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Pediatrics in Review姞 (ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098 Statements and opinions expressed in Pediatrics in Review威 are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an exclusive course of treatment or serve as a standard of medical care. Subscription price for 2011 for print and online/online only: AAP Fellow $177/ $135; Nonmember $222/$172; Allied Health or Resident $165/$111. Institutions call for pricing (866-843-2271). For overseas delivery, add $109. Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing offices. © AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved. Printed in USA. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to PEDIATRICS IN REVIEW威, American Academy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. Pediatrics in Review Print Issue Editorial Board Disclosures The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest before the confirmation of service of those in a position to influence and/or control CME content. All individuals in a position to influence and/or control the content of AAP CME activities are required to disclose to the AAP and subsequently to learners that the individual either has no relevant financial relationships or any financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial interest is defined as any entity producing, marketing, reselling or distributing health-care goods or services consumed by, or used on, patients. Each of the editorial board members, reviewers, question writers, PREP Coordinating Committee members and staff has disclosed, if applicable, that the CME content he/ she edits/writes/reviews may include discussion/reference to generic pharmaceuticals, off-label pharmaceutical use, investigational therapies, brand names, and manufacturers. None of the editors, board members, reviewers, question writers, PREP Coordinating Committee members, or staff has any relevant financial relationships to disclose, unless noted below. The AAP has taken steps to resolve any potential conflicts of interest. Disclosures ● Richard Antaya, MD, FAAP, disclosed that he participates in Astellas Pharma, US, Inc., clinical trials, speaker bureau and advisory board; and that he participates in the Novartis speaker bureau. ● Athos Bousvaros, MD, MPH, FAAP, disclosed that he has research grants from Merck and UCB; and that he is a paid consultant and on the speaker bureau for Millennium. ● Brian Carter, MD, FAAP, disclosed that he participates in the MedImmune speaker bureau. ● David N. Cornfield, MD, FAAP, disclosed that he has National Institutes of Health grants. ● Donald W. Lewis, MD, FAAP, disclosed that he is a consultant for and has a research grant from Astra Zeneca and Merck; and that he has research grants from Ortho McNeil, Lilly, Bristol-Myers Squibb, GlaxoSmithKline, and Boehringer Ingelheim Pharmaceutical. ● Blaise Nemeth, MD, MS, FAAP, has disclosed he has an unrestricted educational grant for fellowship from Biomet. ● Janet Serwint, MD, FAAP, disclosed that she receives a research grant from the Maternal and Child Health Bureau. ● Richard Sills, MD, FAAP, disclosed that he receives a research grant from Novartis.
contents
PediatricsinReview姞 Vol.32 No.6 June 2011 Articles
223
Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini, Robert L. Rosenfield
230
Speech and Language Development: Monitoring Process and Problems Susan McQuiston, Nancy Kloczko
240
Acid-Base Disorders Mara Nitu, Greg Montgomery, Howard Eigen
252 253
Cover Art Contest Visual Diagnosis: Swelling and Redness of the Fourth Toe in a 3-month-old Infant Charles O. Onyeama, Karla Vitale, Kenneth Cochran, Ginikanwa L. Onyeama
Index of Suspicion
257
Case 1: Status Epilepticus, Hypertension, and Tachycardia in a 5-year-old Boy Case 2: Cardiopulmonary Arrest During Gymnastics Practice in a Teenage Girl Case 3: Acute Renal Failure in a Teenage Boy Who Has Autism and Pica Case 1: Corey Chartan, Elizabeth Aarons Case 2: Aliva De, Steven Fishberger, John Messina Case 3: Ifrah Abdirahman, Steven Arora, Maisa Dekna, Keith K. Lau
Online-Only Article
e66
Abstract appears on page 256. Psychogenic Nonepileptic Seizures (Pseudoseizures) Hema Patel, David W. Dunn, Joan K. Austin, Julia L. Doss, W. Curt LaFrance, Jr, Sigita Plioplys, Rochelle Caplan
Pediatrics in Review威 is supported, in part, through an educational grant from Abbott Nutrition, a division of Abbott Laboratories, Inc.
Cover: The artwork on the cover of this month’s issue is by one of the winners of our 2009 Cover Art Contest, 6-year-old Anne C. of Woodbury, NJ. Anne’s pediatrician is Pierre Coant, MD.
Answer Key:
1. A; 2. E; 3. D; 4. E; 5. B; 6. E; 7. A; 8. D; 9. D; 10. B; 11. E; 12. D; 13. B
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Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini and Robert L. Rosenfield Pediatr. Rev. 2011;32;223-229 DOI: 10.1542/pir.32-6-223
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/32/6/223
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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Article
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Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini, MD,* Robert L. Rosenfield, MD*
Objectives
After completing this article, readers should be able to:
1. Explain how puberty is regulated by the hypothalamic-pituitary-gonadal axis. 2. Describe the hormonal interactions involved in pubertal development in boys and girls. Author Disclosure Drs Bordini and
Introduction
Rosenfield have
Puberty is a defining developmental stage of every child’s life, both physically and psychosocially. Concerns about the normalcy of pubertal development and menstrual patterns are among the most common questions posed to every physician caring for children. This article reviews the primary physiologic changes in the hypothalamicpituitary-gonadal (HPG) axis and in adrenal androgen and growth hormone (GH) production that underlie the normal pubertal milestones. Understanding of these changes allows interpretation of laboratory data in children suspected of having pubertal abnormalities. Puberty is the developmental stage during which a child becomes a young adult, characterized by the maturation of gametogenesis, secretion of gonadal hormones, and development of secondary sexual characteristics and reproductive functions. Adolescence is used widely as a generally synonymous term for puberty, but the term often is used to convey an added connotation of cognitive, psychological, and social change. Thelarche denotes the onset of breast development, an estrogen effect. Pubarche denotes the onset of sexual hair growth, an androgen effect. Menarche indicates the onset of menses and spermarche the appearance of spermatozoa in seminal fluid. Gonadarche refers to the onset of pubertal function of the gonads, which produce most of the sex hormones that underlie the pubertal changes in secondary sex characteristics. Adrenarche refers to the onset of the adrenal androgen production that contributes to pubarche.
disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
The Hormonal Axes Underlying Puberty The Hypothalamic-Pituitary-Gonadal Axis Normal puberty results from sustained, mature activity of the HPG axis. (1). The major hormones of the HPG axis are shown in Figure 1. In response to a single gonadotropinreleasing hormone (GnRH), the pituitary gland releases two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH is secreted by specialized neurons of the hypothalamus in a pulsatile fashion. Pituitary LH and FSH secretion consequently is pulsatile and can be sustained only in response to pulsatile GnRH signals. LH acts primarily on the specialized interstitial cells of the gonads to stimulate formation of androgens, and FSH acts primarily on the follicular/tubular compartment to stimulate formation of estrogen from androgen precursors, inhibin, and gametes. The function of the two compartments of the gonads is coordinated by paracrine regulatory mechanisms. Abbreviations The HPG axis is active during three phases of development: fetal, neonatal, and adult, with puberty being the ACTH: adrenocorticotropic hormone period of transition to mature function. Changes in GnRH DHEAS: dehydroepiandrosterone sulfate secretion underlie the changing activity of the HPG axis. The FSH: follicle-stimulating hormone sexually dimorphic patterns of sex hormone secretion during GH: growth hormone the prenatal and neonatal periods of HPG activity appear to GnRH: gonadotropin-releasing hormone play a role in programming sexually dimorphic patterns of HPG: hypothalamic-pituitary-gonadal behavior, metabolism, and neuroendocrine function in later LH: luteinizing hormone life. *Section of Adult and Pediatric Endocrinology, The University of Chicago Pritzker School of Medicine, Chicago, IL. Pediatrics in Review Vol.32 No.6 June 2011 223
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ingly active again in the late prepubertal period, as central nervous system restraint recedes, followed by an increasing tempo throughout puberty. The gonads account for the most important circulating estrogen (estradiol) and androgen (testosterone). Gonadal function accounts for more than 90% of estradiol production in the female (50% in the male) and more than 90% of testosterone production in the male (50% in the female) (Fig. 2). (4)(5)
Figure 1. The hypothalamic-pituitary-gonadal axis. Hypo-
thalamic neurons release gonadotropin-releasing hormone (GnRH) into the pituitary portal venous system, where it stimulates gonadotropin (luteinizing hormone [LH] and folliclestimulating hormone [FSH]) secretion. LH primarily stimulates specialized interstitial cells (theca cells in the ovary or Leydig cells in the testes) to secrete androgens. FSH primarily stimulates the ovarian follicle or seminiferous tubules to form estrogen, inhibin, and gametes (eggs or sperm). The interstitial and follicular/ tubular compartments act cooperatively through paracrine mechanisms to form estrogen and to regulate sex steroid and gamete development. Sex steroids exert endocrine closed-loop negative feedback effects on GnRH and gonadotropin secretion. Inhibin exerts negative feedback on FSH secretion. In mature females, a critical estradiol concentration for a critical duration exerts a transient positive feedback effect to stimulate the LH surge that initiates ovulation.
The HPG axis is established during the first trimester. Its activity in the second trimester contributes to the establishment of normal penile size and the inguinalscrotal phase of testicular descent. (2)(3) In the latter half of pregnancy, activity is suppressed by the high estrogens elaborated by the fetoplacental unit. The HPG axis promptly functions at a pubertal level in the newborn after withdrawal from maternal estrogens. This “minipuberty of the newborn” is subclinical, except for contributing to genital growth, acne, and transient thelarche in the neonate. HPG function subsequently comes under gradual central nervous system restraint at the end of the neonatal period. The axis is relatively, but not absolutely, dormant throughout childhood, particularly in girls, who have slightly higher FSH concentrations than boys and a few ultrasonographically visible ovarian follicles as evidence of this effect. The HPG axis becomes increas224 Pediatrics in Review Vol.32 No.6 June 2011
Figure 2. Simplified diagram of sex steroid production by
the adult adrenal glands, follicular phase ovaries, and testes. Blood production rates shown are the sum of direct secretion (heavy solid arrows) and peripheral formation from secreted precursors (dotted arrows). Several key steroidogenic enzyme activities expressed in these glands, such as sulfotransferase (SULT), 3-hydroxysteroid dehydrogenase (3), aromatase, and 17-hydroxysteroid dehydrogenase type 5 (17HSD5), are also expressed in peripheral tissues such as liver, fat, and skin. Type 3 17HSD (17HSD3) is only expressed in testes. Peripheral conversion from secreted androstenedione accounts for 50% of testosterone in women, and about 10% of estradiol and DHEAS similarly arise from circulating precursors. Estrone, the intermediate in the pathway from androstenedione to estradiol, is not shown. DHEAⴝdehydroepiandrosterone, DHEASⴝ dehydroepiandrosterone sulfate, A’DIONEⴝandrostenedione
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Adrenarche, the “Puberty” of the Adrenal Gland Adrenarche is actually a re-onset of adrenal androgen production. The fetal zone of the adrenal cortex elaborates large amounts of dehydroepiandrosterone sulfate (DHEAS), which is important as the major substrate for placental estrogen formation during pregnancy. This zone then regresses over the first several postnatal months. Adrenarche is the pseudopuberty of the adrenal gland that begins in mid-childhood as the zona reticularis of the adrenal cortex develops. (1) This zone has the capacity to form 17-ketosteroids, but not cortisol, in response to adrenocorticotropic hormone (ACTH), and DHEAS is the primary endpoint of this biosynthetic pathway. Consequently, although cortisol concentrations and the cortisol response to ACTH do not change from childhood to adulthood, DHEAS values gradually rise from mid-childhood until adulthood. This timeframe coincides approximately with the gonadal androgen production of true puberty, but adrenarche is an incomplete aspect of puberty that is independent of pubertal maturation of the HPG axis. The adrenal gland secretes more than 90% of DHEAS in children and women and more than 70% in adult men, while 50% of testosterone in the female and less than 10% of testosterone in the male is produced by the adrenal. (6) Adrenal androgen concentrations increase to a point sufficient to stimulate apocrine odor and mild acne after about 5 years of age and pubic hair growth after about 10 years of age (Table).
Interactions Between Pubertal Hormones and the Growth Hormone/Insulin-like Growth Factor-I Axis Pituitary GH secretion increases during puberty in response to sex steroids. (1) This rise in GH causes a rise in Table.
