to recognize sub-stance abuse in their patients. A child’s selection of druguse is related to its perceived risk, social approval, andavailability. Accordingly, primary preventive strategiesshould focus on the following factors and be incorpo-rated into anticipatory guidance.

Risk EducationThe riskier a medication is perceived to be, the less likelyit will be used nonmedically or abused. Children perceiveprescription opioids to be safer than heroin and illicit/street drugs, despite the fact that their nonmedical usecan pose equally dangerous consequences. As part ofroutine anticipatory education, clinicians should dispelany misperceptions to both patients and family membersthat prescription opioid medications are safer than otherillicit drugs when taken at different dosages, frequencies,or intents than prescribed. Pediatricians must incorpo-rate this same discussion into their opioid prescribinginstructions because even medical opioid users demon-strate potential risk for nonmedical use. When prescrib-ing opioids, pediatricians also should encourage patientsto maintain open communication and return for re-evaluation if pain persists, rather than engage in self-medication for pain, medical misuse, or diversion behav-iors.

AccessibilityIn addition to risk education, pediatricians should incor-porate accessibility issues into their guidance. Well-intended patients and family members must be remindednot to divert prescription opioids to each other orfriends. Diversion discussions should take place wheninitially prescribing opioids and at subsequent visits dur-ing opioid use because this is a relatively high-risk periodfor nonmedical opioid use and diversion. Pediatriciansshould advocate and encourage parents to store and lockopioid medications securely to prevent easy access. Pa-tients and families also should properly dispose of unusedopioid prescriptions. Pediatricians can provide patientsand families information about local community pre-scription medication disposal programs offered throughpolice stations or hospitals at regular intervals. The Office

of National Drug Control Policy website (see Resources)offers further guidelines and resources regarding pre-scription drug disposal because discarding medications inthe toilet is no longer appropriate for most medications.(17)

Parental FactorsIn coordination with clinician counseling, parental in-volvement serves as a protective factor preventing non-medical opioid use. Parents may not perceive the preva-lence and risks of prescription nonmedical opioid use.Pediatricians should educate parents regarding theserisks and encourage parents to talk to their childrenabout nonmedical prescription opioid use at an early age,before behaviors are less likely to have begun. Thisdiscussion should also occur during periods of prescrip-tion opioid medical use. Although not opioid-specific,children who report that their parents strongly disap-prove of their using substances (alcohol, marijuana, orcigarettes) are less likely to use these substances thanrespondents who believe their parents would somewhatdisapprove or neither approve nor disapprove. (1) Simi-larly, past-month illicit drug use is lower among childrenwho report that their parents always or sometimes en-gage in monitoring behaviors (eg, inquiring of friendsand activities) than among those whose parents seldomor never engage in such behaviors. (1) As part of thismonitoring effort, parents should be encouraged to reg-ulate proper prescription opioid use closely. Older chil-dren may be assumed to be independently taking medi-cations correctly and may not always receive suchoversight. Positive reinforcement is equally important inthese discussions because perceived higher levels of par-ents offering positive feedback for desired behaviors cor-relate with decreased opioid misuse. The National FamilyPartnership (18) and The Partnership for a Drug-FreeAmerica® (19) are nonprofit organizations focused onyouth drug prevention, education, and advocacy thatoffer educational resources, medication inventory cards,and drug abuse prevention pledges.

SchoolsWhen prescription opioids must be taken at school,pediatricians should collaborate with their community’sschool districts to create policies directing how medica-tion should be accessed, dispensed, and monitored tominimize potential nonmedical use and diversion atschool. School environments significantly influence sub-stance abuse behaviors. (20) Recommendations are avail-able regarding medication administration at schools.




(21) Such policies should include and address the follow-ing: (21)

1. The requirement for a written medication formsigned by the prescriber and parents that fully explainsthe medication’s dosage and intent.

