Pediatrics feb 2012 (1) by manuel Montellanos

Ethics for the Pediatrician : A Brave New Pediatrics? Managing the Desire for Better Children Through Biotechnological Enhancement Ryan M. Antiel, Robert M. Jacobson and Philip R. Fischer Pediatrics in Review 2012;33;e13 DOI: 10.1542/pir.33-2-e13

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/33/2/e13

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright ÂŠ 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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ethics for the pediatrician

Ethics for the Pediatrician: A Brave New Pediatrics? Managing the Desire for Better Children Through Biotechnological Enhancement Ryan M. Antiel, MA,* Robert M. Jacobson, MD,† Philip R. Fischer, MD‡

Editor’s Note

Author Disclosure Drs Antiel, Jacobson, and Fischer have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/investigative use of a commercial product/device.

In his article published in May 2010, Dr Yates discussed the ethical principles involved in various forms of enhancement (Yates FD. Ethics for the pediatrician: the persuasion of enhancements in pediatrics. Pediatr Rev. 2010;31:216–218). In this commentary, Drs Antiel, Jacobson, and Fischer address the same concept of enhancement, providing their personal views as well as those of others, reminding the reader that pediatricians face ethical decisions in situations much more commonly encountered than the classic clinical dilemmas that involve serious illness and matters of life and death. LFN

Introduction Brave New World, Aldous Huxley’s masterpiece of dystopian literature, begins with a tour of the fertilizing room at the Central London Hatchery and Conditioning Center. The hatchery director, Mr Foster, describes the work in progress to the new employees: “We also predestine and condition. We decant our babies as socialized human beings, as Alphas or Epsilons, as future sewage workers or future Directors of Hatcheries.” (1) In Huxley’s world with the scientiﬁc wherewithal, the state determined the destiny of each child. The state predetermined everyone to a particular class, that is, limited the potential *Mayo Medical School, Mayo Clinic, Rochester, MN. † Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN. ‡ Editorial board member. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

ability of everyone to fulﬁll speciﬁc functions in society. Thankfully, there are no hatchery directors in the modern pediatric clinic. However, children’s parents, sometimes with the spoken or unspoken support of their pediatricians, attempt to use biotechnology in a similar manner: to condition and so predestine their children. Perhaps what we now view as wellmeaning attempts to increase the odds of success for our children will prove a prelude to a fearsome brave new world.

Height Augmentation Although the majority of parents may not be willing to pay exorbitant amounts of money on a gamete for the chance of having a tall child, many parents come to the pediatric clinic with a desire to augment the height of their children. And pediatricians quite frequently and indiscreetly praise parents when their children measure above average in height. Although well meaning, these gestures carry an implicit critique that equates “tall” with “good.” Is it better to be taller? At present, our society greatly values height. For example, a meta-analysis found that height makes a clear difference in workplace success and is a stable variable throughout one’s career. (2) Furthermore, the study demonstrated that height is signiﬁcantly and positively correlated with one’s income potential. Others found that at age 16 years, for every additional inch of adult height, one’s wages would increase by 2.6%. (3) Pediatrics in Review Vol.33 No.2 February 2012 e13

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In the past, growth hormone was limited to the treatment of growth hormone deficiency and other endocrinologic and genetic conditions. The US Food and Drug Administration has approved the use of growth hormone for treating Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome, and even non–growth-hormone-deficient idiopathic short stature. (4) There is, at present, no consensus on the ethics of using growth hormone for children with idiopathic short stature. Growth hormone treatment does increase adult height on average by 4 to 6 cm, which corresponds to treatment costs of $35,000 per inch. (5) Some families and insurance companies might consider the price to be prohibitive, but others would claim that the psychological and fiscal benefits make growth hormone a worthwhile investment.

Performance Enhancement With >30 million children and adolescents participating in organized sports in America, the pediatrician frequently addresses issues related to athletics. One area of concern has been the rise in the use of substances such as anabolic steroids, creatine, and dietary supplements in hopes that these agents will improve athletic performance. (6) Among high school athletes, 12% of juniors and 44% of seniors use creatine. (7) In a survey of high school students, 11% admitted to using anabolic steroids. (6) Certainly, it is now commonplace for role models in professional sports to use nutritional supplements as well as pharmaceuticals to enhance their athletic performance. Whatever their role and effectiveness, these performance enhancers have not been rigorously studied with regard to safety in children and adolescents. And <20% of school-age children report that their pediatrician educated them on

the potential dangers of performanceenhancing substances. (6) We have similar concerns with attempts to enhance academic performance. Many people lament the growing epidemic of stimulant usage on college campuses. Interestingly, nonmedical use of prescription stimulants is highest at colleges with more competitive admission standards. (8) The debate over the use of cognition-enhancing drugs is also taking place among educators and scientists. (9) Should methylphenidate or other enhancers be prescribed to improve late-night studying? And how should the pediatrician correctly evaluate the patient who presents in the teens with a personal and parental report of lifelong distraction and inattention, but up until now has been an A student? Given that the diagnosis of attention deﬁcit hyperactivity disorder depends on those reports, is it possible that pediatricians are being set up to diagnose attention deﬁcit hyperactivity disorder to facilitate the availability of a study-enhancing drug?

Cosmetic Improvement Although questions of cosmetic care are not new to the practice of medicine, more recently, there has been a growing demand for cosmetic procedures among adolescents. According to American Society of Plastic Surgeons statistics, nearly 219,000 cosmetic plastic surgery procedures were performed on people aged 13 to 19 years in 2010. (10) What adjustments of normal variations in physical appearance should we promote? More and more adolescents are undergoing otoplasty, rhinoplasty, breast augmentation, and liposuction in hopes that these pricy quick ﬁxes will bring them happiness and a heightened sense of self-esteem. Although some view plastic surgery among adolescents as extreme, orthodontic appliances

(braces) have become mainstream among the afﬂuent, even when they do not improve chewing mechanics or dental health.

Best Possible Life Height augmentation, performance enhancement, and cosmetic improvements are just a few examples. And although, unlike Brave New World, most parents would not use biotechnology simply for purposes of social utility, parents are concerned with their child’s happiness and precociousness. They want their children to have the best life possible, and pediatricians certainly want to help. Thus, “enhancement” recommendations are common in everyday pediatric practice. Pediatricians strongly advocate immunization, which is an example of using biotechnology to enhance immune defenses. As a result of vaccinations, humans now live longer and healthier lives. Pediatricians also talk frequently about enhancing the environment to maximize well-being. We encourage healthy eating, proper sleep, helmet use when riding bikes, enrollment in educational opportunities, and other healthy means to enhance life experiences and health. Our Reach Out and Read program (now reaching 4.5 million children in the United States) not only provides opportunities for teaching parents developmental appropriateness, but also has at its core an objective to improve the child’s academic functioning. Yet, many physicians do not feel comfortable with some enhancements.

Procreative Beneficence Julian Savulescu argues that reproductive ethics should be guided by two principles: procreative beneficence and reproductive autonomy. (11) We will examine his first argument. For Savulescu, procreative beneficence requires that parents select

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the child with the “best opportunity of having the best life.” Although he is arguing that couples should utilize preimplantation genetic tests, we believe he would extend his argument to postnatal enhancements, as well. Michael Parker challenges the principle of procreative beneficence, the duty to bring about the best possible life for a child. (12) His critique is fourfold: the pursuit of the best possible life is underdetermining, paradoxical, self-defeating, and overly individualistic. First, the pursuit is underdetermining in that it is extremely difficult, if not impossible, to be able to actually say what specifically makes a life good. In a pluralistic society, there are competing notions of what “the best life” actually is. For example, is it really possible to correlate “testable features of embryos in any useful or determinative sense to concepts as rich and complex as that of the ‘good life’”? (12) Does height, athletic performance, or straight teeth produce a more fulfilled life? For Aristotle, to live a full human life, one must include the pursuit of virtue. He wrote, “Human good turns out to be activity of soul in conformity with excellence.” (13) He was careful to differentiate a full human life from money, honor, or pleasure. He did so because one can always attain more money, honor, or pleasure. In a similar fashion, one could always be taller, perform better, or be more attractive. Second, this pursuit is, according to Parker, paradoxical. Parker argues that the best possible life is not a life devoid of all suffering or struggle. He writes, “both strengths and weaknesses of character, and of our lives more broadly, are essential and interdependent elements of the good life.” This argument may seem incomprehensible to a culture obsessed with avoiding suffering or discomfort at any cost. Yet, there may be valuable

lessons from certain types of suffering or failure. Failure, although it can bring humiliation, can also bequeath humility, which would prevent people from being foolhardy. Suffering, eg, the pain that comes with burning your finger on a hot stove, causes you to pull your hand back, thus saving your hand. Parker further argues that, from a consequentialist perspective, the pursuit of the best possible life is actually self-defeating. Given that actually obtaining the best possible life is impossible, even with enhancements pre- or postnatal, the pursuit of this unreachable destiny “would inevitably be both exhausting and unlikely to lead to stable, satisfying or deep interpersonal relationships.” We stay away from individuals who are engrossed in their own happiness and well-being. In contrast, a life demonstrating self-effacement will beget a different kind of happiness and wellbeing—a lasting one, which will influence not only the said individual, but also those around her. In Lines Written a Few Miles Above Tintern Abbey, William Wordsworth claimed that the best portions of a good person’s life are those “little, nameless, unremembered acts of kindness and of love.” (14) Finally, Parker argues that this pursuit is overly individualistic. He acknowledges the fact of reasonable pluralism in a liberal society and the difficulties that subsequently arise from competing notions of the good life. “What counts as the good in a particular case,” writes Parker, “will be meaningful and reasonable only within the context of discursive rules, including rules of justification, of the communities within which it is being used as a justification.” Thus, not only are conceptions of the good life “inseparable from relatively complex intersubjective and social practices and values,” but even the justifications

for what constitutes a good life are intricately tied to one’s particular community. Parker attempts to avoid relativism by appealing to an outside notion of beneficence or perhaps nonmaleficence. But not all parents are able to agree on what is beneficial or harmful. Furthermore, even the actualization of a principle such as beneficence is tied to social and community meta-narratives. Along similar lines, another potential problem with enhancement would be the “lack of imagination” if improvements were focused on a very simplistic idea of what constituted a good life. Frances Kamm offers music as an example. Suppose a parent, who lived 50 years ago, wanted a child who was a gifted classical musician. Kamm believes that these parents “could not have conceived that it would be good to have a child who turned out to be one of the Beatles.” (15) Thus, she argues that there are cases where “greater goods are more likely to come about if chance rather than unimaginative choice is in control.” (15) By extrapolation, what about other advancements? Albert Einstein in physics or Marie Curie in chemistry? In challenging life settings, the imagination allows for advancement in every sphere of knowledge. Although Parker believes the duty of procreative beneficence is undermining, paradoxical, self-defeating, and individualistic, he still believes that the concept of beneficence is important in reproductive ethics. With the exception of rare cases, he argues that women should be free to act according to their own understanding of what would result in a reasonable chance of a good life for their child. Thus, Parker upholds Savulescu’s principle of reproductive autonomy. Whether or not one accepts this principle of reproductive autonomy, we must ask what type of goods the Pediatrics in Review Vol.33 No.2 February 2012 e15

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postnatal enhancements described here actually are.

Competitive Enhancement Although absolute or intrinsic goods (and harms) may still be debated, a good deal of overlap exists regarding intrinsic goods from a variety of social and community perspectives. Yet, many of the enhancements that parents are requesting from pediatricians are advantageous not because of their absolute good, but rather only in comparative terms. In fact, it may be helpful to understand enhancements such as height determinations, athletic performance, or even academic performance as competitive enhancement. These enhancements are derived from competitive motives. The desire is to produce taller, faster, smarter, and better-looking children. Each of these adjectives assumes that the particular child possesses the desired quality in a quantity greater than her or his peers. The desire to enhance is the result of the individual’s (often the parent’s) assessment that the child must always be above average in comparison with her or his peers, yet half of all children will always fall below the average by deﬁnition. Take height enhancement as an example. If one child is enhanced and thereby grows in linear stature above average, another child’s height will become below average as a result. Despite that being taller is correlated with a higher income (as noted above), it cannot be said to be an intrinsic good. Peter Singer argues that, in actuality, it would be better if all humans were shorter for “we would require less food to sustain us, could live in smaller houses, drive smaller, less powerful cars, and reduce our impact on the environment.” (16) Therefore, the majority of enhancements parents seek are not to provide

their children with intrinsic goods, but rather to provide them with what Singer calls “provisional goods.” Of course, not all children will be or could be above average, and simply ensuring equal access will not negate this fact. Even if the rich and poor had equal access to growth hormones, we would still see a normal distribution regarding height. Singer points out that, “If everyone does better [on an admissions examination], the scores needed to get in will rise.” (16) Ultimately, even a Scholastic Aptitude Test score is a provisional good. This focus is to be contrasted with a love of learning, a thoughtful analytical disposition, or a committed work ethic.

Conclusion Pediatric medicine involves important ethical questions that extend far beyond rare clinical situations into commonplace, everyday concerns. These issues include, but are not limited to, height augmentation, athletic and academic performance enhancement, and cosmetic improvements. Although some of these issues have existed for decades, there is a new demeanor and conﬁdence that parents bring when they approach these issues with their pediatricians. This new attitude comes from our ability to engage biotechnology to meet parents’ requests. Many parents in our individualistic society feel a sense of entitlement to satisfy their own desires for their children, and many pediatricians will be enticed to participate in competitive enhancement. Along with motives to improve patients’ “happiness” and to regulate the safety of the technologies, there will be a large monetary incentive for physicians to use these technologies. In competitive enhancement, there is an overarching purpose to the use of biotechnology that seeks to

differentiate an individual from others, to obtain a personal advantage, and to put others at a disadvantage, regardless of health and disease. The desire is to produce taller, faster, smarter, and more beautiful children. Competitive enhancement may always take place, yet it is our hope that pediatricians will bravely advocate for the intrinsic dignity of all children and promote thoughtful and authentic concepts of happiness and selfworth that do not depend on extrinsic characteristics or competitive performance. In the new world of pediatrics, failure to thwart parental demands for competitive enhancement could drastically alter the meaning of childhood, parenting, and the very practice of pediatrics.

References 1. Huxley A. Brave New World. New York, NY: HarperCollins Publishing; 1932 2. Judge TA, Cable DM. The effect of physical height on workplace success and income: preliminary test of a theoretical model. J Appl Psychol. 2004;89(3):428–441 3. Persico N, Postlewaite A, Silverman D. The effect of adolescent experience on labor market outcomes: the case of height. J Polit Econ. 2004;112(5):1019–1053 4. Stein MT, Frasier SD, Stabler B. Parent requests growth hormone for child with idiopathic short stature. Pediatrics. 2004; 114(suppl 6):1478–1482 5. Finkelstein BS, Imperiale TF, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med. 2002;156(3):230–240 6. Koch JJ. Performance-enhancing: substances and their use among adolescent athletes. Pediatr Rev. 2002;23(9):310–317 7. Metzl JD, Small E, Levine SR, Gershel JC. Creatine use among young athletes. Pediatrics. 2001;108(2):421–425 8. McCabe SE, Knight JR, Teter CJ, Wechsler H. Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction. 2005;100(1):96–106 9. Sahakian B, Morein-Zamir S. Professor’s little helper. Nature. 2007;450(7173):1157– 1159

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10. American Society of Plastic Surgeons. Plastic surgery for teenagers brieﬁng paper. Available at: http://www.plasticsurgery.org/ news-and-resources/brieﬁng-papers/plasticsurgery-for-teenagers.html Accessed October 5, 2011 11. Savulescu J. Education and debate: Deaf lesbians, “designer disability,” and the

future of medicine. BMJ. 2002;325(7367): 771–773 12. Parker M. The best possible child. J Med Ethics. 2007;33(5):279–283 13. Aristotle. The Nicomachean Ethics. New York, NY: Oxford University Press; 1998 14. Wordsworth W, Coleridge ST. Lyrical Ballads. New York, NY: Penguin Classics; 1999

15. Kamm F. What is and is not wrong with enhancement. In: Savulescu J, Bostrom N, eds. Human Enhancement. New York, NY: Oxford University Press; 2009 16. Singer P. Parental choice and human improvement. In: Savulescu J, Bostrom N, eds. Human Enhancement. New York, NY: Oxford University Press; 2009

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Childhood Antecedents to Adult Cardiovascular Disease Neal Halfon, Philip A. Verhoef and Alice A. Kuo Pediatrics in Review 2012;33;51 DOI: 10.1542/pir.33-2-51

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Article

preventive pediatrics

Childhood Antecedents to Adult Cardiovascular Disease Neal Halfon, MD, MPH,* Philip A. Verhoef, MD, PhD,† Alice A. Kuo, MD, PhD‡

Author Disclosure Drs Halfon, Verhoef, and Kuo have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of

Educational Gap New recommendations for blood pressure and lipid screening were issued by the American Academy of Pediatrics in November, 2011, and are addressed in this article.

Objectives

After completing this article, readers should be able to:

1. Understand the Life Course Health Development framework for examining the impact that childhood factors have on adult health. 2. Understand cardiovascular disease and the risk factors for its development, including pediatric criteria for the metabolic syndrome. 3. Understand the consequences of poor nutritional habits and obesity in childhood and adolescence. 4. Know the risk factors for hypertension and hypercholesterolemia, as well as how to evaluate and treat both conditions. 5. Screen for, diagnose, and treat type 2 diabetes mellitus.

a commercial product/ device.

Introduction

Many of the most common and costly chronic adult health conditions have their origins in childhood and adolescence. This recognition is leading to both a profound shift in our understanding about the developmental origins of diseases, such as hypertension, dyslipidemia, and type 2 diabetes mellitus (DM), and a greater focus on how different risk and protective factors influence the developmental pathways that determine optimal health across the life span. Scientific breakthroughs in the basic, clinical, and epidemiological sciences reveal how different stressors and exposures during what are now termed “critical” or “sensitive” periods of development can affect growth, tissue differentiation, and physiologic set points that influence an individual’s response to metabolic, physiologic, emotional, and environmental challenges throughout life. In light of this explosion of new scientific data about the importance of the early years for lifelong health and development, general pediatricians will have to play an increasing role in addressing childhood antecedents to adult cardiovascular diseases (CVDs). A growing body of research demonstrates that many of the most common and costly adult chronic health conditions (ie, obesity, hypertension, dyslipidemia, DM, and metabolic syndrome) have their origins in childhood. In utero initialization of metabolic pathways and early childhood priming of behavioral response patterns can lead to overt pathology in the future. Landmark retrospective epidemiological cohort studies, such as one conducted by David Barker and colleagues in Hertfordshire, England, used birth Abbreviations and early nutrition records to demonstrate how nutritional insults to the fetus during pregnancy influence CVD rates CVD: cardiovascular disease decades later. (1)(2) These and related studies also show DM: diabetes mellitus similar birth weight–related risk gradients for hypertension, IDF: International Diabetes Federation stroke, and DM. The transmission of risk across the placenta LCHD: Life Course Health Development is not limited to alterations in maternal nutrition, but also NCEP: National Cholesterol Education Program has demonstrated how high levels of maternal stress can *University of California Los Angeles Center for Healthier Children, Families, and Communities, Los Angeles, CA. † Section of Pulmonary and Critical Care, Department of Medicine, Section of Critical Care, Department of Pediatrics, University of Chicago, Chicago, IL. ‡ University of California Los Angeles Combined Internal Medicine and Pediatrics Residency Program, Los Angeles, CA.

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result in differences in child and adolescent nervous system functioning. Although the connection between early experiences and exposures and the development of adult chronic disease is becoming better understood, the effectiveness and appropriateness of different types of early intervention is just beginning to be elucidated. Nonetheless, it is increasingly apparent that interventions that have the potential to prevent chronic disease as well as augment adult health might need to start early in life, so as to address childhood and adolescent risk and protective factors that can influence an individual’s lifelong health trajectory. More is being learned about the role that the pediatrician can play in recognizing, influencing, and redirecting these developing health trajectories by reinforcing positive behaviors, providing psychosocial support, responding to risk factors or “red flags” with interventions (pharmacologic or otherwise), and playing an active role in preventing diseases that could prove debilitating or lethal in adulthood.