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insulin-like growth factor-I concentrations to peaks in late puberty that are above those of adults, sometimes in the adult acromegalic range. Half of the characteristic pubertal growth spurt is due to the direct effect of sex steroids on epiphyseal growth and half to GH stimulation. Conversely, in accord with the general principle that everything grows better with GH, GH is necessary for optimal gonadotropin effects on gonadal growth and sex steroid effects on secondary sex characteristics. For example, selective GH resistance is characterized by small testes and micropenis, poor breast and sexual hair development, and absence of a pubertal growth spurt. (12)
Regulation of the Onset and Progression of Puberty There is no single “trigger” for puberty; rather, puberty results from a gradual increase in GnRH pulsatility that arises from maturation of central nervous system developmental programs that send inhibitory and stimulatory signals to GnRH neurons. (1) Puberty is associated with changing sensitivity of the neuroendocrine system to negative feedback by gonadal hormones. When GnRH secretory activity is low due to central nervous system inhibition in mid-childhood, it is inhibited by trace amounts of sex steroids. Increasing central activation during puberty permits sex steroids to rise to adult concentrations before exerting negative feedback effects. The major GnRH-inhibitory systems are GABAergic and opioidergic; the major excitatory systems involve glutamate and kisspeptin, with glial cells facilitating GnRH secretion. Kisspeptin is a hypothalamic neuropeptide discovered in the search for the molecular basis of hypogonadotropic hypogonadism; it acts as an important signal for pubertal GnRH release via GPR54, a G-protein coupled receptor located on GnRH neurons. It has been estimated that at least half of the varia-
Typical Early Morning Pubertal Hormone Blood Concentrations
Group
LH (IU/L)
FSH (IU/L)
Estradiol (pg/mL)
TT (ng/dL)
DHEAS (g/dL)
Prepubertal 1 to 5 yr Premenarchal females Postmenarchal females** Adult men***
<0.3 <12 2.0 to 11 1.4 to 9.0
<4.0 1.0 to 12 1.0 to 12 1.0 to 9.2
<10 <50 20 to 85 <60
<20 13 to 44 15 to 59 300 to 950
5 to 40* 35 to 130 75 to 255 100 to 460
DHEAS⫽dehydroepiandrosterone sulfate, FSH⫽follicle-stimulating hormone, LH⫽luteinizing hormone, TT⫽total testosterone Conversions to SI units: estradiol⫻3.61⫽pmol/L, testosterone⫻0.0347⫽nmol/L, DHEAS⫻0.0271⫽mol/L Assay-specific ranges may vary. *Prepubertal children 6 to 9 years of age may have adrenarchal DHEAS values up to approximately 70 g/dL **Early follicular phase values given; mid-cycle LH up to 85 IU/L, FSH up to 19 U/L, estradiol up to 350 pg/mL ***Pubertal males values are between and overlap with prepubertal and adult male values Data from Bordini et al, (7) Mortensen et al, (8) Zimmer et al, (9) Mayo Clinical Laboratories, (10) Esoterix Laboratory Services. (11)
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tion in the timing of puberty is genetically determined, and ethnicity is one such factor. (1)(13) Sex hormones, hormonally active environmental chemicals (“environmental disruptors”), (14) diverse somatic stimuli (including nutrition, the growth hormone/insulin-like growth factor system, thyroid hormones), and general health all affect the pubertal process. Pubertal and skeletal maturation appear to have common somatic determinants. Children generally enter puberty when they achieve a pubertal bone age. Pubertal stage normally correlates better with the bone age than with chronologic age. (15) Thus, for example, the onset of breast development normally occurs at a bone age of about 10 years and menarche occurs at a bone age of about 12.5 years, whether the child is 9 or 14 years of age. Optimal nutrition is necessary for initiation and maintenance of normal reproductive function. The hypothesis that a critical amount of body fat is the weight-related trigger for pubertal development originated with the discovery by Frisch and coworkers that weight correlated with pubertal growth and menarche better than it did with chronologic age or height. (16) Early to mid-childhood may be a critical period for weight to influence the onset of puberty. (17) Suboptimal nutrition related to socioeconomic conditions is an important factor in the late onset of puberty in underdeveloped countries. Conversely, obesity is an important factor in advancing the onset of puberty in United States girls. (13) Leptin, a hormone secreted by fat cells, appears to be an important link between nutrition and the attainment and maintenance of reproductive competence. (1) Leptin acts on the hypothalamus to reduce appetite and stimulate gonadotropin secretion. Leptin deficiency causes obesity and gonadotropin deficiency. Blood leptin concentrations rise throughout childhood and puberty to reach higher values in girls than boys. Attainment of a critical threshold appears to signal that nutritional stores are sufficient for mature function of the GnRH pulse generator and, thus, permits puberty. Although prolactin and pineal gland hormones affect puberty in lower animals and can cause pubertal disorders in humans, neither has a clear role in normal human puberty.
Hormonal Changes of Normal Puberty The first hormonal change of puberty is a sleep-related increase in the pulsatile release of LH by the pituitary gonadotropes. FSH is secreted in parallel but increases relatively less. At the beginning of puberty, a unique diurnal variation of pubertal hormones occurs, with little LH secretion during the day and a significant increase in 226 Pediatrics in Review Vol.32 No.6 June 2011
pulsatile secretion during sleep (Fig. 3). (18)(19) In response to nocturnal LH secretion, the pattern of gonadal sex steroid secretion differs between the sexes: ovarian secretion of estradiol peaks in mid-day and testicular secretion of testosterone peaks promptly during sleep. In addition, girls’ pubertal hormone secretion is subclinically cyclic from early puberty. As puberty progresses, LH secretion persists further into the daytime. After menarche, this diurnal variation no longer exists. Adult sex steroid concentrations, however, have a mild diurnal variation, being highest on awakening. The two gonadotropins each act primarily on specific gonadal cell types. LH stimulates the interstitial cells of the ovaries (theca cells) to form androgenic precursors of estradiol and those of the testes (Leydig cells) to secrete testosterone itself. FSH acts on the sex cord derivatives of the ovary (granulosa cells) and testes (Sertoli cells) to stimulate gametogenesis and gonadal growth. In granulosa cells, FSH strongly stimulates aromatase to form estradiol from thecal androgens. As the gonads become increasingly sensitized to gonadotropin stimulation, they grow and secrete sex hormones at steadily increased rates. Within 3 years of rising above the prepubertal range, estradiol increases an average of 20 pg/mL (73.4 pmol/L) yearly to reach the mid-adult range and testosterone increases an average of 100 ng/dL (3.47 nmol/L) yearly to reach the lower adult range (Table). (20) These concentrations then gradually induce their effects. The hormonal increases culminate in positive feedback in girls, which refers to the female neuroendocrine system becoming capable of secreting a mid-cycle surge of LH when the ovary signals that it is prepared for ovulation via a critical and sustained level of estrogen secretion. Estrogen stimulates the classic female target tissues: the female genital tract (eg, endometrial growth, cervical mucus secretion) and breasts. Androgen stimulates the classic male target tissues (eg, sexual hair and sebaceous gland). Both stimulate sexual drive and function. Both sex steroids account for the pubertal growth spurt, directly and indirectly via growth hormone. Both directly stimulate epiphyseal growth and epiphyseal maturation, which is indexed by bone age radiographs and peak bone mass accrual. (21) However, they differ in some of their effects on skeletal growth. Androgen is responsible for the wider bones (the laryngeal enlargement accounting for the pubertal voice change), while estrogen is ultimately necessary for epiphyseal fusion and is the more potent inhibitor of bone resorption. They also affect growth of a wide variety of other somatic tissues. During puberty, estrogen promotes lipogenesis and lower body
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Figure 4. Diagram of average gonadotropin and sex steroid
concentrations during the normal menstrual cycle. The data are centered in reference to days before (ⴚ) or after (ⴙ) the day of the mid-cycle surge of luteinizing hormone (LH). The gonadotropin concentrations are typical of polyclonal radioimmunoassay, and the baseline values are about twice as high as those obtained by current monoclonal assays. Mⴝmenses begin, E2ⴝestradiol, PROGⴝprogesterone. Reprinted with permission from Rosenfield et al. (1)
Figure 3. Pubertal hormone rhythms. In an early pubertal girl
(top panel), luteinizing hormone (LH) secretion is minimal during waking hours. Pubertal LH pulsations promptly begin with sleep onset and wane with sleep offset, followed several hours later by increased ovarian estradiol secretion that peaks mid-day. Reprinted with permission from Boyar et al. (18) Copyright 1976, The Endocrine Society. In an early pubertal boy (bottom panel), daytime LH values are low, with minimal testosterone secretion. Pubertal LH pulsations begin promptly with sleep onset and cease with sleep offset; testosterone secretion occurs primarily during sleep, beginning about 2 hours after LH increases and waning on awakening. Reprinted with permission from Judd et al. (19) Copyright 1974, The Endocrine Society. Panels are modified by aligning times. This figure demonstrates the clinical importance of considering diurnal and pulsatile hormone secretion in evaluating pubertal status. First, because of diurnal rhythmicity, daytime hormone values during early puberty are not representative of the 24-hour production of pubertal hormones, as indicated for LH in this girl (breast stage 3) and for testosterone and gonadotropins in this boy (stage 2). Second, because of the episodic pulsatile nature of gonadotropin and sex steroid secretion, hormone values may differ markedly within 1 hour. The gonadotropin concentrations were determined by earlygeneration radioimmunoassays, and the baseline values are higher than those obtained by current assays.
fat distribution. In contrast, androgens generally are lipolytic, although they favor the development of visceral fat stores, and promote muscular development. The similar increase of body mass index during puberty in girls and boys, thus, is due to differences in body composition, with a higher percent being body fat in girls and lean body mass in boys. (22) The menstrual cycle arises from cyclic maturation of ovarian follicles that result in cyclic changes in sex hormones, particularly estradiol and progesterone, which entrain cyclic changes in gonadotropin concentrations (Fig. 4). The biologic goal of this monthly variation is to select and nurture one dominant follicle to the point of ovulation for potential fertilization. A normal average 28-day cycle consists of two phases: the follicular phase (variable in duration, averaging 14 days at maturity) and the luteal phase (14⫾1 SD days), with the latter occurring only in ovulatory cycles. The follicular phase begins with the onset of menses and culminates in the mid-cycle LH surge, which induces ovulation from the follicle. The empty follicle forms the corpus luteum, initiating the luteal phase. Progesterone increases steadily to be sustained at very high levels for several days, along with lesser but substantial increases in estradiol. Progesterone and estradiol secretion from the corpus luteum maintain the endometrial layer of the uterus in preparation for potential pregnancy. If pregnancy does not occur, with its resultant increase in human chorionic gonadotropin, Pediatrics in Review Vol.32 No.6 June 2011 227
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the corpus luteum life span is exhausted, which results in withdrawal of female sex steroids, followed by endometrial sloughing and menstrual flow. Assessment of pubertal hormone concentrations requires reliable hormone assays in addition to consideration of the diurnal changes of early puberty and cyclic changes in girls. Although early pubertal children have greater average hormone concentrations than prepubertal children, their values still are much less than those of adults (Table). (7)(8)(9)(10)(11) The widely available, older generation of polyclonal antibody-based radioimmunoassays for gonadotropins do not possess sufficient sensitivity and specificity for optimal diagnosis of pubertal disorders. The modern multichannel platform assays available in many community hospitals are generally adequate for these purposes, as indicated by sensitivities of 0.1 to 0.15 U/L for LH and FSH. These platform assays are also reliable for DHEAS assays. On the other hand, platform assays are very unreliable for measuring testosterone and estradiol at the relatively low values that are normal for pubertal children and women. The practitioner should not order these tests unless provision can be made to assay them by accurate methodology, preferably in consultation with a pediatric endocrinologist. (23) Daytime pubertal hormone concentrations may not indicate the early stages of puberty accurately because of diurnal and cyclic variations (Fig. 3). For this reason, GnRH-stimulated values may be necessary to diagnose pubertal disorders. A peak LH value greater than approximately 4.0 U/L in response to GnRH or GnRH agonist testing has been suggested as indicative of the onset of puberty. (24)(25) Part II of this article, which deals with the clinical aspects of puberty, will be published in the July issue of Pediatrics in Review.
Summary All of the following are based on strong research evidence: • The neuroendocrine control of puberty follows the hierarchy of most other hormone systems: hypothalamic-pituitary-target gland (ie, gonads). • The exact mechanisms that awaken the HPG axis from its childhood quiescence remain unknown, but new neuroendocrine pathways have been recognized. • Pubertal hormones not only bring about the maturation of secondary sexual characteristics and reproductive capacity, but they have important neuroendocrine effects and somatic effects on growth and body composition.
228 Pediatrics in Review Vol.32 No.6 June 2011
References 1. Rosenfield RL, Cooke DW, Radovick S. The ovary and female maturation. In: Sperling M, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: Elsevier; 2008:530 – 609 2. Rosenfield RL, Lucky AW, Allen TD. The diagnosis and management of intersex. Curr Probl Pediatr. 1980;10:1– 66 3. Thorup J, McLachlan R, Cortes D, et al. What is new in cryptorchidism and hypospadias—a critical review on the testicular dysgenesis hypothesis. J Pediatr Surg. 2010;45:2074 –2086 4. Rosenfield RL. Role of androgens in growth and development of the fetus, child, and adolescent. Adv Pediatr. 1972;19:171–213 5. Kelch RP, Jenner MR, Weinstein R, Kaplan SL, Grumbach MM. Estradiol and testosterone secretion by human, simian, and canine testes, in males with hypogonadism and in male pseudohermaphrodites with the feminizing testes syndrome. J Clin Invest. 1972; 51:824 – 830 6. de Peretti E, Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab. 1978;47: 572–577 7. Bordini BD, Littlejohn EE, Rosenfeld RL. Blunted sleep-related LH rise in healthy premenarcheal pubertal girls with elevated body mass index. J Clin Endocrinol Metab. 2009;94:1168 –1175 8. Mortensen M, Ehrmann DA, Littlejohn E, Rosenfield RL. Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population. J Clin Endocrinol Metab. 2009;94:1579 –1586 9. Zimmer CA, Ehrmann DA, Rosenfield RL. Potential diagnostic utility of intermittent short-acting GnRH agonist administration in gonadotropin deficiency. Fertil Steril. 2010;94:2697–2702 10. Mayo Medical Laboratories. Reference Laboratory Services for Health Care Organizations. Rochester, MN: Mayo Clinic; 2010. Accessed March 2011 at: www.mayomedicallaboratories.com 11. Esoterix Laboratory Services. Endocrinology Expected Values and S.I. Unit Conversion Table. Calabasas Hills, CA: Esoterix Laboratory Services, Inc; 2010. Accessed March 2011 at: www. esoterix.com 12. Laron Z. Growth hormone insensitivity (Laron syndrome). Rev Endocr Metab Disord. 2002;3:347–355 13. Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index. Pediatrics. 2009;123:84 – 88 14. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30:293–342 15. Marshall W. Interrelationships of skeletal maturation, sexual development and somatic growth in man. Ann Human Biol. 1974; 1:29 16. Frisch R. Body fat, puberty, and fertility. Biol Rev Camb Philos Soc. 1984;59:161–188 17. Papadimitriou A, Nicolaidou P, Fretzayas A, Chrousos GP. Clinical review: constitutional advancement of growth, a.k.a. early growth acceleration, predicts early puberty and childhood obesity. J Clin Endocrinol Metab. 2010;95:4535– 4541 18. Boyar RM, Wu RHK, Roffwarg H, et al. Human puberty: 24-hour estradiol patterns in pubertal girls. J Clin Endocrinol Metab. 1976;43:1418 –1421 19. Judd HL, Parker DC, Siler TM, Yen SS. The nocturnal rise of plasma testosterone in pubertal boys. J Clin Endocrinol Metab. 1974;38:710 –713
Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on June 3, 2011
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20. Faiman C, Winter JSD. Gonadotropins and sex hormone
23. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position
patterns in puberty: clinical data. In: Grumbach M, Grave C, Mayer F, eds. The Control of the Onset of Puberty. New York, NY: John Wiley & Sons; 1974:32– 61 21. Cooper C, Westlake S, Harvey N, Javaid K, Dennison E, Hanson M. Review: developmental origins of osteoporotic fracture. Osteoporos Int. 2006;17:337–347 22. Deurenberg P, Yap M, van Staveren WA. Body mass index and percent body fat: a meta analysis among different ethnic groups. Int J Obes Relat Metab Disord. 1998;22:1164 –1171
statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:405– 413 24. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123:e752–762 25. Bordini BD, Littlejohn EE, Rosenfield RL. LH dynamics in overweight girls with premature adrenarche and slowly progressive sexual precocity. Int J Pediatr Endocrinol. 2010;2010:724696
PIR Quiz Quiz questions also available online at http://pedsinreview.aappublications.org. 1. Which of the following statements about normal puberty in children is true? A. Bone age correlates better with pubertal development than chronologic age. B. Gonadotropin-releasing hormone (GnRH) secretion in response to negative feedback from sex steroids is constant throughout life. C. Growth hormone secretion is the sole determinant of the pubertal growth spurt. D. Menarche is the first stage of puberty in girls. E. Normal pubertal development is unrelated to nutritional status. 2. Which of the following statements best describes adrenarche? A. B. C. D. E.