2. Maintenance of school medication dispensing re-cords.

3. Prohibition of students self-carrying controlledsubstances.

4. Controlled substance storage in a double-locked,secure location.

In addition to participating in school medication ad-ministration policies, pediatricians may also collaboratewith schools and community centers on community drugprevention programs. Effective programs are known tofocus on problem-solving skills, self-esteem, media influ-ences, stress issues, and “life skills training” (eg, teachingskills to confront specific problems/scenarios). (20) Pe-diatricians not only have familiarity with the social anddevelopmental challenges that older children encounter,but they also have medical knowledge of opioid medica-tions and their associated risks. Pediatrician participationin such programs as an expert resource is beneficial.

ScreeningIn conjunction with primary prevention strategies, clini-cians must also be comfortable with secondary preven-tion measures. Secondary prevention involves early rec-ognition and screening of problematic behaviors beforethey escalate. Most pediatric nonmedical prescriptionmedication users (75%) do not inform their physicians oftheir nonmedical use. (14) Knowledge of nonmedicalopioid use risks and demographics (eg, sex, age, race,health status, and known substance abuse history) assistsclinicians in identifying potentially at-risk individuals andhelps to focus screening efforts. Given the associationbetween medical and nonmedical opioid use, it is impor-tant that pediatricians proactively question pediatricmedical opioid users about potential nonmedical opioidmisuse. Pediatricians similarly should specifically askabout nonmedical opioid use, prescription medicationmisuse, and pain self-medication practices as part of theirmore generalized drug screening efforts because thesepractices may not necessarily be considered risky or prob-lematic by parents or patients.

Formalized clinical screening tools beyond clinicianinquiry also may be employed. Several opioid-specificabuse screening tests have been tested among adults withpromising validity, but none has been tested yet in thepediatric population. A CRAFFT screening test (Table5) identifies teenage substance abuse beyond clinician

inquiry alone. (22)(23) CRAFFT is a mnemonic repre-senting key items in each question (Car, Relax, Alone,Forget, Friends, Trouble). Patients should be counseledthat “drugs” in CRAFFT questioning refer to both pre-scription and illicit substances because they may interpret“drugs” as only illicit street drugs.

Because nonmedical opioid use is associated withsubstance abuse and dependency for a minority of non-medical users, clinicians should be able to screen for thesespecific conditions when initial screening is positive. Fur-ther questioning should focus on identifying hazardoususe, role interference, withdrawal, giving up activities,and continued opioid use despite having physical orpsychological problems, all of which are significantlyassociated with opioid abuse and dependence (Table 3).

State prescription drug monitoring programs (24)have been shown to be beneficial in identifying patientswho receive several opioid prescriptions from multipleHCPs. Most states offer this program; physician registra-tion eligibility and information offered depend on indi-vidual programs. Further information regarding theseprograms, including state-specific programs and contactinformation, may be found on the Drug EnforcementAgency (24) and National Association of State Con-trolled Substances Authorities (25) websites.

Routine laboratory testing is not recommended toscreen for unsuspected opioid use. (26) Drug testing isappropriate when increased clinical suspicion exists andshould follow patient consent, confidentiality, andtamper-prevention recommendations. Because drug

Table 5. CRAFFT ScreenDuring the past 12 months:

● CAR: Have you ever ridden in a car driven by someone(including yourself) who was “high” or has been usingalcohol or drugs?

● Relax: Do you ever use alcohol or drugs to relax, feelbetter about yourself, or fit in?

● Alone: Do you ever use alcohol or drugs while you areby yourself, alone?

● Forget: Do you forget things you did while usingalcohol or drugs?

● Friends: Do your family or friends ever tell you thatyou should cut down on your drinking or drug use?

● Trouble: Have you ever gotten into trouble while youwere using alcohol or drugs?

Two or more “yes” answers indicate a positive screen andneed for further assessment.