Life Course Health Development Current concepts of health have evolved and expanded significantly from early notions of health as merely a state of being free of disease. The 2004 Institute of Medicine Report on Children’s Health, the Nation’s Wealth defined health as the following: “Children’s health is the extent to which individual children or groups of children are able or enabled to (a) develop and realize their potential, (b) satisfy their needs, and (c) develop the capacities that allow them to interact successfully with their biological, physical, and social environments.” (3) In addition to this new developmental definition of health, the Children’s Health, the Nation’s Wealth report proposes a life course framework for how health develops across the life span. Life Course Health Development (LCHD) is shaped by the dynamic and continuous interaction between biology and experiences that is framed and influenced by dynamic developmental contexts over the lifetime. (4) Synthesizing evidence from several fields of scientific inquiry, the LCHD model suggests that • Health development is influenced by the dynamic interactions of risk with protective and promoting factors nested in several different contexts, including socioeconomic, psychological, genetic, and cultural influences, as well as the health care system itself (Fig 1). • Sensitive and critical periods of heightened developmental plasticity means that certain risk, protective, and promoting factors have greater influence during these periods and are potentially more amenable to

intervention. Although many critical and sensitive periods of development occur prenatally and during the early years, research on brain development during adolescence has highlighted the importance of this period to future psychological development and mental health. • Multiple interacting pathways account for variations in trajectories of health development. • Optimizing lifelong health depends on a long-term strategy of enhancing protective and promoting factors and minimizing or eliminating risks through clinical and preventive interventions targeting individuals and populations. • Optimal health trajectories can be facilitated by minimizing risk factors that cause stress and maximizing health-promoting protective factors (Fig 2). By focusing more attention on sensitive and critical periods of development, the LCHD framework recognizes the importance of developmental plasticity as an adaptive process that evolution has selected to promote survival, biological fitness, and reproductive success. Because developmental plasticity focuses on life-course strategies to optimize the biopsychosocial capacity to survive and reproduce, some response patterns may enhance reproduction fitness but impair longevity. This effect is especially true if environmental conditions change strikingly between conception and adulthood. With the modern life expectancy of humans living in developed countries now being twice as long as their Paleolithic ancestors, the harmful effects of poor long-term biobehavioral influences are becoming more apparent. Adaptive anticipatory strategies, such as catch-up growth after prenatal undernutrition, makes adaptive sense for the individual to grow and develop so as to be able to reproduce. (5) Although preventing small-for-gestational age infants can have benefits, interventions to augment prenatal diets to increase birth weights may run the risk of unintended consequences, such as increased adiposity in childhood, DM, and certain kinds of malignancies. A basic premise of LCHD is that optimal health development can be facilitated by reducing the stresses and strains that are induced by specific risks and increasing the protective factors and other conditions that promote the best possible functioning. Stresses occur when environmental influences and experiences disrupt normal patterns of functioning, either through acute shocks, especially during sensitive periods, or a chronic weathering process that grinds away at adaptive response patterns that are in place to guard against external threats and disruptions. Placing demands on developing biobehavioral systems and exceeding their normal capacity to

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Figure 1. A new model of children’s health and its influences. (Reprinted with permission from Institute of Medicine. Children’s Health, the Nation’s Wealth. Washington, DC: National Academies Press; 2004.)

Figure 2. Health development trajectories. (Reprinted with permission from Halfon N,

Inkelas M, Hochstein M. The health development organization: an organizational approach to achieving child health development. Milbank Q. 2000;78(3):447–497.)

respond adaptively induces a range of developmental responses that can be beneficial over the short term, yet lead to longer-term response patterns that are detrimental to lifelong health. (6) One of the most important and ubiquitous stresses that children experience is the stress associated with living in poverty or experiencing socioeconomic disadvantage. A series of longitudinal studies conducted in the United Kingdom, New Zealand, and Scandinavia have demonstrated that children who experience socioeconomic disadvantage are more likely to have major depression, high levels of inflammation (as measured by C-reactive protein), hypertension, obesity, elevated total cholesterol concentrations, high levels of glycosylated hemoglobin, and low maximum oxygen consumption. One recent study from New Zealand indicated that adverse childhood experiences associated with childhood disadvantage accounted for w30% of these clustered metabolic risks when these children became young adults. (7) Retrospective studies conducted in the United States regarding adverse childhood experiences have linked the number of adverse experiences to the prevalence of coronary artery disease, hypertension, alcoholism, and illicit drug use decades later. Growing research on geneenvironment interactions is providing valuable information about specific genetic susceptibilities and the specification of environmental exposures and experiences that are likely to induce genetic expression. Well-recognized examples of such markers, such as the breast cancer genes and the apolipoprotein E gene for late-onset Alzheimer disease, are being joined by new genetic markers that are associated with many other outcomes. In addition Pediatrics in Review Vol.33 No.2 February 2012 53

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to identifying markers of future diseases, many life-course health-development studies are identifying biological and behavioral markers that represent the expression of a particular developmental pathway. A combination of these genetic, biological, and behavioral markers will be used increasingly to develop risk proﬁles, permitting better targeting of speciﬁc interventions, as well as the development of population-based prevention strategies.

Pediatrician’s Role in Preventing Adult CVD The pediatrician can play several important roles in addressing the developmental antecedents of adult CVD. As a clinician who can recognize and intervene to reduce risk, it is important for pediatricians to be aware of childhood risk factors for CVD that are amenable to intervention. Although there are many reasonably straightforward and generic recommendations for reducing risk and promoting health, such as general recommendations that emphasize appropriate nutrition, exercise, and daily activities, there are many areas in which the evidence for what constitutes an appropriate early intervention is less clear. Over the next several years, as more evidence emerges about the connection between childhood risks and later diseases, pediatricians will be called on to play an important role as interpreters of this information for parents and families, highlighting not only what we know about the causes of adverse adult health outcomes, but also what families can do to disrupt chains of associated risks, creating conditions for more optimal health trajectories. Because prevention and health-promotion strategies come in both individual and population-based formats, pediatricians can play an important role in advising parents about what kinds of programs and approaches they might want to adopt at home, and which community-based resources are likely to be reliable purveyors of appropriate interventions. At a population level, pediatricians also can play an important role advocating for evidencebased school- and community-focused prevention and intervention programs that can play an important role in diminishing risks and promoting healthy behaviors. In the next section, we consider several different adult cardiovascular conditions in which the developmental pathways are emerging, and where the early antecedent risks have been deﬁned well enough to permit recommendations for speciﬁc interventions.

CVD

than 60 years. CVD is the most common cause of death in the United States. Although cancer-related deaths slightly exceed deaths related to CVD for persons ages 45 to 74 years, deaths caused by CVD are more than twice as frequent as cancer-related deaths for persons older than 74 years.

Metabolic Syndrome The term metabolic syndrome refers to the clustering of risk factors for CVD and type 2 DM. The International Diabetes Federation (IDF) deﬁnition of metabolic syndrome is central obesity with a waist circumference ‡102 cm (40 in) in men or ‡88 cm (35 in) in women and the presence of at least two of the following four clinical risk factors: 1. Blood pressure (BP) ‡130 mm Hg systolic or ‡85 mm Hg diastolic or drug treatment for hypertension; 2. High-density lipoprotein (HDL) cholesterol level <40 mg/dL (1.0 mmol/L) in men or <50 mg/dL (1.3 mmol/L) in women or treatment for lipid abnormalities; 3. Triglyceride level ‡150 mg/dL (1.7 mmol/L); and 4. Fasting plasma glucose level ‡100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 DM. An estimated 47 million US residents have metabolic syndrome, with the highest prevalence in Mexican American individuals (32%) and the lowest prevalence in white individuals (24%). Persons with metabolic syndrome have a higher risk of developing DM and CVD and have a higher risk of death from CVD. In 2007, the IDF convened a consensus panel to deﬁne the metabolic syndrome in children and adolescents, (8) as a follow-up to the IDF consensus worldwide definition of the metabolic syndrome in adults that was published in 2005. In summary, the IDF states that metabolic syndrome should not be diagnosed in children younger than 10 years of age, although weight management for children who are obese should be strongly encouraged. For adolescents ‡16 years, the adult criteria for metabolic syndrome should be applied. For children between 10 and 16 years, the criteria are generally the same as those for adults, except that waist circumference must be >90th percentile, and the HDL cholesterol level must be <40 mg/dL (1.0 mmol/L) in both boys and girls (as one of the four possible clinical risk factors).

Obesity

More than 80 million adult Americans (one in three) have CVD (hypertension, coronary artery disease, heart failure, stroke), with w47% of these persons being older

Adults with a BMI between 25 and 29.9 are considered overweight, and those with a BMI ‡30 are considered obese. For children and adolescents between the ages

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of 2 and 19 years, overweight is deﬁned as a BMI ‡85th percentile and <95th percentile, and obesity is deﬁned as a BMI ‡95th percentile for children of the same age and sex. In addition, in 2007, an Expert Committee further recognized a third cutoff at the 99th percentile, which indicates severe obesity in children and adolescents. Although the standard Centers for Disease Control and Prevention BMI growth charts stop at the 97th percentile, the Expert Committee report includes a table of 99th percentile cutoff points by age and gender. The recommendations for prevention and treatment of childhood obesity are available in the Expert Committee report, which is published in a 2007 supplement to Pediatrics. (9) Overweight in adolescence can result in immediate adverse effects on health before adulthood. In addition, most overweight teenagers continue to have an elevated BMI in young adulthood, with studies estimating that 80% of overweight adolescents become obese adults. The effect of adolescent overweight on future adult CVD is projected to be substantial even in young adulthood and will continue to rise in middle age. The expected higher rates of hospitalizations, procedures, disability, long-term use of medications, and premature death in a workingage population that would otherwise be at low risk for CVD could be dramatic. As the obesity epidemic unfolds, more attention has been placed on the early life programming of obesity and related metabolic syndromes, as well as other environmental factors that may play a role. Maternal weight gain during pregnancy and excessive postnatal feeding with enriched formulas, especially in children who are small for gestational age, have been implicated in higher weight-for-height growth trajectories. (10) Recent studies suggest that the metabolic syndrome is far more common among children and adolescents than previously reported and that its prevalence increases directly with the degree of obesity, with rates of 39% in moderately obese and 50% in severely obese children in one study. Each element of the syndrome worsens with increasing obesity—an association that is independent of age, gender, and pubertal status. (11)

Hypertension Hypertension affects one in four adults worldwide, and poorly controlled hypertension is the leading cause of death globally. Hypertension is more prevalent in non-Latino black persons and older persons than in the general population. Approximately 67% of patients older than 60 years and more than 75% of patients older than 80 years have hypertension. The following recommendations for the screening and management of pediatric hypertension

come from the latest (2004) report from the National High Blood Pressure Education Program Working Group on high BP in children and adolescents. (12) Hypertension is defined as average systolic BP (SBP) or diastolic BP that is ‡95th percentile for gender, age, and height on more than three occasions. • Prehypertension in children is defined as average SBP or diastolic BP levels that are ‡90th percentile but <95th percentile. • As with adults, adolescents with BP levels ‡120/80 mm Hg should be considered prehypertensive. • A patient with BP levels >95th percentile in a physician’s office or clinic, who is normotensive outside a clinical setting, has “white-coat hypertension.” Ambulatory BP monitoring is usually required to make this diagnosis. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure from 2003 defines prehypertension as a BP level that is ‡120/80 mm Hg and recommends the application of preventive health-related behaviors, or therapeutic lifestyle changes, for individuals having SBP levels that exceed 120 mm Hg. (13) It is recommended also that, as with adults, children and adolescents with BP levels ‡120/80 mm Hg but <95th percentile should be considered prehypertensive. The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure should be released in 2012. Children older than 3 years who are seen in medical care settings should have their BP measured at least once during every health care episode. Children younger than 3 years should have their BP measured in special circumstances (Table 1). High BP in childhood had been considered a risk factor for hypertension in early adulthood; however, primary (essential) hypertension is now identifiable in children and adolescents. Primary hypertension in childhood usually is characterized by mildly elevated BP and often is associated with a positive family history of hypertension or CVD. Children and adolescents with primary hypertension frequently are overweight. Data on healthy adolescents obtained in school health-screening programs demonstrate that the prevalence of hypertension increases progressively with increasing BMI, and hypertension is detectable in w30% of obese children (BMI ‡95th percentile). The strong association of high BP with obesity and the marked increase in the prevalence of childhood obesity indicate that both hypertension and prehypertension are becoming a significant health issue in the young. Pediatrics in Review Vol.33 No.2 February 2012 55

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Secondary hypertension is more common in children than in adults. The possibility that some underlying disorder might be the cause of the hypertension should be considered in every child or adolescent who has elevated BP; however, the extent of an evaluation for detection of a possible underlying cause should be individualized for each child. Very young children, children with moderately elevated BP, and children or adolescents with clinical signs that suggest the presence of systemic conditions associated with hypertension should be evaluated more extensively, as compared with those having mild hypertension. Indications for antihypertensive drug therapy in children include secondary hypertension and insufficient response to lifestyle modifications. Recent clinical trials have expanded the number of drugs that have pediatric dosing information. Pharmacologic therapy, when indicated, should be initiated with a single drug. Acceptable drug classes for use in children include angiotensinconverting enzyme inhibitors, angiotensin-receptor blockers, b-blockers, calcium channel blockers, and diuretics. The goal for antihypertensive treatment in children should be reduction of BP to <95th percentile unless concurrent conditions are present, in which case BP should be lowered to <90th percentile. In adults, hypertension typically is a lifelong condition. Most patients with hypertension will need to remain on medications for the rest of their lives. Given the known long-term adverse consequences of untreated or undertreated hypertension, most adults understand and accept this fact. Although the long-term consequences of untreated hypertension in children are unknown, one could presume that these consequences are likely to be similar to those in adults. In addition, because no data are available on the long-term effects of antihypertensive drugs on growth and development, a definite indication for

Table 1.

initiating pharmacologic therapy should be ascertained before a drug is prescribed. At present, many of these children are referred to pediatric cardiologists or nephrologists to begin medications. As a growing number of children with obesity are identiﬁed as having primary hypertension, however, general pediatricians will need to gain the knowledge and skills to be comfortable with prescribing antihypertensive medications.

Dyslipidemia “Dyslipidemia” refers to a pathologic imbalance in the levels of low-density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglycerides, and is well recognized as a risk factor for adult CVD. Studies have shown that children with elevated cholesterol levels continue to have elevated cholesterol into adulthood. More important, treating childhood dyslipidemia may help prevent or reduce the risk of adult CVD and reduce the atherosclerotic burden later in life. The National Cholesterol Education Program (NCEP) established guidelines in 1992 for screening and treating pediatric hyperlipidemia. (14) In 2011, the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents released its summary report, which includes a revised screening guideline for dyslipidemia based on reviewing and grading of the latest evidence. (15) The Expert Panel concluded that use of family history of premature CVD for targeted screening for dyslipidemia in children missed 30% to 60% of children with dyslipidemias. Thus, the Expert Panel now recommends universal screening of non-fasting non-HDL cholesterol in children 9 to 11 years old (prior to onset of puberty) and again in individuals 17 to 21 years. Targeted screening should occur in children

When to Measure Blood Pressure in Children <3 Years Old

History of prematurity, very low birth weight, or other neonatal complication requiring intensive care Congenital heart disease (repaired or nonrepaired) Recurrent urinary tract infections, hematuria, or proteinuria Known renal disease or urologic malformations Family history of congenital renal disease Solid organ transplant Malignancy or bone marrow transplant Treatment with drugs known to raise BP Other systemic illnesses associated with hypertension (eg, neurofibromatosis, tuberous sclerosis) Evidence of elevated intracranial pressure Reprinted with permission from The Fourth Report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(suppl 2):556.

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2 to 8 years old and adolescents 12 to 16 years old with two fasting lipid profiles (between 2 weeks and 3 months apart, results averaged) for the risk factors listed in Table 2. Once lipid values have been obtained, the Expert Panel used NCEP-established cut points for total cholesterol and LDL concentrations in children and adolescents, and the Bogalusa Heart Study for non-HDL cholesterol (Table 3). The Expert Panel further identified cut points for lipid levels in young adults that are distinct from those used in adults of all ages in the most recent NHLBI adult guidelines, Adult Treatment Panel III (“Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults”). Initial treatment includes lifestyle changes, such as diet and exercise. The Expert Panel identified and graded agespecific recommendations in the Cardiovascular Health Integrated Lifestyle Diet (CHILD-1) for children with identified dyslipidemia, overweight and obesity, riskfactor clustering, and high-risk medical conditions that might require more intensive dietary change. (13) For children with dyslipidemia with persistently elevated LDL cholesterol or triglyceride levels after a 6-month trial of CHILD-1, specific dietary restrictions on saturated fats and dietary cholesterol are made (CHILD-2). All children under 10 years of age for whom medication for dyslipidemia is being considered should be cared for in conjunction with a lipid specialist. For children 10 to 21 years old, those with an average LDL cholesterol level of ‡ 250 mg/dL should be referred directly to a lipid specialist. Otherwise, treatment with medication is based on an assessment of lipid levels in conjunction with associated risk factors or conditions (a more detailed discussion is available on pages S28–S30 of the Expert Panel summary report (15).

The recommended initial medication therapy for dyslipidemia in children and adolescents are the 3-hydroxy3-methyl-glutaryl coenzyme A reductase inhibitors (statins). The statins are generally well tolerated and result in 20 to 50% lowering of cholesterol, depending on the dose used. Adverse effects of statins are related to increased hepatic transaminase levels and also elevations of creatine kinase, which may be associated with rare but clinically important episodes of rhabdomyolysis. There is also a concern about the potential of statin medications to be teratogenic, so they are not recommended for women who are pregnant, seeking to become pregnant, or breastfeeding. Patients should be monitored with periodic measurement of liver transaminase and creatine kinase levels. Patients should also be instructed to report symptoms of muscle aches or cramping. The AAP recommendations are based on the best available evidence and may be altered as new thinking evolves. Readers are advised to stay current on AAP policies regarding this and other clinical topics. While the new lipid screening recommendations may be challenging for primary care pediatricians to espouse, it is incontrovertible that the rising rate of childhood obesity will have a deleterious effect on the future health of children in this country. Primary care pediatricians are in a critical position to intervene as early as possible to optimize children's cardiovascular health.

DM Type 2 DM accounts for 90% to 95% of DM worldwide and has a more insidious onset than type 1. Patients with type 2 DM usually are older than 40 years and typically overweight or obese. Because of increasing obesity rates in the young, type 2 DM is becoming more common in teenagers and older children.

Risk Factors for Targeted Cholesterol Screening in Children and Adolescents

Table 2.

Screen children between 2 and 8 years of age and adolescents between 12 and 16 years of age who: 1. have a moderate- or high-risk medical condition (Table 1) 2. have other cardiovascular risk factors (diabetes, hypertension, BMI ‡ 95th percentile, or smoke cigarettes) or 3. have a family history of early CVD or severe hypercholesterolemia. Of note, a significant family history includes: a. parent or grandparent who at <55 years for males or <65 years for females had suffered a myocardial infarction or sudden death, had undergone a coronary artery procedure, or who otherwise had evidence of coronary atherosclerosis, peripheral vascular disease, or cerebrovascular disease b. parent with total cholesterol ‡ 240mg/dL or known dyslipidemia Data from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Summary Report. Pediatrics. 2011;128;S213–S256.

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Cut Points for Lipid Levels in Children, Adolescents, and Young Adults

Table 3.