Breast development becomes evident in girls. Hypothalamic production of adrenocorticotropin hormone increases. Maternal estrogens are withdrawn, causing neonatal acne. Spermatozoa begin to appear in seminal fluid. The adrenal gland increases production of dehydroepiandrosterone sulfate.
3. Which of the following is the primary action of luteinizing hormone? A. B. C. D. E.
Secretion of follicle-stimulating hormone. Secretion of GnRH from the pituitary gland. Stimulation of gametogenesis in the testes. Stimulation of the gonads to produce androgens. Stimulation of the ovarian follicle to produce estrogen.
4. At which of the following phases of the menstrual cycle is the concentration of progesterone the highest? A. B. C. D. E.
The The The The The
beginning of the follicular phase. beginning of the luteal phase. end of the luteal phase. middle of the follicular phase. middle of the luteal phase.
HealthyChildren.org Parent Resources from AAP 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/ages-stages/gradeschool/ puberty/Pages/default.aspx.
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Normal Pubertal Development: Part I: The Endocrine Basis of Puberty Brian Bordini and Robert L. Rosenfield Pediatr. Rev. 2011;32;223-229 DOI: 10.1542/pir.32-6-223
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Speech and Language Development: Monitoring Process and Problems Susan McQuiston and Nancy Kloczko Pediatr. Rev. 2011;32;230-239 DOI: 10.1542/pir.32-6-230
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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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Article
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Speech and Language Development: Monitoring Process and Problems Susan McQuiston, PhD,* Nancy Kloczko, MD†
Author Disclosure Drs McQuiston and Kloczko have
Objectives
After completing this article, readers should be able to:
1. Describe the progression of normal speech-language development. 2. Recognize delayed and disordered speech-language development and indications for referral. 3. Understand possible biologic and environmental contributions to delayed language. 4. Implement appropriate management strategies.
disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.
Case Study You are seeing a 21⁄2-year-old boy for a routine health supervision visit. On a general developmental screening questionnaire, his mother reports that he is not yet talking. She has not been too concerned because the child’s father was a late talker and they live in a bilingual household. Although the boy has had several episodes of otitis media, she feels strongly that there is no question of hearing loss because he seems to understand what is said to him. Other domains of development are reported as age-appropriate. His physical examination results are normal, and he appears to be a socially engaging toddler. However, you have concerns about his apparent low frustration tolerance and tendency to throw tantrums.
Introduction It has been said that all typically developing children in all cultures master the basics of their language by 4 years of age. (1) However, 5% to 8% of children experience speech-language delays or disorders by the preschool years, which may be associated with later learning, socioemotional, or behavioral problems. The primary clinician often is the first professional to whom parents turn when a developmental problem is suspected, and in the course of routine health supervision visits, the clinician may encounter any of the following language-related questions or concerns: ●
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The parents of a 9 month old wonder what language and social skills should be present at this age, and they have heightened concern because an older sibling has autism. The parents of a 12 month old wonder if their child is hearing impaired because he rarely responds to his name. The parents of an 18 month old who has a history of recurrent ear infections ask if those infections will affect their child’s language development. A 20 month old is reported to have lost the words he was using previously. The mother of a 2 year old reports that her child is not talking as much as her older siblings did at the same age. The parents of a 3 year old report that their child’s speech is very hard to understand and they wonder if this is normal. The father of a 31⁄2 year old expresses concern that his child has started stuttering. The parents of a 51⁄2 year old report that their son failed his kindergarten screening because he did not recognize letters of the alphabet; they wonder if kindergarten entry should be delayed a year.
This article provides a brief review of normal speech and language development from the discrimination and production of speech sounds to the comprehension and use of language for functional communication to the eventual development of reading and written language. The clinical presentation, epidemiology, and prognosis of specific speech *Pediatric Psychologist. † Developmental-Behavioral Pediatrician, Baystate Children’s Hospital, Springfield, MA. 230 Pediatrics in Review Vol.32 No.6 June 2011
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and language disorders is described, and the possible role of biologic and environmental influences on language development are considered. Finally, the clinician’s role in surveillance, screening, and management of language delays or disorders is reviewed.
Milestones in the Development of Normal Speech and Language Speech Discrimination and Receptive Language Language development involves a complex interaction between biology and environmental experience. Typical infants come into the world with many of the foundational skills necessary for learning language, including the capacity to hear speech sounds, recognize speech contrasts, and prefer some sounds (human) over others (inanimate). Speech discrimination and the production of early speech sounds form the basis of oral language and communication. Although children are born with the capacity to detect speech sound differences, their speech perception abilities become more specialized and efficient over the first postnatal year. Their ability to discriminate sounds within their native language becomes more refined, and they become less capable of discriminating nonnative speech sounds that are not relevant to the learning of their primary language. For example, infants raised in an English-speaking environment continue to discriminate the difference between the /r/ and /l/ sounds, but the ability to hear this distinction wanes in children who are learning Japanese. English contains 45 distinct speech sounds (phonemes); experience in hearing the language shapes and sensitizes the child’s speech discrimination skills to those specific sounds. By 8 months of age, infants begin to recognize the boundaries around words embedded within utterance streams; that is, they begin to extract and segment words from speech, a necessary prerequisite to single-word recognition, comprehension, and production. This capacity corresponds to the onset, between 8 to 10 months of age, of single-word comprehension. One of the earliest words the child recognizes is his or her name, a skill that develops as early as 6 months. Shortly thereafter, the infant responds appropriately to names for primary caregivers. Contextually specific words that are part of familiar routines are present by 9 months (eg, no, no; wave bye-bye; play pat-a-cake). From there, single-word receptive vocabulary builds exponentially. Parents (and pediatricians) often are surprised to learn of the size of the single-word receptive vocabulary expected of the average 15-month-old child (150 to 200 words). By 18 months, most parents report that
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their child understands more words than they can count. Typically, children understand far more than they are able to express in the early years of language acquisition.
Early Speech Production, Communicative Gestures, and the Emergence of Expressive Language Early language development proceeds through predictable stages from the early production of vowel sounds in the first few postnatal months (cooing) to the emergence of consonant-vowel sounds by 6 months (babbling), the production of long consonant-vowel strings between 6 and 10 months (a skill known as canonical babbling), the emergence of first words between 9 and 15 months, and finally the combining of words in meaningful and intentionally communicative ways between 18 and 24 months. Just as infants are born with the capacity to hear and discriminate speech sounds, they come into the world prepared to vocalize and eventually to form words and sentences. Oral expression is preceded by intentional, nonverbal communicative gestures such as pointing, showing, and giving, which emerge at approximately 9 months and have been shown to be predictive of receptive and expressive language at age 2 years. Canonical babbling sets the stage for the formation of words and is a precursor to the development of meaningful speech. Delays in the onset of canonical babbling have been associated with both hearing impairment and delayed language development. (2) Clinicians should probe specifically for the onset of canonical babbling when infants are between 6 and 12 months of age. Jargon emerges as infants begin to combine a variety of consonant-vowel sounds with speechlike inflection. As jargon matures, intelligible words are inserted within complex vocal strings. By the time a “critical mass” of approximately 50 words has been achieved at around 18 months, most children experience a vocabulary burst. Between 18 and 24 months, they begin to construct two-word utterances, and the content of their language expands to include not only nouns but verbs and adjectives. By age 3 years, children should be producing threeword utterances, their speech should be 75% intelligible, and vocabulary size should approach 1,000 words. At this stage, children are still mastering production of specific speech sounds, some of which are not wellarticulated until 6 to 8 years of age (eg, /l/, /r/, /s/, /z/, /th/). However, speech should be fully intelligible by age 4 years, when children typically are speaking in Pediatrics in Review Vol.32 No.6 June 2011 231
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sentences, relating experiences, and participating in reciprocal conversations. The age of acquisition of many receptive and expressive language milestones varies (Table 1). For example, in one study, the average word production of 2-year-old children was 312 words, but the range was 7 to 668 words. (3) One factor that has been shown to account for this variability is the amount of language to which children are exposed in the early years of language learning. In an often-cited study of the early language experience of children from different socioeconomic backgrounds, children in economically disadvantaged homes were found to have far less exposure to language and less varied verbal interactions with others in the home than children from advantaged homes. (4) On average, children in advantaged homes were exposed to 215,000 words over the course of 1 week versus 62,000 words in the disadvantaged group. The content of the language directed to the children also differed significantly between the two groups, such that children in economically advantaged homes heard many more approving than disapproving statements over the course of an hour, while the pattern was reversed for children in disadvantaged homes. The more parents talked to their children, the more rapid was the child’s vocabulary growth. By age 3 years, children from advantaged homes had a vocabulary of 1,100 words compared with an average of 525 words for children from disadvantaged families.
Early Literacy Skills and the Emergence of Reading and Written Language The process of reading symbols and connecting those symbols to sounds, sounds to words, and words to meaning is the product of thousands of years of human evolution and brain development. By kindergarten age, typically developing children have acquired the “alphabetic principle”: the understanding that written symbols (letters) correspond to speech sounds. The process requires an ability to attend to the sounds of language, segment sounds within words, and connect individual sounds with their corresponding visual symbols. Just as the richness of the child’s language environment is associated with vocabulary development, the amount of time spent reading aloud to children has been linked to later reading proficiency. Reach Out and Read (ROR), a pediatrics-based intervention in which children are given an age-appropriate book at each health supervision visit and parents receive anticipatory guidance about the importance of reading to young children, has proved to be one of the most effective strategies to 232 Pediatrics in Review Vol.32 No.6 June 2011
support early literacy and language development (www. reachoutandread.org). A series of studies has demonstrated that families participating in ROR report that they are more likely to read to their children and describe reading aloud as a preferred parenting activity. Exposure to ROR has been associated with higher receptive and expressive language scores in toddlers. (5) More research is needed to assess long-term efficacy in promoting language skills and literacy in later school years.
Delayed Versus Disordered Language Development Determining whether a developmental difference is significant and warrants further evaluation and intervention is one of the clinician’s greatest challenges. There is no generally agreed-upon standard for what constitutes a developmental language delay, and clinicians should consider data from multiple sources (history, screening tools, and clinical judgment) in determining which children are delayed or at risk. Parental concern should be acknowledged and is, in itself, sufficient reason for closer examination of the child’s status. Parental worry about language status in the toddler and preschool-age child has been associated with delayed expressive language development. The term “language disorder” refers to a deficit in the comprehension or production of language that causes clinically significant impairment in functioning relative to developmental norms and cultural expectations. A child who has a developmental language delay may or may not develop a speech-language disorder, depending on the severity of the delay and whether it causes significant impairment in functioning. The clinician may identify a child at risk or one who is presenting with delayed language development, but the speech-language clinician usually determines whether a delay is clinically significant or constitutes a disorder. Prevalence studies suggest that 13% to 18% of 11⁄2- to 3-year-old children present with late talking or expressive language delays. (6) At 4 years, approximately 50% of late talkers still present with language difficulties. Current screening measures do not predict reliably persistent language delay versus maturational lag followed by recovery. Factors that have been associated with early delays in expressive language include family history of language delay, low socioeconomic status, and the richness of the language environment. (6) Of those who continue to manifest speech-language delays, many require specific intervention. Early intervention programs often set a percent delay standard to determine eligibility, which typically is 20% to 30% below
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Table 1.