Modified from Knight et al. (22)




screen testing does not detect all opioids and their me-tabolites, opioid use and overdose is predominantly aclinical diagnosis. However, screening may assist in de-tecting other abused substances requiring different man-agement.

Management of Opioid OverdoseIdentification of the overdosed opioid, when possible;

its expected duration of action; associated risk factors;and the anticipated level of appropriate respiratory, car-diovascular, and neurologic care should be considered.

Primary management of opioid overdose should focuson respiratory, cardiac, and neurologic stabilization andreversal of signs. Any airway and breathing compromiseshould be assessed and treated appropriately with supple-mental oxygen, pulse oximetry monitoring, arterialblood gas measurement, bag-mask ventilation, and tra-cheal intubation. Comatose patients who have impairedgag reflexes and are at risk for aspiration should beintubated and ventilated. Positive-pressure ventilationassists in reversing noncardiogenic pulmonary edema.Circulation generally improves after adequate ventilationrestoration, but symptomatic hypotension, bradycardia,and arrhythmias require management found in resuscita-tion guidelines and resources. (27) An opioid antagonist,such as naloxone, should be administered soon after orduring airway and circulation stabilization.

Naloxone is a derivative of oxymorphone and pos-sesses a high binding affinity and antagonistic action at �,�, �, and � receptors. Naloxone is the preferred agent forpediatric opioid overdose and can be administered viavarious parenteral routes. Recommended naloxone dos-ing for acute opioid overdose in older children weighing20 kg or greater is 2 mg intravenously every 2 to 5 min-utes, as necessary, until symptom reversal (maximumcumulative dose, 10 mg). Dosing should be reduced to0.2 to 0.4 mg in older children suspected of havingopioid dependence or addiction to minimize withdrawalsymptoms and seizures. The onset of action for naloxoneis within 1 minute when administered intravenously andgenerally lasts for 1 hour. Naloxone possesses a shorterduration of action than most opioids, and additionaldoses may be required. Continuous naloxone infusionsmay also be administered in such circumstances, (28)with dosing recommendations extending beyond thisreview’s scope.

Nalmefene is a secondary opioid antagonist optionthat possesses a longer duration of action than naloxone.Limited research demonstrates nalmefene to be a safeand effective opioid reversal agent specifically for con-trolled sedation procedures in children, (29) but it has a

less well-established role for acute opioid overdose in thepediatric population. Most authorities, therefore, regardnalmefene as a secondary option to naloxone for acuteopioid overdose.

Additional acute opioid overdose management mayinclude activated charcoal (1 g/kg) and gastric lavage foracute opioid overdoses known to occur less than 2 hoursbefore presentation. Urinary output should be moni-tored. If urinary retention is a concern, bladder ultra-sonography and catheterization should be considered.Pruritus can be managed with histamine-1 blockers suchas diphenhydramine. Nausea and emesis may be treatedwith antiemetics such as ondansetron or metoclopra-mide. Consultations with a pediatric psychiatrist as wellas addiction, pain, and adolescent specialists are war-ranted.

ACKNOWLEDGMENTS. The authors thank Margie C.Andreae, MD, Denise B. Angst, PhD, and Gary L. Freed,MD, MPH, for their guidance and review of this article.

Summary• Prescription opioids constitute most nonmedical

opioid use and abuse in older children, and medicalopioid use places pediatric users at increased risk fornonmedical use.

• Prevalence data demonstrate that pediatricnonmedical use increases over a person’s lifetime,necessitating regular, ongoing prevention andscreening measures.

• Pain control is the most common reason fornonmedical opioid use.

• Research data indicate friends and families are themost common sources for opioid diversion, withrecent medical opioid users being at higher risk todivert opioids.

• Strong evidence correlates nonmedical opioid usewith increased substance abuse, with a significantminority of users experiencing both opioid abuse anddependence.

• Central respiratory depression/apnea, severelydepressed consciousness/coma, and pinpoint pupilsare signs of opioid overdose.