Category

Acceptable, mg/dL

Children and Adolescents Total <170 cholesterol LDL cholesterol <110 Non-HDL <120 cholesterol Triglycerides 0-9 y <75 10-19 y <90 Young Adults (20-24 y) Total <190 cholesterol LDL cholesterol <120 Non-HDL <150 cholesterol Triglycerides <115

BorderlineHigh, mg/dL

High, mg/dL

170-199

‡200

110-129 120-144

‡130 ‡145

75-99 90-129

‡100 ‡130

190-224

‡225

120-159 150-189

‡160 ‡190

115-149

‡150

Reprinted with permission from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Summary Report. Pediatrics. 2011;128;S13–S256.

The pathogenesis of type 2 DM involves the dual defects of insulin resistance and relative insulin deﬁciency. Patients at risk for type 2 DM initially develop insulin resistance alone, accompanied by augmented pancreatic insulin secretion. Because of the resulting hyperinsulinemia, plasma glucose levels are maintained in the normal range. In most patients, however, pancreatic b-cell function ultimately declines, with deterioration of endogenous insulin secretory capacity over time. The increased incidence of type 2 DM diagnosed in the pediatric population has been associated with the epidemic of obesity. The Centers for Disease Control and Prevention and the National Institutes of Health have funded a national childhood DM registry, the multicenter SEARCH for Diabetes in Youth Study, which estimates that 3600 youth will be newly diagnosed with type 2 DM annually in the United States (compared with 15,600 new cases of type 1 DM). (16) Well-designed studies from Europe indicate that type 2 DM remains a rarity in these populations, accounting for only 1% to 2% of all DM cases. In contrast, although the SEARCH study data identiﬁed that type 2 DM in youth is predominantly occurring in high-risk ethnic groups, type 2 DM accounts for 15% of all DM cases

among non-Latino white adolescents aged 10 years or older in the United States. (17) Risk factors and screening recommendations for type 2 DM are found in Table 4 and include obesity, sedentary lifestyle, intrauterine exposure to maternal DM, and low birth weight. In addition, the rates of DM are w60% higher in girls than boys. The mean age of diagnosis for type 2 DM is midpubertal, from 12 to 16 years. (17) Measuring C-peptide levels and anti-glutamic acid decarboxylase antibody levels are helpful in differentiating between types 1 and 2 DM. In general, patients with type 2 DM have an elevated fasting C-peptide level and do not have antibodies to anti-glutamic acid decarboxylase. It is also recommended that screening for the comorbidities and complications of DM (including urine microalbumin measurement and fasting lipid proﬁle) be performed at the time of diagnosis. Lifestyle changes always are indicated in patients with type 2 DM. Despite the lack of successful obesity prevention and treatment programs, aggressive lifestyle modiﬁcation is widely recommended for all children who are at risk for overweight or are overweight, have risk factors for type 2 DM, have impaired glucose tolerance, or have already been diagnosed as having type 2 DM. Weight loss or prevention of weight gain is the best way to prevent type 2 DM among children with risk factors for the disease. The AAP recommends supporting breastfeeding, promoting healthy eating habits and physical activity, and discouraging sedentary activities, such as watching television. (19) Patients presenting with mild hyperglycemia (126– 200 mg/dL) and glycosylated hemoglobin level <8.5% or an incidental diagnosis of type 2 DM can be treated initially with therapeutic lifestyle changes in combination with metformin, the only drug approved by the Food and Drug Administration for pediatric patients with type 2 DM. Metformin, a biguanide, decreases hepatic glucose production and increases insulin-mediated glucose uptake in peripheral tissues, primarily muscle tissue. A child who presents with severe hyperglycemia (>200 mg/dL), glycosylated hemoglobin level >8.5%, or ketosis should be treated initially with insulin to achieve metabolic control. (20) Metformin is associated with disturbances in the gastrointestinal tract and, on rare occasions, with lactic acidosis. A modest amount of weight loss is a desirable side effect. Metformin should not be given to a child with type 2 DM and ketosis because it may precipitate lactic acidosis. Metformin should be started, however, once the child recovers from ketosis after treatment by rehydration and with insulin. Insulin should be added whenever glucose control cannot be achieved after 3 to 6 months of metformin therapy. (20)

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Table 4.

Recommendations for Screening for Type 2 DM in Children

Children who meet the following criteria should be screened for DM beginning at age 10 years or at onset of puberty (if puberty occurs at a younger age). Screening should occur with either a fasting plasma glucose measurement or 2-hour oral glucose tolerance test, and should occur every 2 years. (18) • Obese or at risk for overweight (BMI >85th percentile for age and sex; or weight for height >85th percentile; or weight >120% of ideal [50% percentile] for height) PLUS having any TWO of the following risk factors: • Family history of type 2 DM in first- or second-degree relative • Race/ethnicity (Native American, African American, Latino, Asian or Pacific Islander) • Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome) • History of DM in the mother or gestational DM during the child’s gestation Adapted from American Diabetes Association. Standards of medical care in diabetes 2011. Diabetes Care. 2011;34(suppl 1):S15.

Type 2 DM has a signiﬁcant prevalence of comorbidities already present at the time of diagnosis. It is recommended that BP measurement, a fasting lipid proﬁle, microalbuminuria assessment, and dilated eye examination be performed at the time of diagnosis. Additional problems that may need to be addressed include polycystic ovary disease and the various comorbidities associated with pediatric obesity, such as sleep apnea, hepatic steatosis, orthopedic complications, and psychosocial concerns. (21) The American Diabetes Association consensus statement on this subject (18) provides guidance on the prevention, screening, and treatment of type 2 DM and its comorbidities in young people. For children or youth with type 2 DM who are found to have persistently elevated BP, angiotensin-converting enzyme inhibitors should be considered for the initial treatment of hypertension, following appropriate reproductive counseling owing to the potential teratogenic effects of these agents. The goal of treatment is a BP consistently <130/80 or <90th percentile for age, gender, and height, whichever is lower. For children or youth with type 2 DM who have elevated LDL cholesterol after normalization of glucose levels, treatment should be initiated to lower the LDL cholesterol level. Initial therapy should consist of optimization of glucose control and medical nutrition therapy by using a Step 2 American Heart Association diet aimed at a decrease in the amount of saturated fat in the diet. After the age of 10 years, the addition of a statin in patients who, after medical nutrition therapy and lifestyle changes, have LDL cholesterol >160 mg/dL (4.1 mmol/L), or LDL cholesterol >130 mg/dL (3.4 mmol/L) and one or more CVD risk factors, is reasonable. The goal of therapy is an LDL cholesterol value <100 mg/dL (2.6 mmol/L).

Summary • Through research in the prevention and treatment of adult diseases, it has become clear that many adult diseases have their origins in childhood. As illustrated in this review, these antecedents are largely a function of the nutrition, physical activity, and habits of developing children. • There is also increasing evidence that chronic and toxic levels of stress can play a significant role not only in the development of mental and behavioral conditions but in the developmental pathways that lead to a number of chronic physical health conditions. • Internists, family medicine physicians, and medicinepediatrics physicians generally are comfortable managing patients with a number of cardiovascular risk factors or conditions. Although pediatric clinical guidelines have recommended universal screening for hypertension since 1977 and targeted screening for dyslipidemia since 1992 and type 2 DM since 2000, this screening is not yet common practice in general pediatrics. • As the population of children and youth with risk factors for metabolic syndrome – hypertension, dyslipidemia, and type 2 DM – increases as a result of the obesity epidemic, pediatricians will have to screen routinely, and diagnose and treat these conditions in the primary care setting. • Pediatric residency programs and continuing medical education programs will have to provide knowledge and clinical training in the management of these conditions before primary care pediatricians are comfortable treating children and youth with multiple cardiovascular conditions.

ACKNOWLEDGMENTS We thank Monica Mau, MD, Eric Curcio, MD, and Erik Paschall, MD, for their contributions to this article. Pediatrics in Review Vol.33 No.2 February 2012 59

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References 1. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007;261(5):412–417 2. Eriksson JG, Osmond C, Kajantie E, Forsén TJ, Barker DJ. Patterns of growth among children who later develop type 2 diabetes or its risk factors. Diabetologia. 2006;49(12):2853–2858 3. National Research Council and Institute of Medicine. Committee on Evaluation of Children’s Health. Board on Children, Youth, and Families, Division of Behavioral and Social Sciences and Education. Children’s Health, the Nation’s Wealth: Assessing and Improving Child Health. Washington, DC: National Academies Press; 2004 4. Halfon N, Hochstein M. Life course health development: an integrated framework for developing health, policy, and research. Milbank Q. 2002;80(3):433–479, iii 5. Gluckman PD, Hanson MA, Bateson P, et al. Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet. 2009;373(9675):1654–1657 6. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev. 2010;35(1):2–16 7. Danese A, Mofﬁtt TE, Harrington HL, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inﬂammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. 2009;163(12):1135–1143 8. Zimmet P, Alberti KG, Kaufman F, et al; IDF Consensus Group. The metabolic syndrome in children and adolescents—an IDF consensus report. Pediatr Diabetes. 2007;8(5):299–306 9. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(suppl 4):S164–S192 10. Li C, Goran MI, Kaur H, Nollen N, Ahluwalia JS. Developmental trajectories of overweight during childhood: role of early life factors. Obesity (Silver Spring). 2007;15(3):760–771 11. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350 (23):2362–2374

12. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114 (suppl 2 4th report):555–576 13. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19): 2560–2572 14. National Cholesterol Education Program (NCEP): highlights of the report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89(3):495–501 15. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics. 2011;128: S213–S256 16. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011 17. Dabelea D, Bell RA, D’Agostino RB Jr, et al; Writing Group for the SEARCH for Diabetes in Youth Study Group. Incidence of diabetes in youth in the United States. JAMA. 2007;297(24): 2716–2724 18. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000;23(3):381–389 19. Krebs NF, Jacobson MS; American Academy of Pediatrics Committee on Nutrition. Prevention of pediatric overweight and obesity. Pediatrics. 2003;112(2):424–430 20. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics. 2005;116(2):473–480 21. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11–S61

Parent Resources From the AAP at HealthyChildren.org The reader is likely to find material to share with parents that is relevant to this article by visiting this link: http://www.healthychildren.org/English/health-issues/conditions/heart/pages/heart-disease.aspx.

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PIR Quiz This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Beginning this past January, learners can take Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printed in the journal.

New Minimum Performance Level Requirements Per the 2010 revision of the American Medical Association (AMA) Physicianâ&#x20AC;&#x2122;s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. Starting with 2012 Pediatrics in Review, AMA PRA Category 1 CreditTM be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. 1. Which of the following is a feature of metabolic syndrome in adolescents, as defined by the International Diabetes Federation? A. Height >70 inches B. High-density lipoprotein level >60 mg/dL C. Low-density lipoprotein level <100 mg/dL D. Postprandial glucose level >150 mg/dL E. Waist circumference >40 inches 2. You are evaluating a 12-year-old girl at a health supervision visit. Her BMI is 24 kg/m2, which is between the 90th and 95th percentiles for her age. How would you classify her weight status? A. Normal body weight B. Obese C. Overweight D. Severely obese E. Underweight 3. A 10-year-old boy comes in for a health maintenance visit. The 2011 guidelines recommend that he should be screened for dyslipidemia, even in the absence of risk factors, by obtaining which of the following measurements? A. B. C. D. E.

HDL cholesterol LDL/HDL ratio Non-fasting, non-HDL cholesterol Total cholesterol Triglycerides

4. You are working at a health fair for your community junior high and high schools. Which of the following children should be screened for type 2 diabetes mellitus at this time? A. A 13-year-old white girl with BMI 85% and a father with hypertension B. A 15-year-old white girl with BMI 95% and no additional risk factors C. A 15-year-old African American boy with BMI 75% and no additional risk factors D. A 16-year-old Latino boy with BMI 95% and a mother with type 2 diabetes mellitus E. A 17-year-old African American girl with BMI 75% and a grandmother with high cholesterol 5. A 2-year-old boy is being seen for a health maintenance visit. Which of the following factors would induce you to measure his blood pressure? A. B. C. D. E.

African American race Father has hypertension Mother has diabetes mellitus Repaired Tetralogy of Fallot Weight at 90th percentile Pediatrics in Review Vol.33 No.2 February 2012 61

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Childhood Antecedents to Adult Cardiovascular Disease Neal Halfon, Philip A. Verhoef and Alice A. Kuo Pediatrics in Review 2012;33;51 DOI: 10.1542/pir.33-2-51

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Pediatric Systemic Lupus Erythematosus : More Than a Positive Antinuclear Antibody Jennifer E. Weiss Pediatrics in Review 2012;33;62 DOI: 10.1542/pir.33-2-62

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Article

collagen vascular

Pediatric Systemic Lupus Erythematosus: More Than a Positive Antinuclear Antibody Jennifer E. Weiss, MD*

Author Disclosure Drs Weiss has

Educational Gap For the first time in nearly 50 years, a new medication has been approved by the Food and Drug Administration for treating lupus, and other new medicines are becoming available.

disclosed no financial relationships relevant

Objectives

to this article. This

1. 2. 3. 4. 5.

commentary does contain a discussion of an unapproved/ investigative use of

After completing this article, readers should be able to: Describe the common clinical manifestations of systemic lupus erythematosus (SLE). Understand the meaning of a positive antinuclear antibody. Understand the serologic markers associated with SLE. Discuss the treatment and adverse effects of medications used to treat SLE. Understand the special needs of a pediatric patient who has SLE.

a commercial product/

Introduction

device.

Abbreviations ACLA: ANA: APLS: ARF: DIL: dsDNA: FDA: LA: LAC: MMF: NLE: NSAID: pSLE: SLE:

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease characterized by periods of increased disease activity caused by inflammation of blood vessels and connective tissue. The condition is much more than a positive antinuclear antibody (ANA); it is a disease that causes a great deal of morbidity, and patients can be ill at presentation and throughout their disease course. Pediatric patients with SLE have a more severe clinical course in comparison with their adult counterparts. Patients typically present with rash, fever, and arthritis, although the presentation may be unpredictable. At the time of diagnosis, most patients will fulfill 4 of the 11 American College of Rheumatology criteria for the classification of SLE (Table 1), revised in 1982. (1) These criteria include both clinical and laboratory features of the disease. The criteria were revised again in 1997 with changes to the immunologic disorder criterion that involve deleting a positive lupus erythematosus preparation and adding a positive finding of antiphospholipid antibodies based on (1) abnormal immunoglobulin G or immunoglobulin M anticardiolipin antibodies, (2) a positive test for lupus anticoagulant (LA), or (3) a false-positive serologic test for syphilis as described.

anticardiolipin antibody antinuclear antibody antiphospholipid antibody syndrome acute rheumatic fever drug-induced lupus double stranded DNA Food and Drug Administration systemic lupus erythematosus anticoagulant lupus anticoagulant mycophenolate mofetil neonatal lupus erythematosus nonsteroidal antiinﬂammatory drug pediatric systemic lupus erythematosus systemic lupus erythematosus

Epidemiology Twenty percent of SLE cases are diagnosed during the ﬁrst 2 decades of life. Pediatric SLE (pSLE) usually presents in post-pubescent females, with an average age of onset of w12 years. Before puberty, the male:female ratio is 1:3, but after puberty it increases to 1:9. Ethnicity plays an important role in the incidence of SLE. The incidence of SLE before age 19 years is between 6.0 and 18.9 cases per 100,000 in white girls but is higher in African American (20–30/100,000) and Puerto Rican girls (16.0– 36.7/100,000). (2) In addition, the incidence of SLE is higher in Hispanic, Native American, Paciﬁc Islander, and Asian individuals than in white individuals. With more

*University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; Pediatric Rheumatology, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ.

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Table 1.

1982 Revised Criteria for Classification of SLE*

1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Renal disorder 8. Neurologic disorder

9. Hematologic disorder

10. Immunologic disorder

11. Antinuclear antibody

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation Oral or nasopharyngeal ulceration, usually painless, observed by a physician Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion Pleuritis: convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion OR Pericarditis: documented by electrocardiogram or rub or evidence of pericardial effusion Persistent proteinuria >0.5 g/d or >3D if quantitation not performed OR Cellular casts: may be red cell, hemoglobin, granular, tubular, or mixed Seizures: in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, or electrolyte imbalance OR Psychosis, in the absence of offending drugs or known metabolic derangements; eg, uremia, ketoacidosis, electrolyte imbalance Hemolytic anemia with reticulocytosis OR Leukopenia: <4000/mm3 total on two or more occasions OR Lymphopenia: <1500/mm3 on two or more occasions OR Thrombocytopenia: <100,000/mm3 in the absence of offending drugs Positive LE cell preparation OR Anti-DNA: antibody to native DNA in abnormal titer OR anti-Smith antibody: presence of antibody to Sm nuclear antigen OR False-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome

*The proposed classiﬁcation is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. (Reprinted with permission from Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classiﬁcation of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277.)

aggressive treatment, the 5-year survival rate for pSLE approaches 100% and the 10-year survival rate is 86%.

Recent studies implicate type I interferon, especially dysregulation of interferon-a, as a prime contributor to loss of tolerance, resulting in autoimmunity.

Pathophysiology Lupus is thought to result from a combination of hormonal and environmental factors in a genetically predisposed individual. Ten percent of patients with SLE have a first-degree relative who has SLE, and affected patients are more likely to have a family member who has an autoimmune disease. HLA class II alleles DR2 and DR3 contribute to disease susceptibility in some patients, as do inherited complement deficiencies, most commonly homozygous C2 or C4 deficiency. Environmental triggers can be as varied as infection (parvovirus, Epstein-Barr virus), medication (antihypertensives, anticonvulsants), hormonal changes (especially sex hormones), and UV light. Disturbances in B and T cells and abnormalities in apoptosis contribute to the pathogenesis of the disease.

Clinical Characteristics Each patient afflicted with SLE presents a different clinical scenario. Common signs and symptoms at disease onset include fatigue, fever, weight loss, lymphadenopathy, and hepatosplenomegaly. Other, more specific, findings aid in diagnosis because most patients express classic SLE findings of malar rash and arthritis at presentation. Because SLE is a periodic illness, depending on the constellation and severity of signs and symptoms, often there is a delay in diagnosis with the time from symptom onset to diagnosis ranging from 1 month to 3.3 years (median, 4 months). (3) Flares of the illness can involve almost any organ system and common findings are described later in this Pediatrics in Review Vol.33 No.2 February 2012 63

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article (Table 2). It is important to differentiate SLE from acute rheumatic fever (ARF). Patients with ARF often present with fever and arthritis; however, the rash of ARF, erythema marginatum, can be differentiated from an SLE rash based on its appearance and location. Patients with ARF must have a history of group A Streptococcus infection and fulﬁll the Jones criteria.

Mucocutaneous Involvement Mucocutaneous features of disease are noted in up to 90% of patients with pSLE. Including photosensitivity, there are three rashes described in the SLE classification criteria. The malar or “butterfly” rash is the most common cutaneous manifestation and is the hallmark of the disease. It develops on the malar eminences and crosses the nasal bridge while sparing the nasolabial folds (Fig 1). The forehead and chin also may be affected. The rash can appear as a blush or a maculopapular eruption with an associated scale and usually is not pruritic. A similar rash may be seen in dermatomyositis; however, Gottron papules on the metacarpophalangeal and interphalangeal joints, elbows, and knees are not seen in SLE, and this feature helps distinguish the two. Discoid lupus, named after its coin shape, is an erythematous rash that primarily affects the face, ears, and scalp, although the upper extremities and upper chest and back may be affected (Fig 2). The rash may scale or crust. The central area may be hypopigmented, whereas the active border may appear hyperpigmented. The lesions may heal with a scar or atrophy, and discoid patches on the scalp may result in a scarring alopecia if the hair follicle is damaged. Discoid lupus may manifest as a feature of systemic disease or it may be an isolated finding. Fewer than 5% of patients who have isolated discoid SLE will progress to SLE. It is essential that all patients with pSLE practice sun protection year round with a sun protection factor >30 directed against both UV A and B light to try to prevent development of rash and systemic disease flares. Even if they do not have active rash, it is essential that patients with SLE protect themselves from UV light. Patients should be warned about the risk of rash and disease flares from use of tanning beds. For mild-moderate rash, topical corticosteroids or immunomodulators, such as tacrolimus, also may be used, especially in treating discoid SLE. Hydroxychloroquine, one of four drugs approved for SLE by the Food and Drug Administration (FDA), is one of the mainstays of treatment for any patient with SLE. Not only does the drug help with control of the rash, but it helps to prevent disease flares. In addition, this medication is well tolerated, although some patients suffer abdominal discomfort.