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Language Milestones
Age
Receptive
Expressive
Birth to 3 Months
• Attends to voices/sounds (may quiet, vary suck pattern) • Shows preference for parental voice • May orient to voice by turning eyes or head • Startles/blinks/cries to loud sounds • Works to localize voices/sounds • Responds to change in tone/emotion • Enjoys rattles/ toys that make noise • Responds to own name (6 months) • Looks to family member when named • Begins to understand words and picture names • Understands basic concepts such as “no,” “all gone,” “bye-bye” • Understands verbal cues for practiced routines (eg, “peek-a-boo”) • Recognizes words for common items • Responds to simple requests (“come here,” “give me”) • Looks when name is called • Receptive vocabulary by 12 months: ⬃70 words • Follows one-step direction • Shakes or nods head appropriately • Points to body part when named (15 months) • Rapidly increases receptive vocabulary • Understands simple pronouns (“you,” “me”) • Points to objects/pictures (18 months) • Recognizes common objects by name
• Has differential cries • Vocalizes (coos, gurgles) • Reciprocally vocalizes
3 to 6 Months
6 to 9 Months
9 to 12 Months
12 to 15 Months
15 to 18 Months
18 to 24 Months
• Follows two-step directions • Enjoys simple stories, being read to
24 to 30 Months
• Understands pronouns (“you,” “me,” “my,” “mine”) • Understands some prepositions (eg, in, on, under) • Identifies objects by use
30 to 36 Months
• Follows 2- to 3-step directions • Understands most common objects and pictures • Able to point to different actions in pictures • Identifies several colors • Listens with interest to conversations, longer stories • Points to object by category • Understands concepts of relative amount/ size • Understands past tense
36 to 48 Months
48 to 60 Months
• Exhibits vocal play with emotional content • Babbles, single syllables (/p/, /b/, /d/, /m/) • Babbles, strings of syllables with intonation (canonical babbling) • Uses “mama,” “dada” nonspecifically • Uses “mama,” “dada” specifically • Points with index finger • Gestures to communicate (reaches to be picked up, waves bye) • Imitates speech sounds • Uses 1 or 2 true words • Jargoning with tone and rhythm of speech • Shaking or nodding head appropriately • Use of 3 to 6 words • Repeats words • Says “no” • Uses 5 to 50 words mixed with jargon • Uses words for wants/needs • Learns new words weekly • Experiences a language “explosion,” learning new words daily • Uses two-word phrases/telegraphic speech • Begins to use simple pronouns • Has an average vocabulary of 200ⴙ words by 2 years • Speech ⬃50% intelligible by 2 years • Has decreased jargon and repeating • Commonly uses 2- to 3-word sentences • Increasingly uses pronouns; some adjectives, adverbs, prepositions • Asks simple questions • Joins songs/nursery rhymes • Answers questions • Helps to tell simple story • Average vocabulary: 900 to 1,000 words • Uses 4- to 5-word sentences by 3 years • Speech ⬃75% intelligible by 3 years • Uses 5- to 6-word sentences by 4 years • Can state name, age, sex • Talks about experiences • Has fully intelligible speech by 4 years • Uses complex sentence structure and includes much detail • Uses irregular past tense, future tense • Tells longer stories, staying on topic • Can rhyme words and use some letters and numbers
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chronologic age in one or more domains of development. Many speech-language pathologists use a criterion of 1.25 standard deviations below the mean on standardized measures or below the 10th percentile as a clinical cutoff for identifying a child in need of therapeutic services. These criteria identify a delay or lag in skill mastery relative to some agreed-upon norm. There are various classification systems for speech and language disorders. The Diagnostic and Statistical Manual of Mental Health Disorders-Fourth Edition (DSM-IV) distinguishes among expressive language, mixed receptive-expressive language, and speech production problems (phonologic disorder and stuttering) that interfere with social, academic, or occupational functioning and are not solely the result of environmental deprivation or another disorder (eg, pervasive developmental disorder, intellectual disability, sensory deficit). (7) Speech-language professionals expand the classification system.
Specific Language Impairment Specific language impairment (SLI) refers to a disorder of oral language acquisition in the absence of environmental deprivation, deficits in nonverbal cognitive ability, hearing loss, autism, or other identified neurologic conditions. Recent research suggests, however, that children in whom SLI is diagnosed often have other, more subtle, deficits in nonlanguage areas of functioning relative to normal controls. (8) Children who have SLI have difficulty understanding and using syntax and grammar, such as tense markings, plurals, and possessives. Problems comprehending and formulating responses to open-ended questions (eg, why, what, and how) compromise their ability to participate in sustained conversation. Many children who have SLI eventually have trouble comprehending what they read. Although its cause is unknown, SLI is presumed to be a biologically based neurodevelopmental disorder. Early signs of SLI include late onset of first words and phrases, immature or delayed mastery of the rules of grammar, and short utterance length relative to peers. Symptoms of SLI usually present in the preschool years, and by kindergarten age, an estimated 7% of children have SLI. Interestingly, in a prevalence study, only 29% of the parents of kindergartners in whom SLI was diagnosed had ever been told that their child had a significant speechlanguage problem. (9) The clinician’s role in early detection and timely referral is underscored by the significant morbidity associated with persistent speech-language disorders and the efficacy of appropriate treatment. 234 Pediatrics in Review Vol.32 No.6 June 2011
Phonologic Disorder Phonologic disorder refers to impaired ability to articulate the speech sounds expected for age and developmental level to a degree that negatively affects communicative functioning. The speech production deficit may involve errors of omission (eg, failing to produce beginning or ending consonant sounds: banana⫽ “nana”), errors of commission (substituting one sound for another: thumb⫽“fum”), or errors in the sequencing of sounds (spaghetti⫽“pasghetti”). As described earlier, mastery of all speech sounds in English does not occur until about 8 years of age, but speech should be fully intelligible by 4 years. Moderate-to-severe phonologic problems occur in approximately 2% to 3% of young school-age children. (10)
Childhood Apraxia of Speech Childhood apraxia of speech (CAS) refers to a severe and persistent speech intelligibility disorder marked by an impaired ability to imitate and spontaneously produce speech sounds in isolation or sequentially. The problem is believed to stem from central nervous system-based mechanisms that control the planning, sequencing, and coordination of oral-motor movements for speech. The cause is unknown, but genetic transmission is suspected. Prevalence estimates range from 0.1% to 1%. (11) The typically affected child is a quiet baby who has delayed babbling and limited jargoning. Unlike the child who has phonologic disorder, whose articulation errors often are predictable and consistent, CAS is characterized by irregular and inconsistent speech production patterns. The diagnosis is difficult and should be made by a qualified speech-language pathologist after review of the child’s history; careful examination of oral-motor functions; and thorough assessment of receptive, expressive, and speech production skills. Intensive individual treatment usually is required, and most children improve, although many continue to have some difficulty with higher-level language function.
Stuttering and Developmental Dysfluency A period of developmental dysfluency is not uncommon among 2 and 3 year olds in which they repeat a phrase (“I want, I want, I want some juice”), a word (“I, I, I want some juice”), or even a part of a word (“Wa, wa, want some juice”). This tendency is associated with the rapid increase in speech production around this age and usually resolves by age 4 years. Clinicians should reassure parents of toddlers and preschoolers that this is a normal developmental pattern that typically resolves without treatment. Parents should be cautioned against inter-
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rupting, filling in, or offering prompts to the child (eg, “Slow down,” “Take your time” ) or placing children in situations in which they are pressured to speak. In contrast, stuttering refers to a clinically significant impairment in speech fluency and timing that involves speech sound repetitions, prolongations, and pauses, sometimes accompanied by interruptions in air flow and face or body clenching. The individual may actively avoid certain words and substitute others that are less problematic. Stuttering occurs in approximately 1% of school-age children and is three times more common in boys than girls, with a strong family influence. (7) Onset is usually around 4 to 5 years and almost always before age 10 years. Treatment is effective and involves targeting not only the speech production problem itself but the associated attitudinal and emotional issues that accompany the disorder. Like CAS, remediation of stuttering requires direct speech therapy.
Dysarthria Dysarthria is a disorder involving motor control of muscles required for speech production. Seen in disorders such as cerebral palsy, muscle disorders, and acquired brain injury, this disorder is characterized by abnormalities of tone, strength, or coordination of facial, oralmotor, and respiratory muscles, resulting in speech that is labored and disordered. Speech therapy is indicated, and if the disorder is severe, augmentative communication may be appropriate.
Dyslexia Dyslexia refers to a significant deficit in the ability to recognize words in print and to spell at the age-expected level in spite of adequate cognitive ability, motivation, and appropriate reading instruction. The core deficit most often is impairment in phonologic processing, including difficulty recognizing sounds within words, failure to master sound-symbol relationships, inability to remember and repeat sound sequences, and slow naming of letters and objects. Poor phonemic awareness (the ability to recognize the discrete sounds or phonemes within words) and slow naming of letters are two of the best predictors of later reading problems. Approximately 8% of second graders have a reading disability. (12) Genes are implicated, and children who have a family history of reading disorder are significantly more likely to have reading problems relative to the general population. Early recognition of reading problems is essential because failure to acquire literacy skills in the primary grades is associated with persistent reading problems and school dropout.
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Special Conditions Hearing Impairment Auditory input is critical for organizing the neural pathways associated with speech. This development requires both an intact mechanism for sound perception (intact auditory sensory system) and a languagerich environment. Vocalizations in the first 6 postnatal months are similar in infants who have intact or impaired hearing. Canonical babbling should emerge between 6 and 10 months, and if it does not, hearing impairment must be a primary diagnostic consideration. Infants who have mild-to-profound sensorineural hearing deficits identified early in life and receive appropriate treatment have significantly better language than those identified later in life. (13) Currently, all states have programs for universal newborn hearing screening, with the goal being to complete diagnostic audiologic testing and appropriate medical evaluation by 3 months of age and to assure access to early intervention services not later than 6 months of age. Amplification, if indicated, should occur within 1 month of diagnosis and consideration for cochlear implantation, if appropriate, by 12 to 24 months, depending on the degree of hearing loss. Otitis media with effusion (OME) is common in young children, with most children experiencing this disorder before school years. OME usually results in minimal-to-mild conductive hearing loss, and studies indicate that this level of mild and probably fluctuating deficit does not significantly impair long-term language development for children who are otherwise healthy and not at risk for developmental problems. (14) Hearing assessment as well as speech-language evaluation should be undertaken if the child has OME in the setting of risk factors for communication or academic problems. In addition, because a small proportion of children may have a hearing loss in the moderate range, hearing testing should be performed if effusions persist for 3 months or longer or at any time if delays or hearing impairment is suspected.
Bilingual Language Development A child biologically prepared for normal acquisition of one language is capable of learning a second. Exposure to two languages can occur simultaneously or sequentially, and the learning processes associated with these are somewhat different. With simultaneous exposure to two languages, a child follows the same developmental schedule as a monolingual learner but incorporates elements from both languages. First words may emerge slightly later but still occur within the normal range. Some Pediatrics in Review Vol.32 No.6 June 2011 235
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mixing of words or grammatical rules may occur until the languages are differentiated, often not until ages 3 or 4 years. With sequential learning, mastery of the primary language is important because it provides the foundation for learning the second language. The amount of exposure and the child’s motivation and temperament affect how rapidly the second language is learned. There is consensus among many researchers in the field that bilingualism in the context of normal language learning potential does not cause language delay. Evaluation of the bilingual child who has delayed speechlanguage milestones should use the same criteria as for monolingual children. When a child has weak primary language skills or recognized delay, the family should be encouraged to use the child’s dominant language at home.
Autism and Genetic Syndromes The language skills of children who have autism spectrum disorders vary widely from those who are nonverbal and require augmentative and alternative communication to those who are very verbal but have difficulty using language for social communication. Most children who have autism spectrum disorder have some level of speechlanguage delay, and approximately 25% to 30% have a history of language regression, which occurs usually between 15 and 24 months of age. (15) Developmental regression at any age is an automatic indication for referral. The cognitive phenotypes in many genetic syndromes (eg, William, Turner, velocardiofacial) include impairments in the social or pragmatic use of language, even in the face of normal acquisition of early language milestones. Klinefelter syndrome is associated with deficits in language processing and language-based academic skills. Individuals who have primary intellectual disabilities (eg, Down syndrome) present with speech-language delays commensurate with their cognitive functioning.
Identification and Management of Delayed or Disordered Language Surveillance and Screening The primary care clinician may be the only professional who has regular contact with children before school entry and, therefore, has responsibility for collaborating with parents to enhance their child’s development and to identify the early indications of problems. The American Academy of Pediatrics recommends that surveillance, the ongoing process of assessing the child’s development and behavior, be performed at all health supervision visits. In addition, a formal screening instrument should be administered at the 9-, 18-, and 30-month visits or at 24 months if patients will not be seen at 30 months. 236 Pediatrics in Review Vol.32 No.6 June 2011
Many general screening tools have been identified that vary in age applicability, administration time, and psychometric properties. (16) Because language development provides the best early correlate to cognitive development and because communication delays can result in significant comorbid dysfunction, a child’s speech and language functioning should be a major consideration in surveillance and screening. A mnemonic to aid the pediatric clinician in monitoring speech and language development is offered in Table 2. The anticipatory guidance that clinicians provide at health supervision visits should include information regarding normal language development and expected milestones so that parents can be informed historians who participate in the developmental surveillance process. The United States Preventive Services Task Force recently reviewed data and found insufficient evidence at this time to recommend either for or against the routine use of specific speech and language screening tools for preschool-age children in the primary care setting. (17) Evidence was insufficient, in part, because a “gold standard” for screening is difficult to define in light of inconsistent measures and terminology. Some frequently occurring risk factors were noted and included positive family history, perinatal indices (eg, prematurity, low birthweight), and male sex, but findings were inconsistent. Children who have obvious risk factors, such as hearing impairment, craniofacial abnormalities, and syndromes associated with known language impairment, warrant direct referral for evaluation and intervention.
Referral and Treatment When a speech-language problem is suspected, the clinician should make simultaneous referrals for audiologic and speech-language evaluations. If the child is younger than age 3 years, a referral should be made to the local early intervention program; if 3 years or older, referral should be to the public school early childhood program. If a speech-language problem occurs in the context of global developmental delay or there are concerns about the quality of the child’s social interaction suggesting an autism spectrum disorder, further diagnostic evaluation is indicated. The clinician should educate parents about the importance of a language-rich environment, which includes child-directed conversation, early reading, vocabulary building, and responding contingently to the child’s emerging use of language for communication. Parents should be guided in understanding the importance of
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Speech and Language Development Mnemonic*
Table 2.
⁄ Year
1 2
• Parts of words (babbling) 1 Year • 1 word • Follows 1-step direction • Index finger pointing 11⁄2 Years • “Between words and sentences” – Jargons with words included – Lots of gestural communication (nods, shakes head, points, uses facial expressions) 2 Years • 2-word sentences • Follows 2-step directions • ⬃200 words • Speech 1⁄2 intelligible
speech and language
their active role in collaborating with clinicians and supporting their child’s development at home.