• Pediatricians should incorporate preventionstrategies into their anticipatory guidance andprescribing practices.

• Pediatricians must screen for nonmedical opioid useand associated substance abuse using a combinationof clinical questioning and screening tools.

• Primary opioid overdose management includesappropriate airway and ventilation management,circulation support, and administration of an opioidantagonist.




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ResourcesCommunity Anti-Drug Coalition of America website. Accessed

January 2011 at: http://www.cadca.orgThe National Family Partnership website. Accessed January 2011

at: http://www.nfp.org/The Office of National Drug Control Policy website. Accessed

January 2011 at: http://www.whitehousedrugpolicy.govThe Partnership for a Drug-Free America website. Accessed January

2011 at: http://www.drugfree.org/The United States Department of Education website. Accessed

January 2011 at: http://www.ed.gov/

Suggested ReadingHertz JA, Knight JR. Prescription drug misuse: a growing national

problem. Adolesc Med Clinic. 2006;17:751–759Hollman D, Alderman E. Substance abuse counseling. Pediatr Rev.

2007;28:355–357Sanchez-Samper X, Knight JR. Drug abuse by adolescents: general

considerations. Pediatr Rev. 2009;30:83–93




DOI: 10.1542/pir.32-4-e44 2011;32;e44-e52 Pediatr. Rev.

William A. Frese and Kimberly Eiden Opioids: Nonmedical Use and Abuse in Older Children


http://pedsinreview.aappublications.org/cgi/content/full/32/4/e44including high-resolution figures, can be found at:


ogyhttp://pedsinreview.aappublications.org/cgi/collection/pharmacol

Pharmacology _abusehttp://pedsinreview.aappublications.org/cgi/collection/substance

Substance Abuse _medicine_gynecologyhttp://pedsinreview.aappublications.org/cgi/collection/adolescent

Adolescent Medicine/Gynecologyfollowing collection(s): This article, along with others on similar topics, appears in the






http://pedsinreview.aappublications.org/cgi/collection/adolescent_medicine_gynecology

http://pedsinreview.aappublications.org/cgi/collection/substance_abuse

http://pedsinreview.aappublications.org/cgi/collection/pharmacology





Corrections







CorrectionsThe caption for Figure 2 in the article entitled “Focus on Diagnosis: Urine Electrolytes” inthe February issue of the journal (Pediatr Rev. 2011;32:65–68) is incorrect. The correctcaption should read, “A graphic illustration of a positive urine anion gap, with the numberof unmeasured anions exceeding the number of unmeasured cations. When this situationoccurs in the context of metabolic acidosis, it is consistent with renal tubular acidosis,indicating an impaired ability to excrete protons in the urine as ammonium.” We regret theerror.

The caption for Figure 1 in the article entitled “Sacral Dimples” in the March issue ofthe journal (Pediatr Rev. 2011;32:109–114) is incorrect. The correct caption should read,“Solitary dimple whose location is greater than 2.5 cm above the anus indicated the needfor further evaluation. . . .” We regret the error.

5. A 7-year-old girl presents with a 3-day history of bruising and an episode of epistaxis lasting 30 minutes.On physical examination, the only abnormalities are scleral icterus, widespread bruising, and cutaneous aswell as mucosal petechiae. Laboratory results include a platelet count of 3�103/�L (3�109/L), hemoglobinof 7.8 g/dL (78 g/L), white blood cell count of 12.9�103/�L (12.9�109/L), absolute neutrophil count of8.8�103/�L (8.8�109/L), and mean corpuscular volume of 86 fL. Urinalysis is negative for red blood cells.The most appropriate next study is:

A. Antiplatelet antibodies.B. Bone marrow aspirate.C. Direct antiglobulin (Coombs) test.D. Flow cytometry on peripheral blood.E. Serum blood urea nitrogen and creatinine assessment.





Corrections











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Pediatrics in Review_April2011