The major complication of hydroxychloroquine treatment is retinal toxicity; therefore, patients need to be screened by an ophthalmologist at baseline and then every 6 to 12 months. The risk of retinal changes is rare, especially if patients are on a dosage lower than 6.5 mg/kg per day. If retinal changes are seen early they are reversible, but the drug must be discontinued. Between ophthalmology visits patients can monitor themselves with an Amsler grid (a grid of vertical and horizontal lines used to determine a person’s central visual field). For more severe rashes, systemic corticosteroids (also FDA approved for treating SLE) may be needed, usually with the addition of a steroid-sparing agent, such as methotrexate, azathioprine, or mycofenolate mofetil. For the first time in nearly 50 years, a new medication has been FDA approved for treating SLE. Belimumab, a Blymphocyte stimulator-specific inhibitor, was approved for the treatment of adult patients with active, autoantibodypositive SLE. Adult patients with SLE with active mucocutaneous symptoms have had the best response in clinical trials. No trials have been performed in patients with pSLE, but trials will likely be under way in the future. Vasculitic rashes can be part of active SLE. These rashes take on many forms, including palmar erythema and tender skin nodules (Fig 3), purpura, or ulcerations on fingers or toes, pinnae, or nares. Palatal ulceration (Fig 4), as described in the classification criteria, usually is painless and can be detected easily on examination of the oral mucosa. Because the vasculitis is a more systemic process, systemic corticosteroids may be required to treat these lesions. Raynaud phenomenon can be caused by an underlying connective tissue disease and differs from primary Raynaud disease, in which there is no underlying vasculopathy. Classically, there is a triphasic color change (blue, white, and, on rewarming, red) of the hands or feet, sometimes the ears or nose. Because of vasospasm, the affected area becomes pale and painful, then cyanotic, and on rewarming, erythematous. There may be an associated tingling or burning sensation, especially during the rewarming, erythematous phase. Triggers include exposure to cold, cigarettes, caffeine, and extreme emotion. Patients should avoid triggers and dress warmly, paying attention to keeping the body core, as well as the extremities, warm. Nail fold capillary changes reflect the vasculopathy that may occur in SLE. Periungal erythema is caused by dilatation of these capillaries. Livedo reticularis occurs in <10% of patients with pSLE. This eruption presents as a reddish-purplish lacy rash, usually on the extremities or torso and often is associated with the presence of antiphospholipid antibodies.

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Table 2.

Clinical Characteristics of Patients Who Have SLE

Organ System Involvement Arthritis Mucocutaneous involvement Malar rash Other rash Oral ulcers Alopecia Photosensitivity Nasal ulcers Digital ulcers Nephritisa Mesangial (class II) Focal proliferative (class III) Diffuse proliferative (class IV) Membranous (class V) Nephrotic syndrome Central nervous system Lupus headache Psychosis Cerebrovascular disease Cognitive dysfunction Cardiac Pericarditis Myocarditis Endocarditis Pulmonary Pleuritis Pneumonitis Myositis Diffuse lymphadenopathy Other Raynaud phenomenon Thrombotic thrombocytopenic purpura Constitutional symptoms Fatigue Fever Weight loss Anorexia Headacheb Autoantibody (%) Anti-dsDNA Anti-Smith antibody Anti-ribonucleoprotein antibody Anti-Ro Anti-La Antiphospholipid (any) ACLAc LAC Rheumatoid factor Hematologic (any) Thrombocytopenia Lymphopenia Coombs positive hemolytic anemia

At Diagnosis (%) (n [ 256)

Within 1 Year After Diagnosis (%) (n [ 256)

Ever (%) (n [ 256)

157 (61)

159 (62)

171 (67)

155 96 55 56 44 21 9 95 14 27 45 15 20 40 23 14 13 9

161 106 59 62 45 25 10 117 21 36 50 20 22 53 31 21 14 13

169 111 76 73 52 26 13 141 25 41 65 29 25 68 42 25 20 15

(61) (38) (21) (22) (17) (8) (4) (37) (15) (28) (47) (16) (22) (16) (58) (35) (33) (23)

(63) (41) (23) (24) (18) (10) (4) (46) (18) (31) (43) (17) (19) (21) (58) (40) (26) (25)

(66) (43) (30) (29) (20) (10) (5) (55) (18) (29) (46) (21) (18) (27) (62) (37) (29) (22)

30 (12) 3 (1) 0

33 (13) 5 (2) 0

39 (15) 6 (2) 1 (0.4)

30 1 8 48

32 1 8 50

37 2 9 51

(12) (0.4) (3) (19)

35 (14) 2 (0.8) 129 101 74 51 34

(50) (39) (29) (20) (13)

184 88 68 69 34 82 67 22 28 141 75 73 58

(72) (34) (27) (27) (13) (32) (26) (9) (11) (55) (29) (29) (23)

(13) (0.8) (3) (20)

45 (18) 2 (0.8) 136 104 79 72 39

(53) (41) (31) (28) (15)

(14) (0.8) (4) (20)

49 (19) 2 (0.8) 142 106 82 72 46

(55) (41) (32) (28) (18)

214 124 95 84 37 115 102 32 35 161 80 93 63

(84) (48) (37) (33) (15) (45) (40) (13) (14) (63) (31) (36) (25)

a Type of nephritis was determined by using the World Health Organization classiďŹ cation system. (5) Two patients did not undergo renal biopsy and are not included in this table. b Not requiring narcotic analgesia. c Total number of patients tested was 254 of the 256. (Reprinted with permission from Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and longterm outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008;152(4):550â&#x20AC;&#x201C;556.)

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Figure 3. Vasculitic rash with palmar erythema and tender skin nodules. (Courtesy of Y. Kimura.) Figure 1. Malar erythema. (Courtesy of H. Shin.)

Figure 2. Discoid lupus with follicular plugging and scarring alopecia. (Courtesy of H. Shin.)

Alopecia may be one of the presenting manifestations of the disease. It occurs classically in the frontal area but can be diffuse. As the disease activity lessens, patients usually grow new hair.

Musculoskeletal Involvement Arthralgia and arthritis are very common in pSLE. Unlike the arthritis characteristic of juvenile idiopathic arthritis, SLE arthritis usually is nonerosive. Often there is symmetric involvement of both the large and small joints, primarily the knees, wrists, ankles, and fingers. Patients who have SLE can develop an unusual type of arthritis called Jacoud arthropathy (ulnar deviation of the second to fifth fingers and subluxation of the metacarpophalangeal

Figure 4. Malar rash and palatal ulcerations. (Courtesy of

RheumAtlas.com.)

joints). Myalgia and myositis are less common, but may occur in patients with SLE. Muscle involvement also is common in the so-called “overlap syndrome,” in which there are findings common to SLE as well as other rheumatic illnesses. Nonsteroidal antiinflammatory drugs (NSAIDs) are the usual first-line medications, along with hydroxychloroquine. When there is severe arthritis, particularly when it occurs in parallel with other organ system involvement, corticosteroids may be needed. Methotrexate also can be used to treat arthritis. It is a disease-modifying agent commonly prescribed for juvenile idiopathic arthritis and works well as a steroid-sparing agent in patients with pSLE who have arthritis. With

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severe cases of arthritis, tumor necrosis factor-a inhibitors have been used. Adult patients with SLE with musculoskeletal disease have demonstrated a good response in the belimumab trials.

Renal Involvement Renal disease is the greatest contributor to morbidity and mortality in the pSLE population. Up to 65% of patients with pSLE are affected, usually within the first year of diagnosis. Renal disease may manifest as proteinuria, microscopic hematuria, hypertension, or elevated blood urea nitrogen and creatinine levels. Eighteen percent of patients may develop nephrotic syndrome. (4) Immune complexes involving DNA and anti-double stranded DNA (dsDNA) deposit in the mesangium and subendothelial space, leading to activation of complement and an influx of inflammatory cells. These changes manifest histologically as mesangial, focal, or diffuse proliferative glomerulonephritis, and clinically with an active urine sediment (red blood cells, white blood cells, and cellular and granular casts), low complement levels (C3, C4), elevated anti-dsDNA levels, and proteinuria. A spot first-morning urine protein-to-creatinine ratio often is used as an indicator of proteinuria and active renal disease. A renal biopsy with histologic, immunofluorescent, and electron micrographic analysis is necessary to classify the histologic type of renal disease. Because the class and severity of the renal disease guides treatment, biopsy results play a major role in determining therapy. The International Society of Nephrology and the Renal Pathology Society (5) have revised the original World Health Organization classification of renal biopsy findings in SLE into six different classes (Table 3). Patients may change from one class to another either before or during treatment. Minimal mesangial lupus nephritis (class I) is the mildest form of nephritis and patients may have a normal urinalysis and creatinine level. This class does not require specific treatment and generally has a good prognosis. Approximately 25% of patients with pSLE will have mesangial proliferative lupus nephritis (class II). These patients may have microscopic hematuria or proteinuria. Treatment consists primarily of a low to moderate dose of corticosteroids over several months. This class of renal disease is considered very mild, but there is always risk of progression. Focal lupus nephritis (class III) affects 41% of patients with pSLE and often presents with hematuria and proteinuria. Nephrotic syndrome, hypertension, and abnormal blood urea nitrogen and creatinine levels also may be

found. Diffuse lupus nephritis (class IV) is the most common and most severe type of lupus nephritis, affecting w65% of patients. Patients present with hematuria, proteinuria, hypertension, low C3 and C4 levels, and elevated anti-dsDNA levels. This class is similar to class III with the major difference being that more than 50% of glomeruli have evidence of active proliferation. Most pediatric rheumatologists and nephrologists would treat pSLE patients with class III and IV disease aggressively. This treatment includes high-dose oral corticosteroids (2 mg/kg) or intravenous pulse methylprednisolone (30 mg/kg, max of 1 g) plus potent immunosuppressive agents. In the adult population with SLE, induction of remission therapy with either cyclophosphamide or mycophenolate mofetil (MMF) routinely is used (6) and the same medications are being used to treat pSLE. Most pediatric rheumatologists probably would start induction therapy with 3 to 6 months of cyclophosphamide and, if the patient has a good response, transition to MMF. Although cyclophosphamide is effective, risks associated with this medication include bone marrow suppression, alopecia, infection, malignancy, and infertility. The risk of gonadal failure is dose dependent. Some physicians treat post-pubertal girls with luprolide acetate to suppress oogenesis, thus preventing damage caused by cyclophosphamide to dividing cells and lessening the risk of infertility. Because cyclophosphamide also is toxic to spermatogonia and spermatocytes, the best solution for post-pubertal boys to maintain their reproductive capacity would appear to be sperm banking. MMF inhibits guanosine nucleotides and B- and T-cell proliferation and has antiinﬂammatory properties. This medication is being used more widely in treating pSLE, especially because the issue regarding fertility is not a concern. Unlike cyclophosphamide, which is given intravenously at monthly intervals, MMF is an oral medication, taken twice daily. Its major adverse effects are abdominal pain and diarrhea; as a result, compliance is of greater concern with MMF. In addition, studies comparing it with traditional treatments, such as cyclophosphamide or azathioprine, have not been done in the pediatric population. Treatment of major organ system involvement in SLE has taken a page out of the oncologists’ book with the aim of achieving remission through intensive therapy at the time of diagnosis, followed by less-intensive medications for the maintenance phase (a step-down rather than a step-up approach). Newer medicines are becoming available, such as rituximab, a chimeric monoclonal anti-B-cell antibody directed at the CD20 antigen that can lead to the depletion of Pediatrics in Review Vol.33 No.2 February 2012 67

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International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis

Table 3.

Class I Class II

Class III

Class Class Class Class

III (A) III (A/C) III (C) IV

Class IV-S (A) Class IV-G (A) Class IV-S (A/C)

Class IV-S (C) Class IV-G (C) Class V

Class VI

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial immune deposits May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy Focal lupus nephritisa Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations Active lesions: focal proliferative lupus nephritis Active and chronic lesions: focal proliferative and sclerosing lupus nephritis Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis Diffuse lupus nephritisb Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ‡50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) lupus nephritis when ‡50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ‡50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation Active lesions: diffuse segmental proliferative lupus nephritis Active lesions: diffuse global proliferative lupus nephritis Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed Class V lupus nephritis show advanced sclerosis Advanced sclerosis lupus nephritis ‡90% of glomeruli globally sclerosed without residual activity

Indicate the proportion of glomeruli with active and with sclerotic lesions. Indicate the proportion of glomeruli with fibrinoid necrosis and/or cellular crescents. Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions. (Reprinted with permission from Weening JJ, D’Agati VD, Schwartz MM, et al on behalf of the International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–250.) b

B cells. Its use in nephritis is controversial. Many case reports have demonstrated efﬁcacy, but in a controlled trial of lupus nephritis, the drug did not offer any additional beneﬁt when given as an adjunct to standard therapy. Rituximab can be used alone or with any of the agents mentioned previously. Despite optimal therapy,

proteinuria may not resolve completely and an angiotensin-converting enzyme inhibitor can be used to protect the kidney. Finally, hypertension, if present, must be treated aggressively and maintenance of a normal blood pressure should be the goal. The use of corticosteroids may

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exacerbate the hypertension. Overall, if patients are treated early and aggressively, they should go into remission and experience normalization of laboratory parameters. Patients with membranous lupus nephritis (class V) (29%) commonly present with nephrotic syndrome, which may occur alone or in combination with other types of nephritis. Patients generally are treated with oral corticosteroids for a few months and may require a steroidsparing agent, such as MMF. Class V nephritis tends to have a better prognosis than class III and IV, but can be refractory to treatment and the proteinuria can be signiﬁcant, at times >5 g per day. Patients can suffer from severe secondary effects up to and including anasarca. Advanced sclerosing lupus nephritis (class VI) is characterized by global sclerosis of more than 90% of glomeruli, the result of healing of prior inﬂammatory injury. Unfortunately, these changes represent end-stage kidney disease and immunosuppression is not helpful for these patients.

Neuropsychiatric Involvement Neuropsychiatric disease occurs in up to two-thirds of patients with pSLE and often presents within the first year of diagnosis. (3) It is the second leading cause of morbidity and mortality. The highest percentage of neuropsychiatric involvement is manifested as headache. Most other neuropsychiatric manifestations affect fewer than 60% of patients and may present as decreased concentration and cognitive dysfunction, psychosis, seizures, transverse myelitis, central nervous system vasculitis, or stroke. Indeed, SLE can cause almost any neurologic disorder. Headaches are very common in the adolescent population and it may be difficult to determine if the headache should be attributed to SLE. One rule of thumb has been that SLE headaches are not responsive to non-narcotic analgesia. Treatment of neuropsychiatric disease needs to be directed toward the specific problem, but most patients will require high-dose corticosteroids and immunosuppression with cyclophosphamide, MMF, or azathioprine. Therapy is given in much the same way as for nephritis, by using an induction and maintenance approach.

Hematologic Involvement More than 60% of patients with pSLE will have cytopenia. Leukopenia, usually secondary to lymphopenia, is found in two-thirds of patients and may provide a clue to the diagnosis. Anemia is seen frequently and although it can be the classic Coombs-positive hemolytic anemia, patients also may have a normocytic normochromic anemia of chronic disease. This latter anemia, however, would not be considered as fulﬁlling a criterion for diagnosis of SLE. Thrombocytopenia may be found in up

to 30% of patients. Patients presenting with idiopathic thrombocytopenia and Evans syndrome (idiopathic thrombocytopenia and hemolytic anemia), especially adolescent girls, should be evaluated for SLE. Cytopenias usually respond to moderate- to high-dose corticosteroids. Intravenous g-globulin (2 g/kg) often is effective in treating thrombocytopenia, with refractory cases often responding to rituximab. Very rarely is splenectomy required to control the thrombocytopenia. A more recently described hematologic entity is the antiphospholipid antibody syndrome (APLS). APLS may be primary or secondary to an underlying connective tissue disease, such as SLE. Manifestations can include thrombocytopenia, arterial or venous thrombosis, stroke, transient ischemic attack, chorea, recurrent fetal loss, or avascular necrosis. Laboratory abnormalities include a positive LA, elevated anticardiolipin and antiphospholipid antibodies, or a prolonged partial thromboplastin time. The term LA is a misnomer because patients actually are in hypercoagulable state. Patients with a positive LA are especially at risk for thrombosis, in particular deep vein thrombosis, thromboemboli, and stroke. Patients with lupus who have anticardiolipin antibodies have twice the risk of venous thrombosis, and patients with a positive LA have six times the risk of venous thrombosis compared with patients with SLE without these antibodies. (7) Patients presenting with any of these complications need to be screened for other disorders of coagulation, such as antithrombin III deficiency or protein S or C deficiency. It is still not entirely clear how best to treat patients who have a positive LA but do not have a history of previous thrombosis or signs and symptoms of APLS because low-level titers can be an incidental finding. Guidelines have been developed to help guide decision-making. Some physicians would treat patients with APLS with low-dose aspirin, although there is no documented evidence of efficacy for preventing a vascular event.

Pulmonary Involvement Pulmonary involvement may manifest as pleuritis, pleural effusion, pneumonitis, pulmonary hemorrhage, and pulmonary hypertension. Pleuritis is the most common manifestation and patients may complain of dyspnea and sharp, stabbing chest pain during inspiration. Other causes of dyspnea include restrictive lung disease. Pulmonary function tests will be abnormal, demonstrating a restrictive defect and possibly a decreased diffusion capacity. Radiographs may demonstrate interstitial inﬁltrates, pleural thickening, and elevated hemi-diaphragms. Shrinking lung syndrome results from an impairment of the diaphragm secondary to pleural thickening and ﬁbrosis. A small Pediatrics in Review Vol.33 No.2 February 2012 69

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effusion can be managed with NSAIDs, although most likely these patients will need corticosteroid therapy. Pulmonary hemorrhage, although rare, is life-threatening. This complication must be considered in any patient with pSLE who experiences acute shortness of breath and a sudden drop in hemoglobin concentration. Pulse methylprednisolone in combination with cyclophosphamide therapy usually is required to treat pulmonary hemorrhage.

Cardiac Involvement Patients with lupus are at risk for pericarditis, pericardial effusion, myocarditis, Libman-Sacks endocarditis, bacterial endocarditis, and premature atherosclerosis. The risk of myocardial infarction is low in pSLE, although an infarct must always be considered in the differential diagnosis of chest pain. Pericarditis with pericardial effusion is the most common cardiac complication in pSLE and often is a cause of recurrent chest pain. Pericarditis presents as anterior chest pain and dyspnea that is exacerbated by lying ﬂat. Lupus pericarditis can be treated with NSAIDs alone for mild cases and with the addition of corticosteroids for large effusions or severe pain. Patients who have both adult and pSLE are at risk for premature atherosclerosis. The Atherosclerosis Prevention in Pediatric Lupus Erythematosus trial, a prospective multicenter study of 221 racially and ethnically diverse patients with pSLE, identiﬁed both traditional and nontraditional risk factors for carotid intima-media thickness as a marker for subclinical atherosclerosis. Increased BMI, male gender, increased creatinine clearance, elevated lipoprotein(a) levels, increasing age, weight-adjusted prednisone dose, and azathioprine use all were associated with increased carotid intima-media thickness. (8) Hydroxychloroquine, which most patients are given because of its mild immunosuppressive effect, also has lipid-lowering properties, another reason for using it for treating SLE. All patients should be counseled on proper nutrition and exercise. Limiting the amount and duration of corticosteroid use is extremely important to help minimize atherosclerosis and weight gain, but almost all patients with pSLE will need corticosteroids at times to achieve disease control. Finally, lupus valvulitis (Libman-Sacks endocarditis) may predispose patients undergoing dental procedures to bacterial endocarditis. Although there is no consensus as to the best medical practice, some physicians, out of concern for an undetected Libman-Sacks endocarditis, will prescribe antibiotic prophylaxis to all patients with SLE before dental procedures.