Case Study Discussion This 21⁄2-year-old boy clearly has delayed expressive language development that requires further evaluation. It is important to explain to his mother that his failure to talk cannot be assumed to be due to the history of familial late talking, otitis media, or bilingual exposure. Although his mother is confident that her son’s hearing is normal, his delayed language suggests the need for formal audiologic evaluation. A speech-language evaluation should be conducted either through his local early intervention program or by an independent speech-language pathologist. The early intervention program will also conduct a full developmental evaluation to rule out other problems and to design an individualized family service plan. The clinician can help the family understand the problem, make appropriate referrals, advocate for services, and guide the caregivers in supporting language development in the home environment.
3 Years • 3- to 5-word sentences • Follows 3-step directions • Speech 3⁄4 intelligible • Knows these 3 pieces of information: – First name – Age – Sex 4 Years • Converses • Speech fully intelligible • Proficient in the 4 Ps: – Pronouns, all – Prepositions – Plurals – Past tense, regular • Names 4 colors 5 Years • Extended narrative • Future tense • Knows these 5 pieces of information: – Some letters – Some numbers – Shapes – Full name – Address Recognize that there is wide variability in the range of normal milestone acquisition and that the complexity of grammar is learned as a process spanning many years. *Mnemonic clues that correspond to age are italicized.
Summary • There is consensus regarding the developmental sequencing of receptive, expressive, and phonologic skills in early childhood and the role of exposure to speech sounds in language development. Strong research evidence implicates genetic and environmental factors in the causes of speechlanguage disorders. (18) • Strong evidence suggests that speech-language disorders are prevalent and are associated with increased risk for learning and behavioral problems. (18) • Based on strong evidence regarding the impact of the environment on language development, clinicians should guide parents in providing a language-rich environment, which includes talking to, reading to, and encouraging reciprocal communication with their children from infancy onward. (4) • Scientific evidence is mixed concerning the efficacy of early intervention and treatment of speech-language disorders, and more controlled studies are needed. • There is consensus that the pediatric clinician is in a unique position to identify delays early through a continuous process of surveillance and screening. A “gold standard” for screening is difficult to find because of inconsistent measures and terminology. At this time, evidence is insufficient that a specific speech and language screening instrument is more effective than clinical observation and parental concerns to identify children who require further evaluation.
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References 1. Bates E, Thal D, Janowsky J. Early language development and its neural correlates. Handbook of Neuropsychology: Child Neuropsychology. 1992;7:69 –110 2. Eilers RE, Oller DK. Infant vocalizations and the early diagnosis of severe hearing impairment. J Pediatr. 1994;124:199 –203 3. Fenson L, Dale P, Reznick JS, Bates E, Thal D, Pethick S. Variability in early communicative development. SRCD Monographs #242. 1994;19(5) 4. Hart B, Risley TR. Meaningful Difference in the Everyday Experience of Young American Children. Baltimore, MD: Paul H Brookes; 1995 5. High PC, LaGasse L, Becker S, Ahlgren I, Gardner A. Literacy promotion in primary care pediatrics: can we make a difference? Pediatrics. 2000;105:927–934 6. Horwitz SM, Irwin JR, Briggs-Gowan MJ, Bosson Heenan JM, Mendoza J, Carter AS. Language delay in a community cohort of young children. J Am Acad Child Adolesc Psychiatry. 2003;42: 932–940 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994 8. Marton K. Visuo-spatial processing and executive functions in children with specific language impairment. Int J Lang Comm Dis. 2008;43:181–200 9. Tomblin JB, Records NL, Buckwater P, Zhang X, Smith E, O’Brien M. Prevalence of specific language impairment in kindergarten children. J Speech Lang Hearing Res. 1997;40:1245–1260 10. Shriberg L, Kwiatkowski J. Developmental phonological disorders. I. A clinical profile. J Speech Hearing Res. 1994;37: 1100 –1126 11. Shriberg LD, Aram DM, Kwiatkowski J. Developmental apraxia of speech. I. Descriptive and theoretical perspectives. J Speech Lang Hearing Res. 1997;40:273–285 12. Shaywitz SE, Shaywitz B, Fletcher J, Escobar M. Prevalence of
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reading disability in boys and girls: results of the Connecticut longitudinal study. JAMA. 1990;264:998 –1002 13. Moeller MP. Early intervention and language development in children who are deaf and hard of hearing. Pediatrics. 2000; 106:e43 14. Roberts JE, Rosenfeld RM, Zeisel SA. Otitis media and speech and language: a meta-analysis of prospective studies. Pediatrics. 2004;113:e238 – e248 15. Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics. 1997;99:560 –566 16. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics, Bright Futures Steering Committee, and Medical Home Initiatives for Children With Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405– 420 17. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497–501 18. Simms MD. Language disorders in children: classification and clinical syndromes. Pediatr Clin North Am. 2007;54:437– 467
Suggested Reading Paul R. Language Disorders From Infancy Through Adolescence: Assessment and Intervention. 3rd ed. St. Louis, MO: Mosby Elsevier; 2007 Russell RL, Simms MD. Language, communication, and literacy: pathologies and treatments. Pediatr Clin North Am. 2007;54(3) Wolf M. Proust and the Squid: The Story and Science of the Reading Brain. New York, NY: Harper Perennial; 2007 Wolraich ML, Drotar DD, Dworkin PH, Perrin EC. Developmental-Behavioral Pediatrics: Evidence and Practice. Philadelphia, PA: Mosby Elsevier; 2008
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PIR Quiz Quiz also is available online at http://www.pedsinreview.aappublications.org. 5. Which of the following statements regarding normal speech development in children is true? A. B. C. D. E.
Canonical babbling is the first stage of language development. Children can usually understand speech before they can express words. Infants are not born with the ability to detect speech differences, but they develop it later. Most children who have normal speech say their first word at 18 months of age. Socioeconomic status has no effect on language development.
6. At a health supervision visit, the mother of a 9-month-old girl asks you if her daughter’s language development is normal. Which of the following language milestones is most appropriate for this girl’s age? A. B. C. D. E.
Localizing of voices and sounds. Reciprocal vocalizing. Saying three words, including “mama” and “dada.” Startling to loud sounds. Understanding “bye-bye” and “no.”
7. You are evaluating a 2-year-old boy at a health supervision visit. His mother says that he does not talk as much as her other two children did at his age, and she asks you for a referral for a speech evaluation. Which of the following is the most appropriate indication for this referral? A. B. C. D. E.
Failure to point to pictures when requested. Failure to recognize four colors. Failure to use pronouns appropriately. Failure to use two-word sentences. Speech that is not fully articulate.
8. You are evaluating a 6-year-old girl at a health supervision visit. Her mother is concerned about her speech because she usually only says portions of words and consistently substitutes consonant sounds for others. Her teachers have complained that they often cannot understand what she says. A look at your records reveals that she babbled and jargoned appropriately in infancy. Which of the following is the most likely diagnosis? A. B. C. D. E.
Childhood apraxia of speech. Developmental dysfluency. Dyslexia. Phonologic disorder. Specific language impairment.
HealthyChildren.org Parent Resources from AAP 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/ages-stages/baby/pages/ Language-Development-4-to-7-Months.aspx. Also, the reader can find additional articles on speech development and problems by typing “speech problems” in the search function box on the Healthy Children website.
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Speech and Language Development: Monitoring Process and Problems Susan McQuiston and Nancy Kloczko Pediatr. Rev. 2011;32;230-239 DOI: 10.1542/pir.32-6-230
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Acid-Base Disorders Mara Nitu, Greg Montgomery and Howard Eigen Pediatr. Rev. 2011;32;240-251 DOI: 10.1542/pir.32-6-240
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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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Article
fluids and electrolytes
Acid-Base Disorders Mara Nitu, MD,* Greg Montgomery, MD,† Howard Eigen, MD§
Author Disclosure Drs Nitu, Montgomery, and Eigen have disclosed no financial
Objectives
After completing this article, readers should be able to:
1. Understand the mechanisms for regulating acid-base physiology. 2. Know the differential diagnosis of metabolic acidosis associated with high anion gap and plan for initial management. 3. Know the differential diagnosis of normal anion gap metabolic acidosis. 4. Describe pulmonary compensatory changes in metabolic acidosis and alkalosis. 5. Understand how various diuretics can lead to acid-base imbalance. 6. Describe renal compensatory changes in respiratory acidosis and alkalosis.
relationships relevant to this article. This
Case Study
commentary does not
A 16-year-old girl who has no significant previous medical history presents to the emergency department with a 4-day history of nausea, vomiting, fever, chills, diarrhea, leg cramps, abdominal pain, and headaches. She is finishing her menstrual period and arrives with a tampon in place, which she reports that she inserted yesterday. Her vital signs include a heart rate of 165 beats/min, respiratory rate of 28 breaths/min, blood pressure 65/30 mm Hg, and oxygen saturation of 100% on 4 L/min of oxygen. The most likely diagnosis for this patient is toxic shock syndrome, which was later confirmed with a positive antibody test. The initial arterial blood gas (ABG) values are:
contain a discussion of an unapproved/ investigative use of a commercial product/ device.
● ●
Abbreviations
●
ABG: AG: BE: BUN: Ca2ⴙ: Clⴚ: CNS: DKA: GI: Hⴙ: HCO3ⴚ: Kⴙ: Mg2ⴙ: Naⴙ: NH3: NH4: PCO2: PO2: RTA:
arterial blood gas anion gap base excess blood urea nitrogen calcium chloride central nervous system diabetic ketoacidosis gastrointestinal hydrogen bicarbonate potassium magnesium sodium ammonia ammonium partial pressure of carbon dioxide partial pressure of oxygen renal tubular acidosis
● ●
pH, 7.24 Partial pressure of oxygen (PO2), 138 mm Hg Partial pressure of carbon dioxide (PCO2), 19 mm Hg Bicarbonate (HCO3⫺), 8 mEq/L (8 mmol/L) Base excess (BE), ⫺18 mEq/L (18 mmol/L)
Such findings are suggestive of metabolic acidosis with respiratory compensation. Further laboratory results are: ● ● ● ● ● ● ● ● ●
Serum sodium (Na⫹), 133 mEq/L (133 mmol/L) Potassium (K⫹), 4.2 mEq/L (4.2 mmol/L) Chloride (Cl⫺), 109 mEq/L (109 mmol/L) HCO3⫺, 12 mEq/L (12 mmol/L) Anion gap (AG), 12 mEq/L (12 mmol/L) Blood urea nitrogen (BUN), 49 mg/dL (17.5 mmol/L) Creatinine, 3.96 mg/dL (350 mol/L) Calcium, 5.2 mg/dL (1.3 mmol/L) Albumin, 2.0 g/dL (20 g/L)
The apparently normal AG is misleading. After correcting the AG for hypoalbuminemia, the adjusted AG is 17 mEq/L (17 mmol/L). Lactic acidemia due to shock, one of the likely causes for
*Associate Professor of Clinical Pediatrics, Section of Pediatric Pulmonology, Critical Care and Allergy; Medical Director, PICU/ Riley Hospital for Children; Medical Co-Director of Lifeline Transport Team, Indianapolis, IN. † Assistant Professor of Clinical Pediatrics, Section of Pulmonology, Critical Care and Allergy; Medical Director, Pediatric Bronchoscopy Laboratory, James Whitcomb Riley Hospital for Children, Indianapolis, IN. § Billie Lou Wood Professor of Pediatrics, Associate Chairman for Clinical Affairs; Director, Section of Pediatric Pulmonology, Critical Care and Allergy, James Whitcomb Riley Hospital for Children, Indianapolis, IN. 240 Pediatrics in Review Vol.32 No.6 June 2011
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increased AG metabolic acidosis, is confirmed by a high serum lactate value of 6.9 mg/dL (0.8 mmol/L). One hour later, the ABG values are: ● ● ● ● ●
pH, 7.06 PO2, 63 mm Hg PCO2, 47 mm Hg HCO3⫺, 13.2 mEq/L (13.2 mmol/L) BE, ⫺16 mEq/L (16 mmol/L)
This ABG panel reveals metabolic acidosis without respiratory compensation due to developing respiratory failure.
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Each acid-base disorder leads to countering respiratory or renal compensatory responses that attempt to normalize the pH. In metabolic acidosis, for example, ventilation is increased, resulting in a decrease in PCO2, which tends to raise the pH toward normal. These compensatory attempts never overshoot correcting the pH (Figs. 2 and 3).The process of acid-base regulation involves the respiratory system (controls PCO2), kidneys (regulates plasma HCO3⫺ by changes in acid excretion), and a very complex system of extracellular and intracellular buffers.
The Respiratory System in Acid-Base Balance Introduction The loss of acid-base balance is an expression of various conditions encountered frequently in clinical practice. Changes in hydrogen ion concentration can lead to unraveling of the protein tertiary structure, thereby causing enzyme dysfunction, enzyme loss, and cell death. Understanding the physiology behind various disturbances in acid-base balance is necessary for determining a correct diagnosis and management plan. Maintaining acid-base homeostasis involves the lungs, kidneys, and a very complex system of buffers, all aiming to maintain the normal pH (7.35 to 7.45) of the arterial blood. Lowering the arterial pH below 7.35 is termed acidosis, and an increase of the arterial pH above 7.45 constitutes alkalosis. Metabolic acidosis is associated with a low pH and low HCO3⫺ concentration. Metabolic alkalosis is associated with a high pH and high HCO3⫺ concentration. Respiratory acidosis is associated with a low pH and high PCO2. Respiratory alkalosis is associated with a high pH and low PCO2 (Fig. 1).
Figure 1. Acid-base changes in metabolic versus respiratory
disorders.
The respiratory system contributes to acid-base balance via timely adjustments in alveolar minute ventilation that maintain systemic acid-base equilibrium in response to alterations in systemic pH and arterial PCO2. Systemic pH is monitored by central chemoreceptors on the ventrolateral surface of the medulla oblongata and arterial PCO2 (as well as arterial PO2) by peripheral chemoreceptors located at the carotid and aortic bodies. These chemoreceptors act through central respiratory control centers in the pons and medulla to coordinate the respiratory muscle efforts of inhalation and exhalation, leading to adjustments in both components of minute ventilation: tidal volume and respiratory cycle frequency. Lung-mediated changes in arterial PCO2 can lead to rapid alteration in systemic hydrogen ions (H⫹) because CO2 is lipidsoluble and may readily cross cell membranes according to the following equation: H⫹ ⫹ HCO3⫺7H2CO3 (carbonic acid)7CO2 ⫹ H2O (water). Under normal physiologic conditions, this process allows for tight control of arterial PCO2 near 40 mm Hg.
Figure 2. Primary metabolic acidosis with subsequent respiratory alkalosis compensation. The red arrow does not cross into the alkalosis range, reflecting the concept that overcompensation never occurs. Pediatrics in Review Vol.32 No.6 June 2011 241
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Figure 3. Primary respiratory acidosis with subsequent metabolic alkalosis compensation. The red arrow does not cross into the alkalosis range, reflecting the concept that overcompensation never occurs.
tilation to maintain arterial PCO2. The HCO3⫺ interacts with H⫹, as demonstrated in the following formula: H⫹ ⫹ HCO3⫺ 7H2CO37CO2 ⫹ H2O. This reaction serves as the basis for the Henderson-Hasselbalch equation: pH⫽6.1 ⫹ log (HCO3⫺/0.03 ⫻ PCO2). Although this equation describes a patient’s acid-base status, it does not provide insight into the mechanism of the acid-base disorder. The Henderson-Hasselbalch equation lists PCO2 and HCO3⫺ as independent predictors of acid-base balance, but in reality they are interdependent (as suggested by the chemical reaction H⫹ ⫹ HCO3⫺ described previously). Furthermore, the Henderson-Hasselbalch equation does not account for other important nonbicarbonate buffers present in the body, such as the primary intracellular buffers of proteins, organic and inorganic phosphates, and hemoglobin. In addition, bone is an important site for buffering of acid and base loads.
Laboratory Assessment of Acid-Base Balance The Kidneys in Acid-Base Balance The kidney’s role in acid-base balance consists of reabsorbing filtered HCO3⫺ and excreting the daily acid load derived principally from the metabolism of sulfurcontaining amino acids. Ninety percent of filtered HCO3⫺ is reabsorbed in the proximal tubules, primarily by Na⫹-H⫹ exchange, and the remaining 10% is reabsorbed in the distal nephron, primarily via hydrogen secretion by a proton pump (H⫹-ATPase). Under normal conditions, no HCO3⫺ is present in the final urine. The excretion of the daily H⫹ load occurs in the distal tubule. Once excreted in the urine, the H⫹ must be bound to a buffer to avoid excessive urine acidification and promote further excretion. The two primary buffers in the urine are ammonia (NH3), which is excreted and measured as ammonium (NH4⫹) and phosphate (referred to and measured as titratable acidity). The kidneys synthesize and excrete NH3, which combines with H⫹ excreted by the collecting duct cells to form NH4⫹: H⫹⫹NH3⫽NH4⫹. NH3 diffuses freely across membranes; NH4⫹does not. Failure to produce and excrete sufficient NH4⫹, therefore, leads to the development of metabolic acidosis.
Extracellular and Intracellular Buffers in Acid-Base Balance The most important buffer in the extracellular fluid is HCO3⫺, due both to its relatively high concentration and its ability to vary PCO2 via changes in alveolar ventilation. Chemoreceptor analysis of arterial pH and PCO2 allows for centrally mediated adjustments in minute ven242 Pediatrics in Review Vol.32 No.6 June 2011
Acid-base balance is assessed by blood gas analysis and serum measurement of several important electrolytes, leading to the calculation of the AG. Blood gas analyzers measure the pH and the PCO2 directly. The HCO3⫺ value is calculated from the Henderson-Hasselbalch equation. The BE value also is calculated as the amount of base/acid that should be added to a sample of whole blood in vitro to restore the pH to 7.40 while the PCO2 is held at 40 mm Hg. The PCO2 not only points to the type of disorder (respiratory or metabolic) but also corresponds to the magnitude of the disorder. The AG method was developed to include other nonbicarbonate buffers in the analysis. Based on the principle of electroneutrality, the sum of the positive charges should equal the sum of the negative charges as follows: Na⫹⫹K⫹⫹Mg2⫹ (magnesium) ⫹Ca2⫹ (calcium) ⫹H⫹⫽Cl⫺⫹ HCO3⫺⫹ protein ⫺⫹ PO43⫺ (phosphate)⫹ OH⫺⫹ SO42⫺ (sulfate)⫹ CO32⫺⫹ conjugate base⫺. Sodium, chloride, and HCO3⫺ are measured easily in the serum. Therefore, the AG is calculated by the formula AG⫽{Na⫹} ⫺ {Cl⫺⫹ HCO3⫺}. A normal AG is 12⫾2 mEq/L (12 mmol/L). Some clinicians and some published reports include potassium as a measured cation in the calculation of AG, which raises the normal value by 4 mEq/L (4 mmol/L). The AG is defined as the difference between the unmeasured plasma anions and the unmeasured plasma cations. Clinically, an elevated AG is believed to reflect an increase of unmeasured anions and, therefore, a metabolic acidosis. This concept is explained by the fact that unmeasured cations (Mg2⫹ ⫹ Ca2⫹ ⫹ H⫹) are more
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tightly controlled and the unmeasured anions have a greater tendency to fluctuate. Theoretically, the AG also can increase following a decrease in serum K⫹, Ca2⫹, or Mg2⫹, but the normal concentration of these cations is so low that a reduction does not have a significant clinical impact on the AG. In general, these principles hold true for the previously healthy individual who develops an acute illness. However, for the critically ill host whose plasma protein concentrations are greatly reduced, the low protein values hide an associated increase in unmeasured anions. Without the correction for hypoalbuminemia, it is possible to overlook a true high AG acidosis, mistakenly assuming it to be a normal AG acidosis. According to the Figge formula, each 1-g/dL reduction in the serum albumin concentration is expected to reduce the AG by 2.5 mEq/L:
acid-base disorders
Causes of Normal Anion Gap Metabolic Acidosis Table 1.
Disorders of the Gastrointestinal (GI) Tract Leading To Excessive Bicarbonate Loss • Diarrhea: the leading cause of normal anion gap metabolic acidosis in children • Surgical procedures that lead to an anastomosis of the ureter with the GI tract, such as ureteroenterostomy/ ureterosigmoidostomy, due to bicarbonate loss in the intestine • Pancreatic fistula Iatrogenic Hyperchloremic Metabolic Acidosis • Result of excessive fluid resuscitation with 0.9% sodium chloride or excessive use of 3% sodium chloride to correct hyponatremia Renal Loss of Bicarbonate
Adjusted AG⫽observed AG ⫹ (2.5 ⫻ [normal albumin ⫺ observed albumin]
Metabolic Acid-Base Disturbance Metabolic Acidosis Metabolic acidosis is defined as an acid-base imbalance that leads to anion excess (low HCO3⫺ concentration) and subsequently to an arterial pH below 7.35. Several mechanisms can lead to metabolic acidosis: excess acid production, increased acid intake, decreased renal acid excretion, increased HCO3⫺ loss from the gastrointestinal (GI) tract, and excess HCO3⫺ excretion in the kidney. For a patient who has intact respiratory function, developing metabolic acidosis leads to respiratory compensation by hyperventilation. Each 1-mEq/L reduction in plasma HCO3⫺ concentration prompts a 1.2-mm Hg compensatory fall in the PCO2. Clinically, the patient’s respiratory rate increases within the first hour of the onset of metabolic acidosis, and respiratory compensation is achieved within 24 hours. Failure of the respiratory system to compensate for metabolic acidosis is an ominous sign that should trigger careful evaluation of the patient’s mental status and cardiorespiratory function. Calculating the AG is a very useful initial step in diagnosing various causes of metabolic acidosis.
Metabolic Acidosis With Normal Anion Gap Metabolic acidosis with normal AG reflects an imbalance of the measured plasma anions and cations. According to the formula: AG⫽Na⫹ ⫺ (Cl⫺ ⫹ HCO3⫺), metabolic acidosis with normal AG can be explained by excessive loss of HCO3⫺ (in the stool or in the urine) or by inability to excrete hydrogen ions. Table 1 lists the most
• Renal tubular acidosis type II (proximal) • Iatrogenic: carbonic anhydrase inhibitor (acetazolamide) • Hyperparathyroidism •Medications • Acidifying agents: sodium chloride, potassium chloride, enteral supplements • Magnesium chloride • Cholestyramine • Spironolactone Hypoaldosteronism
frequent conditions leading to normal AG metabolic acidosis. Of particular note is renal tubular acidosis (RTA), a complex set of disorders of the kidney that can lead to normal AG metabolic acidosis. One disorder is the inability to excrete the daily acid load (type 1 RTA), leading to progressive H⫹ ion retention and low plasma HCO3⫺ concentration (⬍10 mEq/L [10 mmol/L]). Another disorder arises from the inability to reabsorb HCO3⫺ normally in the proximal tubule (proximal RTA or type 2 RTA). HCO3⫺ is lost in the urine despite some reabsorption in the distal nephron, leading to metabolic acidosis and alkaline urine. Normal AG metabolic acidosis caused by excessive HCO3⫺ losses may be corrected by slow infusion of sodium bicarbonate-containing intravenous fluids.
Elevated Anion Gap Metabolic Acidosis Elevated AG metabolic acidosis results from an excess of unmeasured anions. Various conditions that cause an Pediatrics in Review Vol.32 No.6 June 2011 243
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accumulation of unmeasured anions, leading to high AG metabolic acidosis, are listed in Table 2. When faced with an elevated AG metabolic acidosis, calculating the osmotic gap may help determine the underlying condition. Similar to the AG, the osmotic gap is the difference between the measured serum osmolality and the calculated value. The calculated serum osmolality is: 2 ⫻ [Na⫹] ⫹ glucose/18 ⫹ BUN/2.8. A normal osmotic gap should be 12⫾2 mOsm/L. A high osmotic gap is a sign of an excess of an unmeasured osmotic active substance such as ethylene glycol (antifreeze), methanol (wood alcohol), or paraldehyde.
Ketoacidosis Ketoacidosis describes accumulation of ketone bodies (beta-hydroxybutyrate and acetoacetic acid) following excessive intracellular use of lipids as a metabolic substrate. This metabolic shift occurs during starvation or fasting or as a reflection of a lack of appropriate metabolic substrate for energy production (during specific diets where carbohydrates are replaced with lipids). Hyperketotic diets sometimes are employed for intractable epilepsy in an effort to decrease the seizure threshold. Diabetic ketoacidosis (DKA) results from a decrease in insulin production that leads to an inability to transport glucose into the cell. The cell shifts to lipid metabolism, despite the surrounding hyperglycemia (also described as “starvation in the middle of the plenty”). The diagnosis of DKA is confirmed by the findings of hyperglycemia, a high AG acidosis, ketonuria, and ketonemia.
Causes of Elevated Anion Gap Metabolic Acidosis Table 2.
Ketoacidosis • Starvation or fasting • Diabetic ketoacidosis Lactic Acidosis • Tissue hypoxia • Excessive muscular activity • Inborn errors of metabolism Ingestions • Methanol • Ethylene glycol • Salicylates • Paraldehyde Renal Failure • Uremia
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The earliest symptoms of DKA are related to hyperglycemia. Older children and adolescents typically present with polyuria (due to the glucose-induced osmotic diuresis), polydipsia (due to the increased urinary losses), fatigue, and weight loss. Hypovolemia may be severe if urinary losses are not replaced, with the presentation of very dry mucous membranes and prolonged capillary refill time. As a result of worsening metabolic acidosis, the patient develops hyperventilation and deep (Kussmaul) respirations, representing respiratory compensation for metabolic acidosis. Hyperpnea develops from an increase in minute volume (rate ⫻ tidal volume) or from increased tidal volume alone without an increase in respiratory rate. When DKA is being managed, the patient’s chest excursion and respiratory rate should be observed carefully to determine if hyperpnea is present. In infants, hyperpnea may be manifested only by tachypnea. Without prompt medical attention, DKA can progress to cerebral edema and cardiorespiratory arrest. Neurologic findings, ranging from drowsiness, lethargy, and obtundation to coma, are related to the severity of hyperosmolality or to the degree of acidosis. Treatment of DKA includes sensitive correction of the underlying insulin, volume, and electrolyte deficiencies.
Lactic Acidosis Lactic acidosis, another cause of an elevated AG, occurs when cells shift to anaerobic pathways for energy production as a result of tissue hypoxia due to inappropriate tissue perfusion, inappropriate oxygen supply, or mitochondrial dysfunction (as seen in inborn errors of metabolism or ingestion of drugs or toxins). The clinical presentation may involve seizures or symptoms consistent with the initial disorder that led to lactic acidosis, such as cyanosis, signs and symptoms suggestive of tissue hypoperfusion, and hypotension. As lactic acidosis worsens, further hemodynamic compromise occurs. Management should be targeted to restoring adequate tissue perfusion and oxygen supply by treating the underlying cause of the lactic acidosis.
Inborn Errors of Metabolism Several inborn errors of metabolism can present with high AG metabolic acidosis. Based on the affected metabolic pathway, the increased AG is caused by a different chemical substance: urea cycle defects present with hyperammonemia; or inborn errors of amino acids, carbohydrate, or organic acid metabolism present either with ketoacidosis, lactic acidosis (as in Krebs cycle defects), or increased organic acids production. Symptoms often are nonspecific and include poor feeding, failure to thrive, seizures, and vomiting.
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Managing inborn errors of metabolism involves identifying the defective or deficient enzyme and limiting the intake of the metabolic substrate that requires the use of that particular enzyme. In selected cases, dialysis may be the appropriate tool for removing the excess anion.