Gastrointestinal Involvement Gastrointestinal involvement occurs in approximately one-third of patients and may manifest as serositis, vasculitis, pancreatitis, or enteritis. Abdominal pain is a primary complaint. Vasculitis puts patients at risk for bowel perforation. Pancreatitis may be caused by several factors, including active SLE, infection, or corticosteroid use. Most patients have functional asplenia and are at risk for sepsis from Streptococcus pneumoniae and other encapsulated bacteria. These patients should be immunized against pneumococcus, meningococcus, and Haemophilus inﬂuenzae type B.

Endocrine Involvement Hypothyroidism is very common in SLE. Hyperthyroidism, on the other hand, has been described rarely. Diabetes mellitus may develop as a result of corticosteroid use and obesity. Delayed puberty is common and studies are under way looking at pubertal development and the role of puberty in affecting pSLE. Irregular menses are common during periods of active disease. The use of estrogencontaining oral contraceptive agents in pSLE is controversial, and other methods of birth control are recommended.

Laboratory Evaluation Laboratory testing serves two important roles: to aid in diagnosis and to monitor disease activity. A complete blood count is needed to evaluate potential cytopenias. A comprehensive metabolic panel may reveal transaminitis, hypoalbuminemia, or an elevated creatinine level. Because most patients present with constitutional symptoms and inflammation, an elevated erythrocyte sedimentation rate is very common. Despite active inflammation, C-reactive protein levels can remain normal in pSLE; however, often these levels are elevated during active infection. A urinalysis should be performed to screen for proteinuria, hematuria, and other components of active urinary sediment. In SLE, there is production of myriad autoantibodies that recognize nuclear antigens, as well as many other cellular and tissue components. The ANA is found in 99% of patients with SLE, but also may be positive in other rheumatic diseases, such as mixed connective tissue disease and dermatomyositis. The ANA also may be positive in up to one-third of the healthy population and in family members of patients with SLE. It is helpful that a negative ANA makes the diagnosis of SLE extremely unlikely. ANA is not useful to monitor disease activity. A positive ANA therefore should be interpreted along with the clinical symptoms and having a definite diagnosis in

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mind. There is no level of ANA that is diagnostic for SLE, but higher levels, such as a titer of 1:1280 would be suspicious for SLE. The anti-dsDNA on the other hand is very speciﬁc for SLE and may be found in >75% of patients with pSLE. The anti-dsDNA level usually is checked at the time of diagnosis and throughout the disease course to monitor disease activity. A high value in conjunction with other disease activity measures is suggestive of active SLE. The anti-Smith antibody and anti-ribonucleoprotein antibody often are ordered together as an anti-extractable nuclear antigen panel. The anti-Smith antibody is highly speciﬁc for SLE and may be found in up to 50% of patients. This antibody may remain elevated regardless of disease activity and therefore is not useful in monitoring disease activity. The anti-ribonucleoprotein antibody may be found in patients who have classic SLE, but often indicates the patient’s diagnosis is a mixed connective tissue disease (SLE with features of systemic sclerosis or dermatomyositis). Other antibodies can also be seen in SLE, such as SS-A (anti-Ro) and SS-B (anti-La). Complement levels, specifically C3 and C4, are monitored in SLE, and low or undetectable levels are expected in SLE during periods of active disease. The anti-dsDNA and complement levels are important disease markers and help guide medication dosing.

Except for the heart block, all other manifestations will resolve without intervention, usually within 6 months— the time it takes for maternal antibodies to disappear. Approximately 30% to 50% of infants who develop congenital heart block will require pacemaker implantation, usually within the ﬁrst 24 months. These children need close follow-up; however, it is unlikely that they will go on to develop SLE.

Drug-Induced Lupus The classic medications that induce drug-induced lupus (DIL) include minocycline, procainimide, hydralazine, penicillamine, isoniazid, quinidine, phenytoin, and carbamazapine. Anti–tumor necrosis factor agents, such as inﬂiximab, adalimumab, and etanercept have also been implicated in DIL. The prevalence of DIL is equal in males and females, although minocycline-induced lupus is usually seen in adolescent girls using the medication

Neonatal Lupus Erythematosus Neonatal lupus erythematosus (NLE) occurs in 1% of infants who experience transplacental passage of maternal SSA or SSB antibodies. The most common manifestations are rash, cytopenias, and hepatitis with hepatomegaly. Congenital heart block from antibody-mediated damage to the conducting system is the most feared complication, and may be seen in up to 30% of infants born with NLE. As a consequence, all pregnancies in mothers with SLE or known positivity for SSA and SSB antibodies are considered high risk and require close monitoring. Fetal bradycardia is the first sign of NLE and must be evaluated at 16 weeks’ gestation and at continuing intervals throughout pregnancy. Mothers are started on dexamethasone as soon as a fetus is identified as having heart block to decrease maternal antibodies and inflammation of the conducting system and to delay the onset of fibrosis. The rash of NLE is similar to that seen in subacute SLE and is erythematous with a raised border, particularly prominent on sun-exposed areas and around the eyes (Fig 5). The skin may have a fine scale. UV light will worsen the rash and should be avoided as much as possible.

Figure 5. Neonatal lupus rash. (Courtesy of Taunton Southwood.) Pediatrics in Review Vol.33 No.2 February 2012 71

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for treatment of acne. Chronic use of the medication is required to develop DIL. Patients often present with constitutional symptoms, photosensitive rash, arthralgia, myalgia, and serositis. Subacute cutaneous lupus also may be present. Positive antihistone antibodies are present in 95% of patients with DIL and help to distinguish these patients from patients with systemic disease, although patients with classic SLE also may test positive for antihistone antibodies. Antineutrophilic cytoplasmic antibodies may be positive. Treatment of DIL requires discontinuing the offending agent. A trial of NSAIDs, hydroxychloroquine, and possibly corticosteroids may be needed. Symptoms usually abate within weeks to months of stopping the medication; however, in some patients DIL will evolve into true SLE.

Complications of Corticosteroids As stated, corticosteroids are a mainstay of treatment for SLE. Unfortunately, a number of adverse effects can affect the patient not only medically but from a psychosocial standpoint as well. Once corticosteroids are started, patients can gain weight easily, become hirsute, and develop acne, striae, and a cushingoid facies. These effects tempt all patients, but particularly the adolescent girl, to abandon adherence to their medical regimen. Infection, thinning of the skin, short stature, personality changes, sleep disturbance, irregular menses, and mood swings may also occur. Hypertension, glaucoma, and cataracts can develop and should be screened for regularly. Patients may develop avascular necrosis of any bone but this complication is particularly common in the femoral head. Any patient with SLE on corticosteroids suffering from hip pain, with or without limited hip motion, should have imaging studies done to rule out avascular necrosis.

Role of the Pediatrician Rheumatologists are involved in the care of patients who have SLE; however, the pediatrician’s involvement does not need to be peripheral. At each office visit, the patient should be screened for hypertension. It is important that patients are up to date on their vaccinations. Those on immunosuppressive medications cannot receive live virus vaccines, but should be given the 23-valent pneumococcal vaccine and the annual influenza vaccine. If patients have a fever they should be seen in the pediatric office for a thorough evaluation and antibiotics should be used judiciously. Care should be given to try to avoid sulfonamides because their use can result in a disease flare.

In the United States, Section 504 of the Rehabilitation Act and the Americans with Disabilities Act mandate that children with chronic disease have a right to have accommodations made to their educational plans that will allow them to succeed academically. A 504 plan or an individual education plan (IEP) should be put in place if needed. School teachers and guidance counselors should know that patients with pSLE may need assistance with note taking or getting from class to class if they have active arthritis. Patients should not be penalized if they cannot keep up with their peers in physical education class. Patients also may be absent from school because of disease ﬂares or doctors’ appointments. Patients with pSLE do best when care is provided by a team approach that involves the rheumatologist, primary care physician, ophthalmologist, nephrologist, and social worker or child life therapist. These patients need close monitoring, and the patient and family often need extra support. It is important to counsel patients on medication compliance and on healthy diet and exercise, and to ensure proper follow-up with the various subspecialists whom the patient sees.

Summary • Based on strong research evidence and consensus, the most common disease manifestations at diagnosis of pSLE are constitutional symptoms, arthritis, and malar rash. (4)(5) • Based on some research evidence and consensus, patients with pSLE tend to have major organ system involvement (renal/central nervous system) and a greater disease burden compared with adults. Despite these findings, mortality is low. (4)(5) • Based on some research evidence and consensus, the diagnosis of pSLE is unlikely if the ANA is negative, and most patients with SLE have a positive ANA at a titer ‡1:160. (9) • Based on strong research evidence, both MMF and cyclophosphamide can be used for induction therapy in class III and IV lupus nephritis. (10) • Based on strong research evidence, patients with SLE and anticardiolipin antibodies or LA have a two and six times greater risk of venous thrombosis, respectively, compared with patients with SLE without antiphospholipid antibodies. (7) • Based on strong research evidence, patients with pSLE have a higher risk for subclinical atherosclerosis when there is weight-adjusted prednisone use, azathioprine use, increasing age, male gender, high BMI, abnormal creatinine clearance, and elevated lipoprotein(a) levels. (8)

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ACKNOWLEDGMENTS The author thanks Drs B. Anne Eberhard and Kathleen A. Haines for critically reviewing this manuscript.

References 1. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725 2. Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum. 1973;3(1):1–54 3. Benseler SM, Silverman ED. Systemic lupus erythematosus. Pediatr Clin North Am. 2005;52(2):443–467, vi 4. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008;152(4):550–556 5. Weening JJ, D’Agati VD, Schwartz MM, et al. on behalf of the International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–250 6. Bertsias GK, Salmon JE, Boumpas DT. Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis. 2010;69(9):1603–1611 7. Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid

antibodies in systemic lupus erythematosus—a meta-analysis. Lupus. 1997;6(5):467–473 8. Schanberg LE, Sandborg C, Barnhart HX, et al; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 2009;60(5):1496–1507 9. Malleson PN, Sailer M, Mackinnon MJ. Usefulness of antinuclear antibody testing to screen for rheumatic diseases. Arch Dis Child. 1997;77(4):299–304 10. Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, Thakkinstian A. Efﬁcacy and adverse events of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: systematic review and meta-analysis. Medicine (Baltimore). 2010;89(4):227–235

Suggested Reading Buyon JP, Rupel A, Clancy RM. Neonatal lupus syndromes. Lupus. 2004;13(9):705–712 Terrier B, Amoura Z, Ravaud P, et al; Club Rhumatismes et Inﬂammation. Safety and efﬁcacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010; 62(8):2458–2466

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New Minimum Performance Level Requirements Per the 2010 revision of the American Medical Association (AMA) Physicianâ&#x20AC;&#x2122;s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. Starting with 2012 Pediatrics in Review, AMA PRA Category 1 CreditTM be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. 1. The most common skin manifestation of systemic lupus erythematosus is: A. Alopecia B. Discoid lupus C. Gottron papules D. Malar (butterfly rash) E. Psoriasis 2. A patient with discoid lupus is prescribed hydroxychloroquine. Of the following, what intervention should be performed at least annually to monitor for drug toxicity? A. B. C. D. E.

A bone density study (DEXA) Opthalmologic examination Plasma creatinine Prothrombin time Pulmonary function testing

3. According to the American Rheumatologic Association, which of the following conditions is a diagnostic criterion for systemic lupus erythematosus? A. B. C. D. E.

Arthralgia Hemolytic anemia Interstitial pneumonitis Splenomegaly Vaginal ulcerations

4. The leading cause of morbidity and mortality in systemic lupus erythematosus is: A. Arthritis B. Nephritis C. Neuropsychiatric lupus D. Pericarditis E. Pneumonitis 5. Approximately what percentage of children with SLE will have anti-double-stranded DNA antibodies at the time of diagnosis? A. B. C. D. E.

1% 10% 25% 50% 75%

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Pediatric Systemic Lupus Erythematosus : More Than a Positive Antinuclear Antibody Jennifer E. Weiss Pediatrics in Review 2012;33;62 DOI: 10.1542/pir.33-2-62

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References

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Consultation with the Specialist : Thyroid Nodules Jennifer N. Osipoff and Thomas A. Wilson Pediatrics in Review 2012;33;75 DOI: 10.1542/pir.33-2-75

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Thyroid Nodules Jennifer N. Osipoff, MD,* Thomas A. Wilson, MD*

Educational Gap Although most pediatric thyroid masses are benign, some are malignant; thus, pediatricians must be able to assess for risk of malignancy and order appropriate diagnostic tests in conjunction with consultation with an endocrinologist.

Objectives

Author Disclosure Drs Osipoff and Wilson have disclosed

After completing this article, readers should be able to:

1. Develop a differential diagnosis and initial evaluation plan for a child or adolescent presenting with a thyroid mass. 2. List the risk factors associated with malignant thyroid nodules. 3. Understand the limitations of ultrasonography and fine-needle aspiration biopsy in the assessment of a thyroid nodule. 4. Recognize the risk factors inherent in surgical thyroidectomy. 5. Appreciate the current controversies in the management of pediatric thyroid nodules.

no financial relationships relevant to this article. This commentary does

Introduction

contain a discussion of an

Whether as part of a well-child examination, or in response to a patient or parent concern, it is important for the pediatrician to feel comfortable examining the thyroid gland. Although most pediatric thyroid masses are benign (Table 1 and Fig 1), in the event that a lesion is discovered, the pediatrician should be able to assess risk factors for malignancy and order appropriate diagnostic tests while awaiting consultation from the pediatric endocrinologist.

unapproved/investigative use of a commercial product/device.

Abbreviations ﬁne-needle aspiration biopsy I-131: a radioactive isotope of iodine MTC: medullary thyroid carcinoma PTC: papillary thyroid carcinoma rh-thyrotropin: recombinant human thyrotropin WDTC: well-differentiated thyroid carcinoma WBS: whole-body scan

FNAB:

Epidemiology Palpable thyroid nodules in the pediatric and adolescent population are relatively rare, having an estimated prevalence of 0.2% to 1.4%, which is 5 to 10 times less than in adults. (1) Despite their lower occurrence, studies estimate 9% to 50% (mean, 26.4%)

*Division of Pediatric Endocrinology, Department of Pediatrics, Stony Brook Children’s Hospital, State University of New York, Stony Brook, NY.

of thyroid nodules in children and teenagers are cancerous, signiﬁcantly higher than the estimated 10% to 14% of lesions in adults. (2) In fact, thyroid cancers are the third most common solid tumor in children and adolescents, with an annual incidence of 1.75 per 100,000. (3) The femaleto-male ratio of malignant thyroid disease is age speciﬁc, with a ratio of 1 to 6 in children 5 to 9 years old, 1 to 1 in 10- to 14-year-olds, and 5 to 2 in 15to 19-year-olds. (4) Well-differentiated thyroid carcinomas (WDTCs) comprise the vast majority of pediatric thyroid malignancies, with papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma accounting for 80% to 95% and 5% to 15% of these tumors, respectively. (5)(6)

Clinical Aspects The History: Assess for HighRisk Factors Most patients who have a malignant thyroid nodule present with an incidentally found, painless thyroid mass Pediatrics in Review Vol.33 No.2 February 2012 75

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and are clinically and biochemically euthyroid. A thorough history is essential in assessing the likelihood of malignancy once a thyroid nodule is discovered. A history of ionizing radiation to the head or neck is an independent risk factor for the development of thyroid malignancies. Several decades may pass between the radiation exposure and the development of thyroid cancer. Historically, radiation was used to treat tonsillar hypertrophy, thymic enlargement, facial acne, and hemangiomas of the face and neck. Although these treatment modalities are not used today, irradiation of the

Benign Thyroid Masses Table 1.

Simple colloid cyst Follicular adenoma Multinodular goiter Thyroglossal duct cyst Ectopic thymic tissue Inflammatory changes Unilateral thyroid agenesis Thyroid abscess Teratoma

head and neck is relatively common in children undergoing treatment for other forms of childhood cancer; thus, screening for thyroid malignancies should be a routine part of their posttreatment follow-up care. The family history is of particular significance during the evaluation of a thyroid nodule because there are several syndromes (Table 2) associated with thyroid cancer that follow an autosomal dominant mode of inheritance. A family history of thyroidectomies, thyroid malignancies, or other cancers suggests that the child with the thyroid nodule has a genetic predisposition to the development of thyroid carcinoma. Although extremely rare in the United States, iodine deficiency has been linked to thyroid cancers, and determining if the child originates from an area of endemic iodine deficiency is crucial. Thyroid nodules in prepubertal children have a higher risk of malignancy. A thyroid nodule found in a male younger than 15 years old has the greatest chance of being malignant. The review of systems is invaluable in stratifying the risk of malignancy and guiding the evaluation. If a patient has symptoms consistent with

Figure 1. A. A patient with an ectopic thyroid gland (upper protuberance) before treatment. B. The same patient a few months after starting levothyroxine. Note how the gland has shrunk in response to treatment.

hyperthyroidism, such as tachycardia or tremulousness, the thyroid mass is likely a solitary toxic adenoma or a multinodular goiter, both of which secrete thyroid hormone autonomously. Caution must be exhibited when a patient presents with a discrete thyroid mass and symptoms of hypothyroidism, such as cold intolerance or constipation. Although the nodule in this situation likely represents inﬂammatory change in the setting of Hashimoto thyroiditis, some literature suggests that the presence of chronic lymphocytic thyroiditis raises the risk for thyroid cancers. (7) Although rare in young patients with thyroid nodules, voice changes, symptoms of airway compression, or rapid growth of the lesion are worrisome for malignancy. However, if the patient complains of pain or tenderness over the nodule, hemorrhage into a cyst, thyroid abscess, or an inﬂammatory process should be considered before malignancy.

The Physical Examination The physical examination also provides clues to help differentiate between a benign and malignant process. The size of the nodule does not have any diagnostic value. (1)(2)(3) A nodule that is ﬁrm to palpation, irregularly shaped, ﬁxed to the surrounding tissue, or associated with regional lymphadenopathy is concerning for malignancy (Fig 2). However, if the mass is painful to the touch or associated with overlying erythema, a suppurative thyroiditis is higher on the differential and should be treated appropriately. Occasionally, thyroid carcinoma will present as a peripheral, nontender lymph node enlargement without a detectable thyroid nodule being present. Therefore, it is imperative to consider thyroid malignancy in the differential diagnosis of all painless cervical lymphadenopathy, especially if the patient has any other risk factors.

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Autosomal Dominant Syndromes With Predisposition to Thyroid Malignancy

Table 2.

Medullary thyroid carcinoma (MTC) Multiple endocrine neoplasia type 2a: MTC, pheochromocytoma, and parathyroid adenoma Multiple endocrine neoplasia type 2b: MTC, pheochromocytoma, mucosal neuromas, marfanoid habitus Familial MTC: isolated MTC Non-MTC Gardner syndrome: thyroid, breast, and colon cancers; lipomas; intestinal polyposis; osteomas Cowden disease: thyroid and breast cancers, multiple hamartomas Familial adenomatoid polyposis

Figure 2. A patient with marked cervical lymphadenopathy (all protuberances) before diagnosis of PTC.