Ingestions Ingestions of various chemical substances are another cause of metabolic acidosis with an elevated AG. Salicylate overdose is well known to cause increased AG metabolic acidosis by interfering with cellular metabolism (uncoupling of oxidative phosphorylation). Early symptoms of salicylate overdose include tinnitus, fever, vertigo, nausea, vomiting, and diarrhea. More severe intoxication can cause altered mental status, coma, noncardiac pulmonary edema, and death. Most patients show signs of intoxication when the plasma salicylate concentration exceeds 40 mg/dL. Treatment of salicylate ingestion involves promoting alkaline diuresis to enhance renal salicylate excretion. In severe cases, dialysis may be required (generally considered when plasma salicylate concentrations exceed 80 mg/dL in acute intoxication and 60 mg/dL in chronic ingestions). Toluene inhalation also can lead to metabolic acidosis with an increased AG. In patients who experience toluene ingestion (glue sniffing), the overproduced hippurate is both filtered and secreted by the kidneys, leading to rapid elimination in the urine. As a result, the AG may be near-normal or normal at the time of presentation and the patient might be diagnosed mistakenly as having a normal AG acidosis. Ethylene glycol (antifreeze), methanol, and paraldehyde ingestion lead to an increased AG metabolic acidosis and an increased osmotic gap. Both the AG and the acidosis due to methanol and ethylene glycol ingestions result from metabolism of the parent compound. Neither may be seen in patients early in the course of ingestion or when there is concurrent ingestion of ethanol. Ethanol combines competitively with alcohol dehydrogenase, thereby slowing the metabolism of methanol or ethylene glycol to their toxic metabolites and slowing the appearance of both the acidosis and the high AG. This effect explains why ethanol administration is used in the medical management of methanol and ethylene glycol ingestions, along with fomepizole (alcohol dehydrogenase inhibitor). Management of ethylene glycol and methanol toxicity also involves hemodialysis, which removes both the ingested substance and the metabolic byproducts from the serum.
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Massive ingestions of creams containing propylene glycol (eg, silver sulfadiazine) also can lead to increased AG metabolic acidosis.
Renal Failure Renal failure causes an increased AG metabolic acidosis due to the failure to excrete H⫹. Normally, elimination of the serum acid load is achieved by urinary excretion of H⫹, both as titratable acidity and as NH4⫹. Titratable acid is a term used to describe acids such as phosphoric acid and sulfuric acid present in the urine. The term explicitly excludes NH4⫹ as a source of acid and is part of the calculation for net acid excretion. The term titratable acid was chosen based on the chemical reaction of titration (neutralization) of those acids in reaction with sodium hydroxide. As the number of functioning nephrons declines in chronic kidney disease and the glomerular filtration rate decreases to below 25% of normal, the patient develops progressive high AG metabolic acidosis (hyperchloremia may occur transiently in the initial phases of renal failure). In addition to the decrease in NH4⫹ excretion, decreased titratable acidity (primarily as phosphate) may play a role in the pathogenesis of metabolic acidosis in patients who experience advanced kidney disease. Of course, dialysis often is employed to correct the severe fluid and electrolyte imbalances generated by renal failure.
Management of Metabolic Acidosis Regardless of the cause, acidemia, if untreated, can lead to significant adverse consequences (Table 3). Use of HCO3⫺ therapy to adjust the pH for patients who have metabolic acidosis is controversial. Slow infusion of sodium bicarbonate-containing intravenous fluids can be used in cases of normal AG metabolic acidosis to replenish excessive HCO3⫺ losses (eg, as a result of excessive diarrhea). However, infusing sodium bicarbonate-containing fluids for increased AG metabolic acidosis has questionable benefit and should not be used clinically. As discussed, HCO3⫺ combines with H⫹, leading to H2CO3 that subsequently dissociates to CO2 and H2O. Infusing HCO3⫺ decreases serum pH and raises CO2 and H2O. Neither the cell membranes nor the blood-brain barrier is very permeable to HCO3⫺; CO2 diffuses freely to the intracellular space, where it combines with H2O, leading to H2CO3 and worsening of the intracellular pH. Administering intravenous sodium bicarbonate to a patient who has an increased AG metabolic acidosis can lead to a false sense of security because the underlying problem is hidden by an artificially improved serum pH. Pediatrics in Review Vol.32 No.6 June 2011 245
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Consequences of Metabolic Acidosis Table 3.
Cerebral • Inhibition of metabolism • Cerebral edema • Obtundation and coma Cardiovascular • Decreased cardiac contractility • Decreased cardiovascular responsiveness to catecholamine • Decreased threshold for arrhythmias • Reduction of cardiac output, blood pressure, and end-organ perfusion • Pulmonary vasoconstriction Respiratory • Hyperventilation as a result of respiratory compensation • Decreased respiratory muscle strength • Increased work of breathing Hematologic • Oxyhemoglobin dissociation curve shifts to the right (the oxygen is more easily released at the tissue level due to a lower pH) Metabolic • Inhibition of anaerobic glycolysis • Insulin resistance • Decreased adenosine triphosphate synthesis • Hyperkalemia • Increased protein degradation
Sodium bicarbonate once held a prominent position in the management of cardiac arrest. Reversing the acidosis caused by global hypoperfusion made physiologic sense because severe acidemia may worsen tissue perfusion by decreasing cardiac contractility. However, the most effective means of correcting the acidosis in cardiac arrest is to restore adequate oxygenation, ventilation, and tissue perfusion. Because most pediatric cardiac arrests are due to respiratory failure, support of ventilation through early intubation is the primary treatment, followed by support of the circulation with fluids and inotropic agents. Currently, the American Heart Association recommends that sodium bicarbonate administration be considered only in children who suffer prolonged cardiac arrest and documented severe metabolic acidosis and who fail to respond to oxygenation, ventilation, intravenous fluids, and chest compressions combined with epinephrine in recommended doses. 246 Pediatrics in Review Vol.32 No.6 June 2011
Metabolic Alkalosis Metabolic alkalosis is defined as an acid-base imbalance leading to increased plasma HCO3⫺ and an arterial pH above 7.45. Several mechanisms can lead to the elevation in the plasma HCO3⫺: excessive hydrogen loss, functional addition of new HCO3⫺, and volume contraction around a relatively constant amount of extracellular HCO3⫺ (called a “contraction alkalosis”). The kidneys are extremely efficient in eliminating excess HCO3⫺ in the urine. A confounding factor is required for serum HCO3⫺ to accumulate, such as impaired renal function, K⫹ depletion, or volume depletion. In general, a patient compensates for a metabolic alkalosis by decreasing ventilation. Respiratory compensation by hypoventilation raises PCO2 by 0.7 mm Hg for every 1 mEq/L (1 mmol/L) of serum HCO3⫺ increase. Excessive H⫹ losses can occur either in the urine or GI tract and lead to HCO3⫺ accumulation as the result of the following reactions: H2O7H⫹⫹HO⫺ HO⫺⫹CO27HCO3⫺ Increased loss of gastric content, which has high concentrations of hydrogen chloride, as a result of persistent vomiting (eg, self-induced, pyloric stenosis) or high nasogastric tube drainage leads to metabolic alkalosis. If fluid losses continue unreplaced, dehydration and lactic acidosis ultimately develop. Of note, infants of mothers who have bulimia have metabolic alkalosis at birth. High H⫹ loss in the urine can occur in the distal nephron. Increased secretion of aldosterone stimulates the secretory H-ATPase pump, increasing Na⫹ reabsorption, thereby making the lumen more electronegative and causing more H⫹ and K⫹ excretion, which results in concurrent metabolic alkalosis and hypokalemia. Patients who have primary mineralocorticoid excess present with hypokalemia and hypertension. In contrast, secondary hyperaldosteronism due to congestive heart failure or cirrhosis usually does not present with metabolic alkalosis or hypokalemia because the above-mentioned mechanism is blunted by decreased distal nephron Na⫹ delivery. Iatrogenic metabolic alkalosis along with volume contraction can occur in patients treated with loop or thiazide diuretics, which cause Cl⫺ depletion and increased delivery of Na⫹ to the collecting duct, which enhances K⫹ and H⫹ secretion. Bartter and Gitelman syndromes present with metabolic alkalosis and hypokalemia due to a genetic defect in the transporters in the loop of Henle and distal tubule,
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respectively, the same locations as those inhibited by loop and thiazide diuretics. In addition to H⫹ loss, metabolic alkalosis also can be induced by the shift of H⫹ into the cells. As discussed previously, hypokalemia is a frequent finding in patients who have metabolic alkalosis. Hypokalemia by itself causes intracellular acidosis and increased serum alkalosis by the following mechanism: intracellular K⫹ shifts into the serum to replete the extracellular stores, and to maintain electroneutrality, H⫹ enters the cells. Hydrogen movement into the cells lowers the intracellular pH and leaves unbuffered excess HCO3⫺ in the serum. The intracellular acidosis in renal tubular cells promotes H⫹ secretion and, therefore, HCO3⫺ reabsorption. Metabolic alkalosis due to functional addition of “new” HCO3⫺ can occur by several mechanisms: decreased renal excretion of HCO3⫺, posthypercapnic alkalosis, or excessive intake or administration of alkali.
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of large administrations of citrate are infusion of more than 8 units of banked blood or fresh frozen plasma or administration of citrate as an anticoagulant during dialysis.
Contraction Alkalosis Contraction alkalosis occurs when relatively large volumes of HCO3⫺-free fluid are lost, a situation frequently seen with administration of intravenous loop diuretics. Contraction alkalosis also may occur in other disorders in which a high-Cl⫺, low-HCO3⫺ solution is lost, such as sweat losses in cystic fibrosis, loss of gastric secretions in patients who have achlorhydria, and fluid loss from frequent stooling by patients who have congenital chloridorrhea, a rare congenital secretory diarrhea. Regardless of the cause, alkalosis, if untreated, can lead to significant adverse consequences (Table 4).
Management of Metabolic Alkalosis Decreased Renal Bicarbonate Excretion Renal failure can lead to metabolic alkalosis because the kidneys fail to excrete excess HCO3⫺.
Three general principles apply to the therapy of metabolic alkalosis: correct true volume depletion, correct K⫹ depletion, and correct Cl⫺ depletion (in Cl⫺-responsive metabolic alkalosis). For patients who have true volume
Posthypercapnic Alkalosis Chronic respiratory acidosis (retention of CO2) leads to a compensatory increase in hydrogen secretion and an ensuing increase in the plasma HCO3⫺ concentration to correct the pH. When the PCO2 is decreased rapidly by mechanical ventilation of a patient who has chronic respiratory acidosis, the ensuing metabolic alkalosis is slow to disappear. Because Cl⫺ loss often is present in posthypercapnic alkalosis, repleting the Cl⫺ deficit may be essential to correct the alkalosis. Furthermore, the acute fall in PCO2 in a person who has chronic respiratory acidosis raises the cerebral intracellular pH acutely, a change that can induce serious neurologic abnormalities and death because CO2 can diffuse freely across the blood-brain barrier out of the intracellular space, leading to severe alkalosis. Accordingly, the PCO2 must be reduced gradually in mechanically ventilated patients who present initially with chronic hypercapnia.
Excessive Intake or Administration of Alkali Alkali administration does not induce metabolic alkalosis in healthy people because the healthy kidney can excrete HCO3⫺ rapidly in the urine. However, metabolic alkalosis can occur if very large quantities of HCO3⫺ are administered acutely or if the ability to excrete HCO3⫺ is impaired. The administration of large quantities of citrate is known to lead to metabolic alkalosis. Examples
Consequences of Untreated Alkalosis Table 4.
Cerebral • Cerebral vasoconstriction with reduction of cerebral blood flow • Tetany, seizures, lethargy, delirium, and stupor Cardiovascular • Vasoconstriction of the small arterioles, including coronary arteries • Decreased threshold for arrhythmias Respiratory • Compensatory hypoventilation with possible subsequent hypoxemia and hypercarbia (respiratory failure) Hematologic • Oxyhemoglobin dissociation curve shifts to the left (the oxygen is bound more tightly to the oxyhemoglobin) Metabolic and Electrolyte Imbalances • Stimulation of anaerobic glycolysis • Hypokalemia • Decreased plasma ionized calcium • Hypomagnesemia and hypophosphatemia
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depletion, fluid administration of normal saline replaces the Cl⫺ and free water deficits. Potassium chloride administration for patients who have concurrent hypokalemia is an important component of treatment. This agent becomes particularly helpful in patients who are edematous due to heart failure or cirrhosis and cannot receive sodium chloride because an infusion can increase the degree of edema. Another method for treating metabolic alkalosis in an edematous patient is to administer acetazolamide, a carbonic anhydrase inhibitor, which causes a mild increase in production of urine that has high HCO3⫺ content, thus reacidifying the blood. Correcting metabolic alkalosis (usually diureticinduced) may be particularly important for intubated patients who have chronic respiratory acidosis. The higher pH caused by the metabolic alkalosis subsequently impairs the respiratory drive and leads to hypoventilation that exacerbates hypoxemia, delaying weaning and extubation. In these patients, metabolic alkalosis usually is corrected by enteral supplements of potassium chloride or sodium chloride. Very rarely, in the intensive care unit setting, the metabolic alkalosis can be so severe that it impairs weaning from mechanical ventilation. In these circumstances, intravenous infusion of hydrogen chloride can correct the alkalosis. Measuring the urinary Cl⫺ is the preferred method for assessing the renal response to Cl⫺ therapy. For patients experiencing Cl⫺ depletion (urinary Cl⫺ ⬍10 mEq/L [10 mmol/L]) (eg, GI losses, diuretic therapy, and sweat losses in cystic fibrosis), every attempt should be made to correct hypochloremia. Conditions that cause metabolic alkalosis due to high aldosterone concentrations are unresponsive to Cl⫺ and are associated with high urine Cl⫺ concentrations. Minimizing continuing acid and chloride losses by excessive nasogastric fluid drainage with a histamine2 blocker or proton pump inhibitor also may be helpful.