Evaluation Laboratory Tests The function of the thyroid gland should be assessed by measuring thyrotropin, thyroxine, and, in cases where hyperthyroidism is suspected, triiodothyronine. Any endocrinologic abnormalities should be corrected before surgical intervention. Although laboratory tests cannot differentiate a benign process from a malignant one, a suppressed thyrotropin level is suggestive of a hyperfunctioning nodule. In this situation, an iodine-123 thyroid uptake and scan is warranted to evaluate for a toxic adenoma or a multinodular goiter. Anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies

also should be measured because their presence may signify an increased risk of malignancy. Calcitonin is used to screen for medullary thyroid carcinoma (MTC), a cancer that originates from the parafollicular or C cells of the thyroid gland. Although an elevated level is highly suggestive of MTC, a normal level does not rule out microscopic disease. Although less sensitive than calcitonin, a serum carcinoembryonic antigen is useful for detecting MTC and monitoring for disease recurrence. Sporadic MTC is rare in the pediatric population, and MTC usually clusters in families. The inherited forms of MTC, either as part of multiple endocrine neoplasia or familial MTC, are due

to an activating mutation in the RET gene. If such a condition is suspected, genetic analysis should be performed. Additionally, evaluation for a concomitant pheochromocytoma with a 24-hour urinary catecholamine collection is imperative, because this tumor would need to be removed before thyroid surgery to prevent hypertensive crisis.

Ultrasonography Ultrasonography of the thyroid gland and regional lymph nodes offers a radiation-free method of characterizing thyroid nodules and assessing for local metastasis. Although carcinoma cannot be diagnosed by ultrasonography alone, certain imaging ﬁndings are more commonly seen in malignant lesions (see Table 3 and Fig 3). Ultrasonography can detect changes in the cervical lymph nodes, a ﬁnding that greatly increases the likelihood of malignancy. Nonpalpable thyroid nodules, which carry the same risk for malignancy as palpable nodules, may be detected. (3) Studies have found that, if there are multiple nodules, the individual risk of malignancy in each nodule decreases, but the overall cancer risk remains the same as for a patient with a solitary nodule. (8)

Fine-Needle Aspiration Biopsy Fine-needle aspiration biopsy (FNAB) is considered the gold standard for preoperative diagnosis of thyroid nodules in adults. Three recent studies (1)(5)(9) investigated the utility of FNAB in pediatrics, and each concluded that FNAB is a highly sensitive test that should be utilized in all pediatric patients presenting with a thyroid nodule. A meta-analysis of 12 studies of pediatric FNAB found the pooled sensitivity to be 82% and speciﬁcity 91%. (9) Assuming that 20% of pediatric thyroid nodules are malignant, the meta-analysis determined the accuracy, positive predictive Pediatrics in Review Vol.33 No.2 February 2012 77

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Ultrasonographic Findings Suspicious for Malignancy Table 3.

Hypoechoic lesions Intranodal microcalcifications Intranodular central vascularization Lesions that are more tall than wide Lymph nodes alterations: irregular margins, increased size, lack of echogenic hilum, calcifications, irregular vascularity There is considerable overlap between ultrasonographic ﬁndings of benign and malignant lesions.

Figure 3. Ultrasonographic imaging of a thyroid nodule. Note the internal calcifications. The patient was diagnosed ultimately as having PTC and underwent a total thyroidectomy followed by radioactive iodine ablation.

value, and negative predictive value of FNAB to be 83.6%, 55.3%, and 98.2%, respectively. FNAB under ultrasonographic guidance allows for nonpalpable nodules to be biopsied and decreases the chance of a nondiagnostic biopsy. Benign FNAB results, such as the finding of a colloid nodule, can prevent unnecessary surgery. Atypical or malignant cytology guides the appropriate surgical intervention. FNAB is not without limitations. The diagnostic yield depends on the person obtaining the biopsy to collect a sufficient sample and on the skill of the pathologist making the cytology report. It is difficult to obtain a

diagnostic sample from nodules <1 cm. Although FNAB can identify PTC, follicular adenomas and carcinomas cannot be distinguished by FNAB alone and require surgical pathologic analysis to determine if the lesion invades the thyroid capsule. Nine to 20% of FNABs are nondiagnostic. (5) In that event, the physician must use other clinical criteria to decide whether to proceed with surgical resection or continued observation. The small neck size of young children and the need for sedation in most pediatric patients pose additional challenges in obtaining an FNAB. Adverse events, such as

hemorrhage or abscess formation, are extremely rare after an FNAB.

Surgical Management Although a consensus exists for early, prophylactic total thyroidectomy in children at risk for inheritable MTC, (10) the optimal surgical management of WDTC in the pediatric and adolescent population remains controversial. Proponents of lobectomy cite lower rates of surgical complications in comparison with total or near-total thyroidectomy. The most frequent complications of total thyroidectomy, permanent hypoparathyroidism with resultant hypocalcemia and permanent laryngeal nerve paralysis causing voice changes and dysphagia, occur in w2% and 1% of patients, respectively. (11) Studies comparing the recurrence rate in children who underwent total thyroidectomy versus lobectomy are conﬂicting. Some authors refute that intergroup differences exist, whereas others have found recurrence rates up to 50% higher in the lobectomy group. Although no ofﬁcial recommendations exist, most centers today support total or near-total thyroidectomy for pediatric WDTC. Despite a slightly higher surgical risk, total thyroidectomy allows radioiodine scanning and thyroglobulin levels to be used to detect metastases and disease recurrence (see next section). The majority of patients with PTC have microscopic foci of PTC in the contralateral thyroid lobe. Removing the entire gland eliminates these foci as potential sites of disease recurrence. This procedure decreases the need for a “completion thyroidectomy,” a second surgery associated with higher rates of surgical complications. (6) The extent to which cervical lymph nodes should be surgically explored and dissected remains debated; broad

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exploration increases the risk of surgical complications, whereas less extensive investigation may miss disease. (12) After lobectomy, most individuals remain euthyroid without medication, but a total thyroidectomy will necessitate lifelong levothyroxine supplementation.

Postoperative Management Assessing and Treating Metastases With Radioiodine Pediatric patients afﬂicted with thyroid cancer have a higher incidence of lymph node involvement and distant metastases at initial presentation in comparison with adults. Each thyroid cancer metastasizes differently. PTC invades regional lymph nodes and the lungs, follicular thyroid carcinoma seeds hematologically to the lungs and liver, and MTC utilizes the lymphatic system to spread cancerous cells. WDTC cells, unlike those of MTC, are able to concentrate iodine. This property is utilized to identify WDTC metastases and remnant tissue in the thyroid bed by the use of a radioiodine whole-body scan (WBS). WBS can be done only after a near-total or total thyroidectomy because iodine-avid thyroid tissue concentrates radioiodine more efﬁciently than cancerous cells, thereby limiting the detection and treatment of metastases. To maximize uptake, radiographic contrast must not have been administered in the previous 2 to 3 months, and high iodine content foods must be avoided for several weeks. Levothyroxine is replaced by triiodothyronine supplementation 4 to 6 weeks before the scan. Two weeks before all thyroid hormone support is withdrawn causing a rise in thyrotropin, ideally >30 mIU/L. Because this action renders the patient hypothyroid, some centers utilize recombinant human thyrotropin (rh-thyrotropin) injections

instead, although its use in children does not have Food and Drug Administration approval. After confirming thyrotropin elevation, the patient drinks radioactive iodine (I-131) and 24 to 72 hours later undergoes WBS by the use of a scintillation camera designed to capture emitted radiation from the ingested isotope (Fig 4). Residual tumor or significant tissue in the thyroid bed warrants surgical reexploration. If WBS reveals metastases or minimal remnant thyroid tissue, a larger treatment dose of I-131 is given with the goal of destroying the cancerous cells or ablating the remaining tissue. Dosing of I-131 is another area of debate in managing pediatric WDTC, because no research-driven guidelines exist regarding its administration. The benefits of I-131, namely decreased disease recurrence, need to be weighed against the risks of treatment. Acute, and generally transient, side effects of I-131 include nausea, sialadenitis, altered taste, leucopenia, thrombocytopenia, and menstrual irregularities. Potential long-term risks of I-131 include decreased fertility, pulmonary fibrosis, and an increased risk of secondary malignancy, such as leukemias and solid tumors. (3) A second WBS is completed 6 months after the initial administration of radioiodine therapy to assess if a second treatment dose of I-131 is warranted.

Thyroglobulin Levels Thyroglobulin, a protein used in the production of endogenous thyroid hormone, is produced exclusively by the thyroid gland and thyroid cancers. This property allows thyroglobulin to be used in athyreotic patients as an adjuvant to WBS in disease surveillance for WDTC. Thyrotropin stimulation causes thyroglobulin to rise, and levels should be measured after levothyroxine withdrawal or

Figure 4. Example of a radioactive iodine whole body scan (WBS). Patient had a total thyroidectomy for papillary thyroid carcinoma (PTC). At the time of the scan, the patient’s thyrotropin level was 39 mIU/L. The blue arrow points to remnant tissue in the thyroid bed. The red arrow points to the kidney and bladder. As the radioactivity is excreted through the urine, this pattern is a normal finding on a WBS. There is no evidence of metastases.

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or >2 ng/mL after rh-thyrotropin injection suggest disease recurrence or a residual thyroid remnant. Levels of thyroglobulin should be undetectable when thyrotropin levels are not elevated. Antithyroglobulin antibodies interfere with the thyroglobulin assay, so it is important to screen patients for the presence of these antibodies.

Thyrotropin Suppression Because thyrotropin promotes WDTC growth, it is believed that depriving the cancerous cells of this stimulation will limit their expansion. This deprivation is achieved by administering sufficient levothyroxine to suppress endogenous thyrotropin production. The degree of suppression is also under debate, with most advocating for thyrotropin levels of 0.1 to 0.4 mU/L in patients with low risk of recurrence and <0.02 mU/L in high-risk patients. The benefits of thyrotropin suppression need to be balanced against its potential risks. Long-term complications of excessive levothyroxine include headaches, insomnia, difficulty concentrating, and problems with skeletal maturation and mineralization.

Long-Term Follow-up Speciﬁc guidelines for long-term follow-up of pediatric thyroid carcinomas do not exist and recommendations are based on the individual institution’s experiences. Most centers advocate that, for the ﬁrst 18 to 24 months after thyroidectomy, patients should undergo WBS and thyroglobulin measurement twice a year. I-131 can be administered every 6 months until WBS and thyroglobulin levels suggest that the WDTC has been eliminated. When there has been no evidence of disease for 12 consecutive months, these studies can be performed annually for the next 2 years, and then again 3 years later.

Assuming that there has been no disease recurrence, these surveillance studies should be conducted every 5 years. As the child grows older, it is important to arrange for continuity of care with an adult endocrinologist.

Prognosis Fortunately, even when there is advanced tumor staging and metastases at presentation, pediatric and adolescent patients with WDTC have an excellent prognosis, having higher survival rates than their adult counterparts who have less invasive disease. The overall survival rate is w99% at 10 years, 95% at 20 years, and 90% at 30 years. Although thyroid carcinoma is rarely fatal in children and teenagers, this population is at an increased risk for disease recurrence. Historically, the progression-free survival rates are markedly lower, being 65% to 70% at 5 years, 61% at 10 years, and 46% at 20 years. (6)(12) Thyroid capsule invasion, soft-tissue invasion, positive surgical margins, presence of distant metastases at diagnosis, and presentation at <15 years old have been cited as risk factors for disease recurrence. (12) The impact of more aggressive surgical treatment, use of radioiodine, and thyrotropin suppression remains to be seen.

Summary • Based on strong research evidence, thyroid nodules in children and teenagers are more likely to be malignant than in adults. • Based on strong research evidence, a history of ionizing radiation to the head or neck is an independent risk factor for the development of thyroid malignancies.

• There is strong research evidence, including a recent meta-analysis, (9) supporting the use of fine-needle aspiration biopsy in the evaluation of all pediatric and adolescent patients presenting with a thyroid nodule. • The surgical management and postoperative care of pediatric and adolescent patients who have well-differentiated thyroid carcinomas remains controversial, because the rarity of the disease limits the ability to conduct randomized, prospective research studies. • Numerous studies have demonstrated that, despite presenting with more advanced disease, pediatric and adolescent patients with thyroid carcinoma have a higher survival rate than adults. • The American Thyroid Association has issued strong evidence-based recommendations for the management of medullary thyroid carcinoma, including RET mutation testing and early prophylactic total thyroidectomy in children with high-risk mutations. (10)

References 1. Corrias A, Einaudi S, Chiorboli E, et al. Accuracy of ﬁne needle aspiration biopsy of thyroid nodules in detecting malignancy in childhood: comparison with conventional clinical, laboratory, and imaging approaches. J Clin Endocrinol Metab. 2001;86(10): 4644–4648 2. Niedziela M. Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr Relat Cancer. 2006;13 (2):427–453 3. Dinauer C, Francis GL. Thyroid cancer in children. Endocrinol Metab Clin North Am. 2007;36(3):779–806, vii 4. Hung W, Sarlis NJ. Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review. Thyroid. 2002;12(8): 683–702 5. Bargren AE, Meyer-Rochow GY, Sywak MS, Delbridge LW, Chen H, Sidhu SB. Diagnostic utility of ﬁne-needle aspiration

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cytology in pediatric differentiated thyroid cancer. World J Surg. 2010;34(6): 1254–1260 6. Parisi MT, Mankoff D. Differentiated pediatric thyroid cancer: correlates with adult disease, controversies in treatment. Semin Nucl Med. 2007;37(5): 340–356 7. Hung W. Solitary thyroid nodules in 93 children and adolescents: a 35-years experience. Horm Res. 1999;52(1):15–18

8. Stevens C, Lee JK, Sadatsafavi M, Blair GK. Pediatric thyroid ﬁne-needle aspiration cytology: a meta-analysis. J Pediatr Surg. 2009;44(11):2184–2191 9. Kloos RT, Eng C, Evans DB, et al; American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565–612 10. Bargren AE, Meyer-Rochow GY, Delbridge LW, Sidhu SB, Chen H. Outcomes

of surgically managed pediatric thyroid cancer. J Surg Res. 2009;156(1):70–73 11. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res. 2009;156(1): 167–172 12. Grigsby PW, Gal-or A, Michalski JM, Doherty GM. Childhood and adolescent thyroid carcinoma. Cancer. 2002;95(4): 724–729

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Age >15 years Cervical lymphadenopathy Male gender Nodule is tender Tachycardia

2. The boyâ&#x20AC;&#x2122;s mother has had thyroid carcinoma, a risk factor for his having a malignancy. He undergoes ultrasonography. Which of the following ultrasonographic findings is most consistent with malignancy? A. B. C. D. E.

A lymph node having a sharp margin is noted Intranodal microcalcifications are present Lesion is hyperechoic Lesion is wider than tall Nodule lacks central vascularization

3. The decision is made to perform a fine-needle aspiration biopsy (FNAB). Which of the following statements about FNAB is true? A. B. C. D. E.

Fifty percent of FNABs are nondiagnostic FNAB is specific but not sensitive FNAB is straightforward and performed easily Hemorrhage and abscess formation are common complications It is difficult to obtain a diagnostic sample from nodules <1.0 cm

4. The boy is found to have a well-differentiated thyroid carcinoma. Most medical centers would recommend the following therapy: A. B. C. D. E.

Chemotherapy Radiation therapy Radioactive iodine Thyroid lobectomy Total thyroidectomy

5. After surgery, the boy and his parents ask about his prognosis. Given his age, lack of metastases, and absence of local invasion, you feel comfortable telling them that the probability of 10-year survival is approximately: A. B. C. D. E.

55% 67% 75% 85% 99%

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Consultation with the Specialist : Thyroid Nodules Jennifer N. Osipoff and Thomas A. Wilson Pediatrics in Review 2012;33;75 DOI: 10.1542/pir.33-2-75

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Complementary, Holistic, and Integrative Medicine : Crohn Disease Alycia Leiby and Minal Vazirani Pediatrics in Review 2012;33;83 DOI: 10.1542/pir.33-2-83

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complementary medicine

Complementary, Holistic, and Integrative Medicine: Crohn Disease Alycia Leiby, MD,*

Introduction

Minal Vazirani, MD†

Crohn disease (CD) is a chronic inflammatory bowel disease (IBD) characterized by periods of relapse and remission. In a genetically predisposed individual, environmental factors lead to a dysregulated adaptive immune response resulting in chronic intestinal inflammation and the potential long-term complications of intestinal stricture and perianal disease. (1) In pediatric CD, there is the additional complication of corticosteroid dependence, resulting in growth failure and significant psychosocial impact. (2) The need for surgical intervention in children is considerable also, with 5% requiring surgery at 1 year from diagnosis and 18% at 5 years. (3) The clinical severity and location of disease often dictate what agents are chosen to treat CD, with the goal being to induce and then maintain long-term remission. Conventionally, 5-aminosalicylate (5-ASA) therapy, such as mesalamine, is used often for mild disease, although the evidence for this approach is not considered robust. (4) For moderate to severe disease, data reveal that earlier use of immunomodulators, such as the thiopurines or methotrexate, may act to decrease corticosteroid exposure and hospitalizations. (5)(6) Recently, infliximab, a monoclonal antibody directed against tumor necrosis factor a, has been shown to be efficacious in the induction and maintenance of remission in moderate to severe pediatric CD. (7) Despite strong evidence for benefit, potential adverse effects, including infection and malignancy, affect the acceptance of immune modulating therapies. (8) The incidence of complementary and alternative medicine (CAM) use in pediatric patients with IBD ranges from 40% to 70%, (9)(10)(11)(12) with concern over adverse effects and lack of efficacy of conventional therapies being common reasons for such use. Use of CAM is increased particularly in patients who have a worse quality of life (QoL). (10)(13) In this article, we review the evidence for CAM therapy in CD as drawn from adult and pediatric data available in the English language.

Author Disclosure Drs Leiby and Vazirani have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Supplements Glutamine The amino acid glutamine is the preferred substrate for enterocytes, essential in a catabolic state such as IBD. Animal studies reveal glutamine decreases damage in IBD models, potentially by improving intestinal epithelial cell integrity. At this time, however, the beneficial effects of glutamine on human intestinal inflammation have not been demonstrated clearly. (14) The authors of one pediatric and two adult studies have looked both at glutamine as a supplement (15) and as part of a glutamine-enriched polymeric diet (16) and have not supported the use of glutamine for CD. Another study revealed no difference in plasma glutamine and intestinal permeability in a mixed IBD sample of patients who were randomly assigned to glutamine-enriched total parenteral nutrition versus glutamine-free total parenteral nutrition. (17) At this time, the available data do not support a recommendation of glutamine for maintenance of remission or treatment of disease flares.

Omega-3 Fatty Acids (Fish Oil)

Abbreviations 5-ASA: CAM: CD: IBD:

5-aminosalicylate complementary and alternative medicine Crohn disease inﬂammatory bowel disease

Fish oil and other sources of omega-3 fatty acids have been theorized to be effective in IBD therapy due to their inhibitory effect on the cyclooxygenase pathway, decreasing the formation of arachadonic acid as a substrate for the production of proinﬂammatory cytokines. (18) A 2009 Cochrane

*Pediatric Gastroenterology, Atlantic Health, Morristown Memorial Hospital, Morristown, NJ. † Integrative Pediatrics and Internal Medicine, Atlantic Health, Morristown Memorial Hospital, Morristown, NJ.

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meta-analysis reviewed the effectiveness and adverse events of fish oil when used for maintaining remission in CD. (19) Six randomized, placebo-controlled studies, including one pediatric trial, (20) were reviewed. The dose of fish oil ranged from 2 to 4 g per day, with varying blends of eicosapentaenoic acid and docosahexaenoic acid in differing delivery systems. Two other trials (EPIC-1 and EPIC-2), with w380 patients in each, revealed no significant difference in the relapse rate between omega-3 fatty acid supplementation and placebo. (21) The Cochrane review revealed that to date the existing studies do not support routine use of omega-3 essential fatty acids. The Cochrane analysis also revealed that adverse effects, including diarrhea and upper gastrointestinal symptoms, were more common in the fish oil groups compared with placebo, although the pediatric trial specifically did not reveal any adverse effects. (19) The type of fish oil preparation and delivery system would likely influence the rate of adverse reactions. The authors of the single pediatric study compared 18 patients who received 5-ASA in combination with 3 g/day of omega-3 fatty acid with 20 patients who received 5-ASA and an olive oil placebo. (20) The omega-3 fatty acid group had a significantly lower relapse rate at 1 year compared with the placebo group (61% vs 95%, P ¼ .0016). This small but well-designed trial is the only one to use fish oil supplementation in combination with other CD therapy. It is possible that the combination of 5-ASA and fish oil may have a synergistic antiinflammatory effect. Additional large pediatric studies using a combination of omega-3 fatty acid supplementation and conventional immunosuppressive therapy are needed to demonstrate a role for routine fish oil use in CD.

Probiotics Probiotic use is popular, with an average of 40% of pediatric patients with IBD having tried a probiotic preparation, (9)(10)(11)(12)(22) but evidence for clinical efficacy in CD is limited. In vitro and animal studies have revealed that probiotics can stimulate anti-inflammatory cytokine production and strengthen the intestinal epithelial cell barrier. (23) The authors of adult trials have examined the use of probiotics, including Lactobacillus GG, (24) Lactobacillus johnsonii, (25)(26) and a blend of preand probiotics (27) for prevention of postoperative recurrence; however, no effect was found. Some preliminary adult data reveal that Saccharomyces boulardii might be beneficial for CD by strengthening the intestinal barrier. (28) In a single randomized, double-blind trial of 75 children, GG versus placebo was used in addition to standard therapy. (29) There was no significant difference in time

to relapse. The authors of two studies looked at a Lactobacillus probiotic mixture VSL number 3 and found it to be efficacious for pediatric ulcerative colitis. (30)(31) Although theoretically beneficial, to date there is insufficient pediatric research done on the effects of probiotics to treat pediatric CD. Additional research using other strains or targeting specific CD phenotypes may show more promising results.

Diet Diet and bacteria may play a significant role in the etiology of IBD because they are the most common antigens to which the gastrointestinal lumen is exposed. (32) Epidemiologic data demonstrating an increased incidence of CD in emigrants to countries with a more western diet has been used as evidence that diet may be an environmental factor in the rising incidence of CD. (33) The authors of a case-control study investigated dietary patterns in pediatric CD cases and reported a positive association of CD with diets high in meats, saturated fatty foods, and desserts, whereas a diet high in vegetables, fruits, olive oil, fish, grains, and nuts was inversely associated with CD. (34) Enteral nutrition therapy is a purely dietary approach more commonly prescribed in Canada and Europe than in the United States. Treatment consists of 50% to 100% of the diet being formula, the aim being to induce and maintain remission in some patients. (35) Because oral consumption of the volume necessary is difficult, nasogastric administration of the formula is the route most commonly used and this modality may limit acceptance. Diets such as the specific carbohydrate diet, elimination diets, and Ayurvedic diets are anecdotally purported to be beneficial but lack evidence, and therefore further study is needed. As more research is done in the fields of epigenetics and nutrigenomics, perhaps dietary modification may become a more useful and precise tool in the prevention and treatment of CD. Until then, it is important to enforce the basic principles of a healthy diet low in saturated fats and sugar for children with CD.

Acupuncture Acupuncture is thought to act on many different mediators in the inﬂammatory cascade, including changing the cytokine proﬁle to reset the imbalance between T helper 1 and T helper 2 cell activity and stimulating a sustained low-concentration release of calcitonin gene-related peptide, a neuropeptide with vasodilator effect. (36) There is one randomized controlled study in adults in which acupuncture and moxibustion for the treatment of

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CD were used. (37) Remission rates and inﬂammatory markers did not differ between groups, but QoL measures also improved in both groups, although not signiﬁcantly. More research is needed to study the effectiveness of acupuncture for CD in adults and children.

Homeopathy Homeopathy is used by 3% to 4% of pediatric patients with IBD who are using CAM modalities. (9)(10) Although there are no randomized controlled trials to recommend routine use of homeopathic remedies, there is also no evidence that it is harmful. In general, homeopathic remedies are considered to be safe and nontoxic due to their extreme diluteness (usually 10 6 or greater), and thus can be tolerated in conjunction with conventional care.

an overall cognitive behavioral therapy (CBT) program. (42) Additionally, there is a potential role for “gut-focused hypnotherapy.” The authors of a small study done in the United Kingdom in 2008 demonstrated a reduction of corticosteroid requirements after 12 sessions of gutfocused hypnotherapy. (43) There has been signiﬁcant adult and pediatric research in the therapeutic applications of yoga to prevent and treat medical conditions. (44)(45) Yoga has been shown to decrease functional disability and anxiety in children with irritable bowel syndrome. (46) Yoga may be helpful for similar reasons as stated above for IBD, but further studies are needed. The use of biobehavioral techniques in conjunction with conventional care may improve QoL in children with CD and incorporate a holistic approach.

Biobehavioral Methods The role that stress may play in triggering flares of IBD has been investigated in the adult IBD population. Stress has been shown to alter gut permeability and cause the release of neuropeptides that have immune modulatory effects. (38) Although some studies reveal conflicting results, several prospective studies have revealed a positive association between stress and IBD flares, particularly the perception of stressful events, as opposed to discrete events. (38) Unpredictable and potentially embarrassing symptoms of IBD add to the stress and challenges of adolescence. The incidence of psychiatric disorders in children with CD is increased compared with healthy children and is comparable to the incidence in children with other chronic diseases, such as cystic fibrosis. (39) QoL may be impaired by pain and school absences, and patients having increased disease severity often have worse QoL. (39) Biobehavioral CAM techniques, such as relaxation, meditation, and prayer, are popular and are used by adolescents with IBD, especially those with more severe disease. (13) Various strategies have been tried in order to improve QoL and psychosocial functioning in pediatric patients with IBD, such as a prospective analysis of children attending a 1-week camp sponsored by the Crohn’s and Colitis Foundation of America, (40) cognitive behavioral therapy, (41) and a psychological program that included relaxation, imagery, and deep-breathing as part of

Summary • Although the use of CAM in pediatric CD is common, quality evidence-based research is limited. There is clearly a need for further randomized controlled trials. • The role of psychosocial distress in children with CD should not be overlooked and thus biobehavioral techniques should be considered and incorporated when possible. • Considering the potential for growth failure and need for surgical intervention in CD, any CAM therapies that are not harmful should be used only in combination with conventional medical treatment. • The importance of all health care providers partnering with their patients and asking about CAM use, as well as maintaining an awareness of efficacy, safety, harm, drug-supplement interactions, and appropriate referral sources, should be kept in mind when caring for those afflicted with this chronic disease.

ACKNOWLEDGMENTS The authors thank Dr Joel Rosh for his assistance in article preparation, and Dr Nancy Cotter for her support and review of the article. Note: To view the references for this article, visit http:// pedsinreview.aappublications.org and click on the article title.

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Complementary, Holistic, and Integrative Medicine : Crohn Disease Alycia Leiby and Minal Vazirani Pediatrics in Review 2012;33;83 DOI: 10.1542/pir.33-2-83

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References 1. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427–434 2. Markowitz J, Hyams J, Mack D, et al; Pediatric IBD Collaborative Research Group. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4 (9):1124–1129 3. Schaefer ME, Machan JT, Kawatu D, et al. Factors that determine risk for surgery in pediatric patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2010;8(9): 789–794 4. Faubion WA Jr, Bousvaros A. Medical therapy for refractory pediatric Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4 (10):1199–1213 5. Punati J, Markowitz J, Lerer T, et al; Pediatric IBD Collaborative Research Group. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis. 2008;14(7): 949–954 6. Turner D, Grossman AB, Rosh J, et al. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn’s disease. Am J Gastroenterol. 2007;102(12):2804–2812; quiz 2803, 2813 7. Hyams J, Crandall W, Kugathasan S, et al; REACH Study Group. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007; 132(3):863–873, quiz 1165–1166 8. Siegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol. 2009;7(8):874–881 9. Wong AP, Clark AL, Garnett EA, et al. Use of complementary medicine in pediatric patients with inflammatory bowel disease: results from a multicenter survey. J Pediatr Gastroenterol Nutr. 2009;48(1): 55–60 10. Markowitz JE, Mamula P, delRosario JF, et al. Patterns of complementary and alternative medicine use in a population of pediatric patients with inflammatory bowel

disease. Inflamm Bowel Dis. 2004;10(5): 599–605 11. Heuschkel R, Afzal N, Wuerth A, et al. Complementary medicine use in children and young adults with inflammatory bowel disease. Am J Gastroenterol. 2002;97(2): 382–388 12. Day AS, Whitten KE, Bohane TD. Use of complementary and alternative medicines by children and adolescents with inflammatory bowel disease. J Paediatr Child Health. 2004;40(12):681–684 13. Cotton S, Humenay Roberts Y, Tsevat J, et al. Mind-body complementary alternative medicine use and quality of life in adolescents with inflammatory bowel disease. Inflamm Bowel Dis. 2010;16(3):501–506 14. Coëffier M, Marion-Letellier R, Déchelotte P. Potential for amino acids supplementation during inflammatory bowel diseases. Inflamm Bowel Dis. 2010;16(3):518–524 15. Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P. Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn’s disease. JPEN J Parenter Enteral Nutr. 1999;23(1):7–11 16. Akobeng AK, Miller V, Stanton J, Elbadri AM, Thomas AG. Double-blind randomized controlled trial of glutamineenriched polymeric diet in the treatment of active Crohn’s disease. J Pediatr Gastroenterol Nutr. 2000;30(1):78–84 17. Ockenga J, Borchert K, Stüber E, Lochs H, Manns MP, Bischoff SC. Glutamine-enriched total parenteral nutrition in patients with inflammatory bowel disease. Eur J Clin Nutr. 2005;59(11):1302–1309 18. Fürst P, Kuhn KS. Fish oil emulsions: what benefits can they bring? Clin Nutr. 2000;19(1):7–14 19. Turner D, Zlotkin SH, Shah PS, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009; (1):CD006320 20. Romano C, Cucchiara S, Barabino A, Annese V, Sferlazzas C. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn’s disease: a double-blind, randomized, placebo-controlled study. World J Gastroenterol. 2005;11(45): 7118–7121 21. Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA. 2008;299(14):1690–1697 22. Wong A, Bass D, Dubinsky M, Silber G. Complementary and alternative medicine

use by pediatric IBD patients and families in the western United States. J Pediatr Gastroenterol Nutr. 2007;45(4):E78 23. Guandalini S. Update on the role of probiotics in the therapy of pediatric inflammatory bowel disease. Expert Rev Clin Immunol. 2010;6(1):47–54 24. Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut. 2002;51(3):405–409 25. Marteau P, Lémann M, Seksik P, et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut. 2006;55(6):842–847 26. Van Gossum A, Dewit O, Louis E, et al. Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn’s disease after lleo-caecal resection. Inflamm Bowel Dis. 2007;13(2): 135–142 27. Chermesh I, Tamir A, Reshef R, et al. Failure of Synbiotic 2000 to prevent postoperative recurrence of Crohn’s disease. Dig Dis Sci. 2007;52(2):385–389 28. Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn’s disease in remission. Scand J Gastroenterol. 2008;43(7):842–848 29. Bousvaros A, Guandalini S, Baldassano RN, et al. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn’s disease. Inflamm Bowel Dis. 2005;11(9):833–839 30. Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104(2):437–443 31. Huynh HQ, deBruyn J, Guan L, et al. Probiotic preparation VSL#3 induces remission in children with mild to moderate acute ulcerative colitis: a pilot study. Inflamm Bowel Dis. 2009;15(5):760–768 32. Abraham C, Cho JH. Bugging of the intestinal mucosa. N Engl J Med. 2007;357 (7):708–710 33. Montgomery SM, Ekbom A. Epidemiology of inflammatory bowel disease. Curr Opin Gastroenterol. 2002;18(4):416–420 34. D’Souza S, Levy E, Mack D, et al. Dietary patterns and risk for Crohn’s disease

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in children. Inflamm Bowel Dis. 2008;14 (3):367–373 35. El Matary W, Zachos M. Nutritional therapy. In: Mamula P, Markowitz JE, Baldassano R, eds. Pediatric Inflammatory Bowel Disease. New York, NY: Springer; 2008:337–347 36. Zijlstra FJ, van den Berg-de Lange I, Huygen FJ, Klein J. Anti-inflammatory actions of acupuncture. Mediators Inflamm. 2003;12(2):59–69 37. Joos S, Brinkhaus B, Maluche C, et al. Acupuncture and moxibustion in the treatment of active Crohn’s disease: a randomized controlled study. Digestion. 2004;69 (3):131–139 38. Singh S, Graff LA, Bernstein CN. Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol. 2009;104(5):1298–1313, quiz 1314

39. Mackner LM, Sisson DP, Crandall WV. Review: psychosocial issues in pediatric inflammatory bowel disease. J Pediatr Psychol. 2004;29(4):243–257 40. Shepanski MA, Hurd LB, Culton K, Markowitz JE, Mamula P, Baldassano RN. Health-related quality of life improves in children and adolescents with inflammatory bowel disease after attending a camp sponsored by the Crohn’s and Colitis Foundation of America. Inflamm Bowel Dis. 2005; 11(2):164–170 41. Szigethy E, Kenney E, Carpenter J, et al. Cognitive-behavioral therapy for adolescents with inflammatory bowel disease and subsyndromal depression. J Am Acad Child Adolesc Psychiatry. 2007;46(10): 1290–1298 42. McCormick M, Reed-Knight B, Lewis JD, Gold BD, Blount RL. Coping skills for

reducing pain and somatic symptoms in adolescents with IBD. Inﬂamm Bowel Dis. 2010;16(12):2148–2157 43. Miller V, Whorwell PJ. Treatment of inﬂammatory bowel disease: a role for hypnotherapy? Int J Clin Exp Hypn. 2008; 56(3):306–317 44. Khalsa SB. Yoga as a therapeutic intervention: a bibliometric analysis of published research studies. Indian J Physiol Pharmacol. 2004;48(3):269–285 45. Birdee GS, Yeh GY, Wayne PM, et al Clinical applications of yoga for the pediatric population: a systematic review. Acad Pediatr. 2009;9(4):212–220, e1–e9 46. Kuttner L, Chambers CT, Hardial J, Israel DM, Jacobson K, Evans K. A randomized trial of yoga for adolescents with irritable bowel syndrome. Pain Res Manag. 2006;11(4):217–223

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The following references are included online only for the article “Complementary, Holistic, and Integrative Medicine: Crohn Disease.”

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Index of Suspicion Sowmya Ananthanarayanan, Mohammed Al-Owain, Lisa Nguyen, Rani Gereige, Sujay Kansagra, Andrew Shaw and Heather McLean Pediatrics in Review 2012;33;89 DOI: 10.1542/pir.33-2-89

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/33/2/89

Data Supplement (unedited) at: http://pedsinreview.aappublications.org/content/suppl/2012/01/26/33.2.89.DCSupplementary_Data.htm l

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Case 1: Lymphadenopathy, Prolonged Hematuria, Proteinuria, and Weight Loss in a Teenage Boy Case 2: Red, Swollen, Painful Eye in a 12-year-old Boy With Methylmalonic Acidemia Case 3: Ptosis and Diplopia After a Respiratory Infection in a 7-year-old Girl Case 1 The reader is encouraged to write possible diagnoses for each case before turning to the discussion.

The editors and staff of Pediatrics in Review find themselves in the fortunate position of having too many submissions for the Index of Suspicion column. Our publication slots for Index of Suspicion are filled through 2013. Because we do not think it is fair to delay publication longer than that, we have decided not to accept new cases for the present. We will make an announcement in Pediatrics in Review when we resume accepting new cases. We apologize for having to take this step, but we wish to be fair to all authors. We are grateful for your interest in the journal.

Author Disclosure Drs Ananthanarayanan, Gereige, AlOwain, Nguyen, Kansagra, Shaw, and McLean 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.

Presentation

A 14-year-old African American boy presents with fever, right-sided neck swelling, and weight loss of 20 lb over 2-month period. He denies night sweats, illness contacts, or recent travel. He was seen 1 month ago for fatigue, body aches, decreased appetite, and 10 lb weight loss over the previous month. Due to a family history of diabetes, urinalysis was performed, which revealed moderate hemoglobin, protein of 200 mg/dL, white blood cell (WBC) count of 13/high power field, and red blood cell (RBC) count of 5/high power field. He was scheduled to be reevaluated in 1 week but has been lost to follow-up. The boy appears tired. His weight is 54.2 kg (>50th percentile), height is 165 cm (75th percentile), temperature is 38.9°C, heart rate is 106 beats/minute, respiratory rate is 20 breaths/minute, and blood pressure is 113/64 mm Hg. Physical examination reveals a 3 4 cm, tender, nonerythematous, nonfluctuant, slightly mobile right cervical mass located behind the sternocleidomastoid muscle. Findings on the rest of the examination are normal. Complete blood count reveals a WBC count of 5.5 103/mL, with 65% granulocytes, 30% lymphocytes, and 5% monocytes, platelet count of 267 103/mL, hemoglobin level 9.5 g/dL, hematocrit 29%, mean corpuscular volume 71 fL, RBC distribution width 15.2%, and normal peripheral smear. His erythrocyte sedimentation rate (ESR) is 65 mm/h,

and C-reactive protein (CRP) level is 1.081 mg/dL. Metabolic panel reveals a sodium concentration of 141 mEq/L, potassium 4.5 mEq/L, chloride 111 mEq/L, bicarbonate 24 mEq/L, serum urea nitrogen 33 mg/dL, creatinine 1.7 mg/dL, total protein 6 g/dL, and albumin 1.9 g/dL. Urinalysis reveals a protein of 200 mg/dL and rare granular casts. Chest radiograph is normal. Blood and urine cultures are obtained, and a tuberculin test is performed on admission. Additional evaluation reveals the diagnosis.

Case 2

Presentation

A 12-year-old boy with methylmalonic acidemia and secondary renal impairment presents to the emergency department with 4-day history of a red, swollen, painful left eye. The swelling has been gradual in onset and worsens with eye movements. He was diagnosed as having periorbital cellulitis in a private clinic and treated with oral amoxicillin/clavulanate for 2 days before this visit. Physical examination reveals an alert boy whose height is 128 cm and weight is 27 kg, both below the 3rd percentile. His temperature is 37.2°C, respiratory rate 20 breaths/ minute, heart rate 79 beats/minute, and blood pressure 125/91 mm Hg. The left upper eyelid is erythematous, swollen, hot, and tender. He has mild exophthalmos and bulbar conjunctivitis of the left eye (Fig 1). There is ophthalmoplegia of the left eye, more pronounced on lateral gaze. Pediatrics in Review Vol.33 No.2 February 2012 89

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peroxidase antibody are within normal range. His ESR is 30 mm/h, and CRP is 5.9 mg/dL. An imaging study leads to the correct diagnosis.

Case 3 Figure 1. Chemosis and bulbar conjunctivitis associated with redness around the eye with mild proptosis. Note that the vascular engorgement is located more toward the lateral aspect of the left eye (lateral rectus position).

The remaining ﬁndings are normal except for mild hypotonia associated with the methylmalonic acidemia. Laboratory evaluation reveals a WBC count of 7.81 103/mcL with 64.9% neutrophils and 27.2% lymphocytes, hemoglobin of 10.2 g/dL, and platelet count of 151 10 3 / mcL. His serum creatinine level is elevated at 116 mmol/L. However, serum levels of serum urea nitrogen, electrolytes, ammonia, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, angiotensin converting enzyme (ACE), thyroid stimulating hormone, free thyroxine, and antithyroid

Frequently Used Abbreviations ACE: angiotensin converting enzyme CNIII: cranial nerve III CNS: central nervous system CSF: cerebrospinal ﬂuid CT: computed tomography ESR: erythrocyte sedimentation rate Ig: immunoglobulin LN: lupus nephritis RBC: red blood cell SLE: systemic lupus erythematosus TB: tuberculosis WBC: white blood cell

Presentation

A previously healthy 7-year-old girl is hospitalized for evaluation of right eyelid droop and double vision for 2 days. She denies eye pain, redness, or drainage. Two weeks before presentation, she had several days of runny nose, fever to 38.3°C, and cough. Those symptoms resolved; however, she has since experienced intermittent headaches. She denies recent travel or known tick exposure. She reports no trauma, vertigo, syncope, weakness, numbness, paresthesias, dysphagia, or dysarthria. Her family history is significant for a grandmother who had a brain aneurysm. Physical examination reveals an alert, oriented, obese girl who has normal cardiovascular, pulmonary, and abdominal findings. The neurologic examination reveals a right eye that is deviated downward and laterally with notable ptosis. She is able only to abduct the right eye, with no vertical movement or adduction past midline noted. The left eye has normal extraocular movement. The right pupil is dilated to 5 mm, is minimally reactive to light, and has no consensual response when light is shone into the left eye. The left pupil is 3 mm and reacts normally, with a normal consensual response. Her visual acuity is 20/100 in the right eye and 20/30 in the left eye. The remainder of her neurologic examination is completely normal. Her gait is intact. Complete blood count, serum electrolyte levels, and cerebrospinal fluid (CSF) studies are normal. Her ESR is 21 mm/h and CRP level is 0.48 mg/dL. Further laboratory and imaging studies reveal the diagnosis.

Case 1

Discussion

The patient was started empirically on clindamycin for lymphadenitis. The differential diagnosis at this point included cervical lymphadenopathy or lymphadenitis, malignancy, and an autoimmune disorder. Ultrasonography of his neck revealed right posterior cervical and supraclavicular lymphadenopathy. Rheumatoid factor was <20, antinuclear antibody was positive, and antidouble stranded DNA antibody titer was positive at 3663. He was diagnosed as having systemic lupus erythematosus (SLE). It was important to rule out malignancy and active tuberculosis (TB) before starting corticosteroids. The tuberculin test was negative and this result was attributed to low T lymphocyte numbers (absolute CD3 count of 511/mm3 [71%], absolute CD4 count of 252/mm3 [35%], absolute CD8 count of 238/mm3 [33%]). Therefore, a serum interference-g release assay was done and came back positive. This test measures a cellmediated immune response as a sign of TB infection. Right cervical lymph node biopsy revealed lupus lymphadenopathy, and kidney biopsy revealed stage III lupus nephritis (LN). The patient was presumed to have latent TB and started on isoniazid and pyridoxine and treated for 9 months. He also was started on lisinopril and corticosteroids. He was placed on a high calorie/high protein diet and has started gaining weight.

The Condition LN is one of the most serious manifestations of SLE and usually arises within 5 years of the diagnosis of SLE. LN is an inﬂammatory process caused by glomerular deposition of autoantibodies. The incidence is 3:10,000 in the general population and occurs in 30% to 90% of individuals who have SLE. LN is more common

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in African American individuals, Asian individuals, children older than 15 years, and females. The causes of SLE are unknown. SLE is more common in first-degree relatives of patients who have the disorder, with higher concordance in monozygotic than in dizygotic twins. The concordance rate in monozygotic twins is not 100%, suggesting an environmental trigger. Other risk factors include human lymphocyte antigen class II, cytokine and mannose– binding lectin genes, and complement C2, C4 deficiencies. The pathogenesis of LN is based on at least three potentially overlapping mechanisms: (1) circulating DNA anti-DNA immune complexes deposited in the kidney; (2) complement activation and leukocytemediated injury triggered by in situ antigen-antibody complexes; and (3) renal injury caused by antibodies against specific cellular targets.

Clinical Manifestations Fewer than one-half of patients have symptoms such as fever, fatigue, weight loss, rash, arthritis, serositis, and anemia of SLE at the time of diagnosis of LN. Patients with active LN often present with proteinuria, hypoalbuminemia, peripheral and sometimes periorbital edema, normal or mildly elevated creatinine levels, and hypertension. Clinically, the disease is evaluated by urinalysis, concentrations of serum creatinine and albumin, antiDNA titers, and serum complement levels. Abnormal urinary ﬁndings include albuminuria, leukocyturia, hematuria, casts (granular, hyaline, RBC, and fatty), and oval fat bodies. A rising anti-DNA titer, together with hypocomplementemia and a low C3 level, is a strong indicator of active lupus renal disease. Hypoalbuminemia with signiﬁcant proteinuria and hypercholesterolemia are markers of the nephrotic syndrome, which may accompany active lupus renal disease.

LN is defined also histologically by renal biopsy, light microscopy, immunofluorescence, and electron microscopy. A kidney biopsy is used to confirm the diagnosis, determine the stage, and guide the choice of appropriate treatment. Patients with “silent” LN have normal urinalyses and serum creatinine levels but may show evidence of mesangial to proliferative nephritis on renal biopsy.

Management Treatment depends on clinical manifestations and the results of renal biopsy. Treatment is indicated for patients with membranous changes and severe nephrotic syndrome. Patients generally are started on corticosteroids, ACE-inhibitors, lipid lowering agents, and anticoagulants as needed. Immunosuppressive therapy is used in patients with membranous LN who have persistent severe and symptomatic nephrotic syndrome; in patients with nephrotic syndrome experiencing protein excretion >3.5 g/day; and in patients with mixed membranous and proliferative lesions on biopsy. Agents used are cyclophosphamide, cyclosporine, mycophenolate mofetil, and chlorambucil. Maintenance of adequate nutrition with high protein and calories is very important. Despite treatment, some patients with LN develop progressive loss of kidney function leading to renal failure requiring dialysis and eventually transplantation.

Complications and Prognosis Complications include nephrotic syndrome, acute renal failure, chronic renal failure, and end-stage renal disease. Prognosis depends on the speciﬁc form of LN. Better outcomes are reported in patients with pure membranous LN. Patients with proliferative lesions are more likely to develop end-stage kidney disease.

Lessons for the Clinician • In patients with LN, active or latent TB must be ruled out before starting corticosteroids. • An interference-g release assay should be considered as the test of choice in patients with an SLE flare-up and negative tuberculin skin test to rule out active or latent TB. • Dietary modification is very important and includes restrictions in sodium intake in patients with hypertension, restrictions in protein intake in patients with renal insufficiency, and restrictions in fat intake in patients with hypercholesterolemia. In the absence of the conditions mentioned above, a diet high in protein, fat, and calories is recommended. (Sowmya Ananthanarayanan, BSc, MD, MPH, University of South Florida, Tampa, FL; Rani Gereige, MD, MPH, University of South Florida, Tampa, FL, but currently affiliated with Miami Children’s Hospital, Miami, FL)

Case 2

Discussion

The symptoms and ﬁndings on physical examination (see Fig 1) suggested the diagnosis of orbital cellulitis in this patient. The normal thyroid studies and ACE level excluded orbital thyropathy and sarcoidosis, respectively. Both computed tomography (CT) and MRI are valuable for diagnosing orbital pathology. The orbital CT in this patient revealed moderate enlargement of the lateral rectus muscle on the left with associated enlargement of the muscle tendon at the insertion into the sclera (Fig 2). The medial, superior, and inferior rectus muscles appeared normal. There was no sinus involvement or abnormality in the course of the optic nerve. This pattern was diagnostic of orbital pseudotumor.

The Condition The best deﬁnition of orbital pseudotumor is an inﬂammatory mass of Pediatrics in Review Vol.33 No.2 February 2012 91

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characterized by a mixed inﬁltrate of plasma cells, lymphocytes, macrophages, and polymorphonuclear cells, with ﬁbrosis seen in the chronic form.

Diagnosis

Figure 2. CT scan of the orbit revealing

fusiform swelling of the left lateral rectus.

unknown etiology that involves orbital tissue and simulates a tumor. Orbital myositis, in which there is nonspeciﬁc orbital inﬂammation that involves primarily the extraocular muscles, often is included under the broad description of orbital pseudotumor. Sometimes these two terms are used interchangeably. Orbital pseudotumor is more prevalent in adults than children. In two large series, only 6% to 16% of patients who had orbital pseudotumor were younger than 20 years of age. The condition usually is unilateral, and the majority of studies indicate no sexual predilection. The cardinal feature of orbital pseudotumor is acute orbital pain exacerbated by eye movement. Other characteristics include decreased ocular motility, lid or conjunctival edema, and proptosis of varying degrees. Unusual symptoms include cluster headache. Bilaterality, trauma, and iritis are more common in children than in adults with orbital pseudotumor. The cause of orbital pseudotumor still remains obscure. The condition is likely to be autoimmune in origin, with viral, genetic, and environmental factors implicated as possible triggers. Involvement can range from a single extraocular muscle to the entire orbit. Pathologically, the pseudotumor is

Orbital pseudotumor should be considered in a patient with an acutely painful, proptotic eye. Leukocytosis and elevated ESR and CRP levels are nonspecific findings that suggest an active inflammatory process. Thyroid stimulating hormone and free thyroxine tests are performed to exclude thyroid-related ophthalmopathy. Testing for antinuclear antibody and more specific autoantibodies may be warranted if autoimmune diseases such as SLE are suspected. Imaging with orbital CT or MRI is essential for the diagnosis. Fine needle aspiration and biopsy should be reserved for patients having an atypical clinical course, a poor response to systemic steroid therapy, or recurrence of the disorder. These imaging techniques are helpful also in ruling out orbital malignancies or other diseases. Orbital pseudotumor is associated with SLE, myasthenia gravis, Crohn disease, Lyme disease, Kawasaki disease, and paraneoplastic syndromes. Differentiating orbital tumor from orbital cellulitis is extremely important (Table). In orbital pseudotumor, usually there is no associated sinus infection, the condition does not respond to antibiotic therapy, and characteristic CT findings are present.

Management Systemic corticosteroid therapy is the accepted primary treatment for the pseudotumor of the orbit. Recurrent or chronic orbital myositis may be difﬁcult to treat, requiring long-term corticosteroids, immunotherapy, chemotherapy, radiation therapy, or surgery. Failure to institute early therapy may result in permanent restriction of ocular mobility. Although orbital

pseudotumor is considered a selflimiting disease, the duration without treatment is unpredictable. The condition responds rapidly to corticosteroids, and complete resolution occurs within 1 to 2 weeks. However, the process may recur in up to 30% of patients, usually within the ﬁrst 6 months. This patient was started on intravenous ceftazidime and clindamycin and did not reveal any response for 48 hours. Once the diagnosis of orbital pseudotumor was established, he was started on oral prednisone (2 mg/kg per day) for 3 weeks, followed by tapering over another 3 weeks. He showed dramatic improvement within 48 hours and full resolution within 2 weeks. Follow-up at 3, 6, and 12 months revealed normal eye ﬁndings without recurrence.

Lessons for the Clinician • Orbital pseudotumor, also known as orbital myositis, is an idiopathic orbital inﬂammation. • The diagnosis relies on clinical, radiologic, and sometimes pathologic ﬁndings. • The condition should be differentiated from orbital cellulitis and neoplasms. • Orbital pseudotumor has a good response to systemic corticosteroid therapy. (Mohammed Al-Owain, MD, Department of Medical Genetics, King FaisalSpecialist Hospital and Research Center, Riyadh, Saudi Arabia)

Case 3

Discussion

MRI of the head revealed thickening and abnormal enhancement of the cisternal segment of the right oculomotor nerve (Fig 3). Magnetic resonance angiography did not reveal a vascular aneurysm. MRI/magnetic resonance angiography was chosen over

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Table 1.

Differential Diagnosis of Orbital Pseudotumor

Diagnosis

Important Features

Orbital cellulitis

Characterized by proptosis, chemosis, ophthalmoplegia, and potentially decreased visual acuity and commonly caused by direct bacterial extension from the ethmoid sinus. Aggressive and prompt treatment is mandatory. Very uncommon in the setting of normal sinuses in children. No limitation of eye movement and no proptosis. CT scan reveals swelling of the lids and subcutaneous tissue anterior to the orbital septum. Antibiotic therapy is the treatment of choice. Nasal congestion and discharge, cough, fever, halitosis, and less commonly periorbital edema and facial pain. There is sinus tenderness sometimes. Sinus CT scan helps in establishing the diagnosis. Acute form can be viral or bacterial. Chronic form is seen with systemic diseases such as syphilis, tuberculosis, and sarcoidosis. Benign tumors include hemangiomas and dermoid and epidermoid cysts. The most common malignant tumors are rhabdomyosarcoma, retinoblastoma (orbital extension), lymphosarcoma, metastatic neuroblastoma, and optic glioma. Biopsy is required for definitive diagnosis. Although lymphoid tumors probably are the most common orbital neoplasms in adults, they are exceedingly rare in children. Should be suspected in the pediatric age group, especially in the presence of stigmata of child abuse. Conjunctival foreign body may give a picture indistinguishable from pseudotumor. Thorough ophthalmologic examination is necessary for diagnosis. Secondary to immune mechanism leading to inflammation of the extraocular muscles and fat. Characterized by exophthalmos, proptosis, and lid retraction and associated with late motility problems. Usually bilateral and not accompanied by constitutional symptoms.

Preseptal (periorbital) cellulitis Contiguous sinusitis Dacryoadenitis (inflammation of the lachrymal gland) Orbital neoplasm

Trauma Foreign body Orbital thyroid disease

CT/CT angiography for greater diagnostic speciﬁcity of structural brain lesions as well as less radiation exposure; additionally, there was low suspicion for a hemorrhage or vasculopathic

Figure 3. Contrasted T-1 axial image of

patient’s brain MRI, revealing thickening and abnormal enhancement of the cisternal segment of the right oculomotor nerve.

process. These images could not distinguish tumor from an infectious or inflammatory condition. Blood and CSF samples were obtained in search of an infectious agent and for markers of inflammation. CSF studies were negative for evidence of neurosyphilis, Lyme disease, acid fast bacilli, Cryptococcus, fungal infections, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus. The CSF also revealed no evidence of leukemic cell infiltrate, oligoclonal bands suggestive of multiple sclerosis, or ACE levels suggestive of neurosarcoidosis. Serology for Lyme disease was negative and serum ACE levels were normal. However, serum immunoglobulin M (IgM) and IgG antibody titers against Mycoplasma were elevated by enzyme immunoassay. The positive IgM Mycoplasma titer was later confirmed by immunofluorescence antibody assay.

Differential Diagnosis The differential diagnosis of isolated cranial nerve III (CNIII) palsy is extensive, ranging from acutely lifethreatening to relatively benign conditions. One important point of discrimination is the presence or absence of isolated extraocular movement involvement, isolated pupillary involvement, or both. The parasympathetic ﬁbers that mediate pupillary constriction run along the outside of the oculomotor nerve, whereas innervation to extraocular muscles and the levator palpebrae muscle are more interior. Therefore, structural lesions that are compressive are more likely to present initially with pupillary involvement with sparing of extraocular movements, whereas vascular injuries to the nerve are more likely to affect extraocular movements with pupillary sparing. The following discussion Pediatrics in Review Vol.33 No.2 February 2012 93

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applies to processes that may lead to complete CNIII palsies. The location of injury to the oculomotor nerve can be within its midbrain nucleus or anywhere along the nerve as it courses through the brainstem, subarachnoid space, and cavernous sinus, then into the orbit. A brainstem process is likely to affect additional cranial nerves, but this involvement may not always occur. It is worth noting that many cases of isolated oculomotor nerve palsies are idiopathic. The causes of CNIII palsy include vascular, malignant, infectious or parainfectious, inflammatory, traumatic, congenital, toxic, and migranous conditions. Vascular causes merit particular attention, because an expanding aneurysm, most commonly of the posterior communicating artery, needs prompt intervention. Although more common in adults, aneurysms must be excluded in children. Other vascular causes include infarct or ischemia of the nucleus or nerve, vasospasm of the arterial blood supply, carotid arterycavernous sinus fistula, and vascular malformation within the midbrain. Malignant causes include schwannoma, carcinomatous meningitis, teratoma, meningioma, lymphangioma, and leukemia. Infectious causes are numerous but most notable are Mycoplasma pneumoniae infection, cysticercosis, measles, Cryptococcus infection, Lyme disease, TB, and HIV. The CNIII palsy may be due to either direct infection or result from a parainfectious process that may be immune-mediated. Abscess formation within the brainstem may selectively affect only a single cranial nerve. Inflammatory causes include Wegener granulomatosis, TolosaHunt syndrome, vasculitis, sarcoidosis, SLE, and demyelinating processes such as multiple sclerosis. Trauma to the orbit and ophthalmoplegic migraines can lead to isolated CNIII

palsy but should be diagnosed with caution in the appropriate clinic setting and only after other conditions have been carefully excluded. The same caution applies to the diagnosis of congenital CNIII palsy.

The Condition Central nervous system (CNS) manifestations are the most common extrapulmonary manifestations of M pneumoniae infections, occurring in 1 in 1000 cases. CNS involvement more commonly presents as acute encephalitis, although meningitis, myelitis, facial nerve palsy, and radiculitis have been reported. A literature search reveals only one case report of another patient having specifically a CNIII palsy associated with Mycoplasma infection. (1) The pathophysiologic mechanism still is debated. Mycoplasma has been found in CSF, but the organism has never been recovered from brain tissue, making direct invasion less likely. The most accepted pathophysiologic explanation remains a postinfectious autoimmune inflammatory response targeting the CNS, often appearing w1 week after a respiratory illness, usually accompanied by evidence of edema, perivascular infiltration, microthrombi, or areas of demyelination of CNS tissue.

obtained. On follow-up 1 week after discharge, improvement had continued and she was able to adduct her involved eye past midline. At this point, she was placed on a corticosteroid wean, to be completed over a 2-week period. She was lost to follow-up after this visit, so recovery could not be documented. A previous case report reveals recovery of function by 4 months (1); similarly, a report of a Mycoplasma-associated abducens nerve palsy revealed spontaneous resolution within 21 days and no recurrence at 10 months. (2)

Lessons for the Clinician • There are many causes for isolated oculomotor nerve palsy. • It is important to determine whether there is extraocular involvement, pupillary involvement, or both in order to help guide evaluation. • Evaluation of isolated oculomotor nerve palsy may involve neuroimaging and lumbar puncture. • M pneumoniae infection has been associated with many CNS disorders, including isolated oculomotor nerve palsy. (Lisa Nguyen, MD, MPH, Sujay Kansagra, MD, Andrew Shaw, MD, Heather McLean, MD, Duke University Medical Center, Durham, NC.)

Management and Prognosis There are no published guidelines or case reports that discuss treatment of Mycoplasma-associated CNIII palsy. This patient was given initial treatment of prednisone 30 mg twice a day (0.75 mg/kg per day) on day 2 of admission, due to concern for a progressive inﬂammatory or parainfectious process. Within 24 hours, she had subtle improvement in her ptosis and pupillary constriction to light. She was started on azithromycin once the Mycoplasma result was

References 1. Fink CG, Butler L. A cranial nerve palsy associated with Mycoplasma pneumoniae infection. Polymerase chain reaction evidence against an infectious mechanism. Br J Ophthalmol. 1993;77(11):750–751 2. Wang CH, Chou ML, Huang CH. Benign isolated abducens nerve palsy in Mycoplasma pneumoniae infection. Pediatr Neurol. 1998;18(1):71–72

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94 Pediatrics in Review Vol.33 No.2 February 2012

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Index of Suspicion Sowmya Ananthanarayanan, Mohammed Al-Owain, Lisa Nguyen, Rani Gereige, Sujay Kansagra, Andrew Shaw and Heather McLean Pediatrics in Review 2012;33;89 DOI: 10.1542/pir.33-2-89

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Zandman-Goddard G, Shoenfeld Y. Infections and SLE. Autoimmunity. 2005;38 (7):473–485