Respiratory Acid-Base Disturbances As noted, chemoreceptor analysis of arterial pH and PCO2 allows for centrally mediated adjustments in minute ventilation to maintain arterial PCO2 near 40 mm Hg. Primary respiratory disturbances in acid-base equilibrium may result from different pathologic scenarios. Arterial PCO2 rises abnormally (respiratory acidosis) if systemic CO2 production exceeds the ventilatory capacity or when efficient ventilation is inhibited by intrinsic or acquired conditions. Conversely, arterial PCO2 decreases abnormally (respiratory alkalosis) in response to physiologic disorders that result in excessive ventilation. Both respiratory acidosis and alkalosis may appear in association 248 Pediatrics in Review Vol.32 No.6 June 2011
with other metabolic acid-base disturbances, often making accurate diagnosis and treatment of the underlying disease difficult to achieve.
Respiratory Acidosis Respiratory acidosis occurs when arterial PCO2 increases and arterial pH decreases due to a reduction in alveolar minute ventilation or, less commonly, an excessive increase in CO2 production. Acute respiratory acidosis occurs with an acute elevation in PCO2 as a result of sudden limitation or failure of the respiratory system. Chronic respiratory acidosis is due to more indolent increases in PCO2 as a consequence of systemic disease over the course of several days. Reduction in minute ventilation can result from depression of central nervous system (CNS) respiratory drive, anatomic obstruction of the respiratory tract, or intrinsic or acquired impairments of normal thoracic excursion (Table 5).
Common Causes of Respiratory Acidosis in Children
Table 5.
Central Nervous System Depression • Medication effects – Sedative: benzodiazepines, barbiturates – Analgesic: narcotics – Anesthetic agents: propofol • Central nervous system disorders – Head trauma – Infection – Tumor – Congenital central hypoventilation Impairments of Thoracic Excursion or Ventilatory Efficiency • Chest wall/lung disorders – Asphyxiating thoracic dystrophy – Progressive thoracic scoliosis – Thoracic trauma – Acute lung injury/pneumonia – Pneumothorax/parapneumonic effusion – Severe obesity • Nerve/muscle disorders – Congenital myopathies – Spinal cord injury – Toxin exposure: organophosphates, botulism – Guillain-Barre´ syndrome Respiratory Tract Obstruction • Upper airway obstruction – Adenotonsillar hypertrophy • Status asthmaticus
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The body’s compensatory changes in response to acute respiratory acidosis initially are limited to buffering via systemically available cellular HCO3⫺ stores. Because of this limitation, serum HCO3⫺ concentrations rise acutely by only 1 mEq/L (1 mmol/L) for every 10-mm Hg elevation in arterial PCO2. In response to chronic respiratory acidosis, the kidney retains HCO3⫺ and secretes acid, an alteration in function that takes several (3 to 5) days to have a noticeable physiologic effect. Eventually, in chronic respiratory acidosis, serum HCO3⫺ concentrations ultimately rise by approximately 3.5 mEq/L (3.5 mmol/L) for every 10-mm Hg elevation in arterial PCO2. Respiratory acidosis can affect both the CNS and cardiovascular system adversely. CNS effects include increased cerebral blood flow and increased intracranial pressure, which can present clinically as disorientation, acute confusion, headache, and mental obtundation. Cardiovascular effects include peripheral vasodilation and tachycardia. Severe hypoventilation leads to higher arterial PCO2 and more severe hypoxemia. Hypoxemia may be partially compensated by improved tissue extraction of oxygen via an acute acidosis-mediated rightward shift in the oxyhemoglobin dissociation curve and release of oxygen to the tissues. However, as respiratory acidosis persists, a reduction in red blood cell 2,3 diphosphoglycerate (an organophosphate created in erythrocytes during glycolysis) results in a shift of the curve to the left and an increase of hemoglobin affinity for oxygen.
Management of Respiratory Acidosis Treatment of respiratory acidosis usually focuses on correcting the primary disturbance. Immediate discontinuation of medications that suppress central respiratory drive or administration of appropriate reversal agents should be considered. Noninvasive ventilation or intubation with mechanical ventilation may be necessary to achieve adequate alveolar ventilation and appropriate reduction in arterial PCO2. As arterial PCO2 is corrected, individuals who experience excessive Cl⫺ depletion may subsequently suffer poor renal clearance of HCO3⫺, leading to a concomitant state of metabolic alkalosis.
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Common Causes of Respiratory Alkalosis in Children
Table 6.
Medication Toxicity • Salicylate overdose • Central nervous system stimulants – Xanthines (eg, caffeine) – Analeptics (eg, doxapram) Central Nervous System Disorders • Central nervous system tumor • Head injury/stroke • Hyperventilation syndrome: stress/anxiety Respiratory Disorders • Pneumonia • Status asthmaticus • Pulmonary edema • Excessive mechanical or noninvasive ventilation • Hypoxia/high altitude
tory acidosis, renal compensation improves as the disorder persists. Serum HCO3⫺ concentrations decline by 2 mEq/L (2 mmol/L) for every 10-mm Hg decrease in arterial PCO2 in acute respiratory alkalosis. In chronic respiratory alkalosis, serum HCO3⫺ concentrations decline by 4 mEq/L (4 mmol/L) for every 10-mm Hg decrease in arterial PCO2.
Adverse Effects of Respiratory Alkalosis Adverse systemic effects of respiratory alkalosis include CNS and cardiovascular disturbances. Respiratory alkalosis often provokes increased neuromuscular irritability, manifested as paresthesias or carpopedal spasms. In addition, cerebral blood vessels vasoconstrict acutely and impede adequate cerebral blood flow. Myocardial contractility may be diminished and cardiac arrhythmias may occur. The oxyhemoglobin dissociation curve shifts to the left in response to acute respiratory alkalosis, impairing peripheral oxygen delivery.
Management of Respiratory Alkalosis Respiratory Alkalosis Respiratory alkalosis occurs when there is reduction in arterial PCO2 and elevation in arterial pH due to excessive alveolar ventilation. Causes of excessive alveolar ventilation include medication toxicity, CNS disease, intrinsic lung diseases, and hypoxia (Table 6). Compensatory changes in response to respiratory alkalosis involve renal excretion of HCO3. As in respira-
Treatment of respiratory alkalosis centers on correcting the underlying systemic cause or disorder. Close assessment of oxygenation status and correction of hypoxemia via oxygen administration is paramount. Acute hyperventilation syndrome often is treated simply by having the patient breathe into a paper bag. To prevent high altitude-associated respiratory alkalosis, slow ascent to allow for acclimatization is recommended; administraPediatrics in Review Vol.32 No.6 June 2011 249
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Summary • A wide array of conditions ultimately can lead to acid-base imbalance, and interpretation of acid-base disorders always involves a mix of art, knowledge, and clinical experience. • Solving the puzzle of acid–base disorders begins with accurate diagnosis, a process requiring two tasks. First, acid-base variables in the blood must be reliably measured to determine the effect of multiple ions and buffers. Second, the data must be interpreted in relation to human disease to define the patient’s acid–base status. • History, physical examination, and additional laboratory testing and imaging help the clinician to identify the specific cause of the acid-base disturbance and to undertake appropriate intervention.
tion of acetazolamide before ascent should be considered. The only cure for acute mountain sickness, once it has developed, is either acclimatization or descent. However, symptoms of acute mountain sickness can be reduced with acetazolamide and pain medications for headaches.
Suggested Reading Brandis K. Acid-Base Physiology. Accessed March 2011 at: http:// www.anaesthesiamcq.com/AcidBaseBook/ABindex.php Carrillo-Lopez H, Chavez A, Jarillo A, Olivar V. Acid-base disorders. In: Fuhrman B, Zimmerman J, eds. Pediatric Critical Care. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2005:958 –989 Grogono AW. Acid-Base Tutorial. 2010. Accessed March 2011 at: http://www.acid-base.com Kraut JA, Madias NE. Approach to patients with acid-base disorders. Respiratory Care. 2001;46:392– 403
PIR Quiz Quiz also available online at: http://www.pedsinreview.aappublications.org. 9. Which of the following statements best describes the roles of the different nephron segments in maintaining acid-base balance? A. The proximal and distal tubules are equally responsible for acid excretion. B. The proximal tubule is the primary segment responsible for bicarbonate reabsorption and acid excretion. C. The distal tubule is the primary segment responsible for bicarbonate reabsorption and acid excretion. D. The proximal tubule is the primary segment responsible for bicarbonate reabsorption, and the distal nephron principally promotes acid excretion. E. The proximal tubule and loop of Henle are primarily responsible for both bicarbonate reabsorption and acid excretion. 10. Which of the following constellation of choices best describes sequelae of metabolic acidosis?
A. B. C. D. E.
Cardiac Output
Respiratory Rate
Oxyhemoglobin Dissociation Curve Shift
Adenosine Triphosphate Synthesis
Increased Decreased Increased Increased Decreased
Decreased Increased Increased Decreased Decreased
To To To To To
Increased Decreased Increased Increased Decreased
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the the the the the
left right left right right
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11. Among the following, the most common mechanism leading to metabolic alkalosis is: A. B. C. D. E.
Chronic diarrhea. Secondary hypoaldosteronism. Hypokalemia. Hypoventilation. Primary hyperaldosteronism.
12. The most common sequelae of early acute respiratory acidosis are:
A. B. C. D. E.
Intracranial Pressure Increased Decreased Increased Increased Decreased
Heart Rate
Oxyhemoglobin Dissociation Curve Shift
Renal Bicarbonate Reabsorption
Decreased Increased Increased Increased Decreased
To To To To To
Increased Decreased Increased Increased Decreased
the the the the the
right right left right left
13. The most accurate statement about respiratory alkalosis is that: A. B. C. D. E.
Cardiac arrhythmias are never observed. It occurs when there is a reduction in PCO2. It results in decreased renal excretion of alkali. It results in vasodilation of cerebral blood vessels. Oxygen delivery is generally unaffected.
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Acid-Base Disorders Mara Nitu, Greg Montgomery and Howard Eigen Pediatr. Rev. 2011;32;240-251 DOI: 10.1542/pir.32-6-240
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Visual Diagnosis: Swelling and Redness of the Fourth Toe in a 3-month-old Infant Charles O. Onyeama, Karla Vitale, Kenneth Cochran and Ginikanwa L. Onyeama Pediatr. Rev. 2011;32;253-255 DOI: 10.1542/pir.32-6-253
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/32/6/253
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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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visual diagnosis
Swelling and Redness of the Fourth Toe in a 3-month-old Infant Charles O. Onyeama, MD,*† Karla Vitale, DO,*† Kenneth Cochran, MD,*† Ginikanwa L. Onyeama†
Case Presentation
Figure 1. Swelling and sloughing of the skin of the fourth toe.
Figure 2. Note marked indentation and demarcation by pre-
sumed “constricting” band.
A 3-month-old boy presents to the emergency department (ED) with a history of fussiness and inconsolable crying throughout most of the day. His mother states that there is no identifiable cause for his discomfort. He is tolerating feeding and does not have any signs of illness, including cough, nasal congestion, fever, or change in stool pattern. As the day has progressed, the infant’s fussiness has subsided, but he has developed purplish discoloration and swelling of the fourth right toe. The mother is concerned that something is constricting the toe and has attempted to find the cause but cannot, which has prompted the visit to the ED. The infant was born at term after an uneventful pregnancy. He has remained in good health, receiving appropriate immunizations at birth and at 2 months of age. He was circumcised at birth, has never been hospitalized, and has not undergone any other surgical procedure. He is not taking any medication and has no history of allergies. He is the younger of two children. There are no findings of note in the family history. On physical examination, the infant’s vital signs are normal and he appears comfortable. Examination of the head, ears, eyes, nose, throat, chest, heart, and abdomen show no unusual findings. Examination of the right fourth toe reveals a swollen, erythematous tip (Fig. 1), with sharp indentation and demarcation between the area of edema and erythema at the tip of toe and a normal-appearing proximal toe (Fig. 2). There is some sloughing of the skin on the affected area. Capillary refill of the affected toe is brisk. The diagnosis is based on clinical findings.
Author Disclosure Drs Onyeama, Vitale, and Cochran and Ms Onyeama have disclosed no financial relationships relevant to this case. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
*Cibola Family Health Center, Grants, NM. † Cibola General Hospital, Grants, NM. Pediatrics in Review Vol.32 No.6 June 2011 253
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visual diagnosis
Diagnosis: Hair-Thread Tourniquet Syndrome The sharp indentation and demarcation between the reddish-purple, swollen skin and the normalappearing skin of the fourth toe suggested the presence of a tight-fitting ligature or tourniquet. Close examination of the indentation and zone of demarcation of the toe revealed a strand of hair wrapped around the toe. This finding has been described in the literature as part of the hair-thread tourniquet syndrome.
autoamputation may result if the syndrome is not identified and treated promptly. Direct cutting action by the tourniquet also may injure the affected appendage. Most cases of HTTS are seen in young children of 4 days to 6 years of age. Of note, Alverson reported a case of HTTS involving the clitoris in a 9-year-old girl. (3) In general, young children initially may present with excessive fussiness or a caregiver may notice a red, swollen appendage incidentally during routine care.
Discussion Hair tourniquet occurs when a strand of hair wraps tightly around a body appendage, such as a finger, toe, external genitalia, tongue, and even umbilical stump. Although reported in the medical literature, this is a relatively rare yet easily recognized problem. Barton and associates (1) suggested calling the condition “hair-thread tourniquet syndrome” (HTTS) and indicated that the incidence seemed to be increasing, based their personal experience of managing six cases in 2 years. The toe is the most commonly affected appendage. HTTS can result in pain, swelling, injury, loss of blood supply, and subsequent necrosis and loss of the affected appendage. Typical offending tourniquets are a strand of hair or a thread. Hair tourniquets are associated more commonly with toes and external genitalia. Threads tend to affect the fingers. How most hair tourniquets develop remains unknown, but most cases appear to be accidental. However, Johnson cautions that banding of an extremity may not always be accidental and may be due to abuse. (2) Abuse should be considered if there is a knot at the end of the constricting strand or if a larger appendage, such as the hand, forearm, or arm, is constricted, as if by a restraint. Congenital annular bands or congenital cutaneous constriction bands missed at birth also may present as HTTS. However, congenital annular bands are rare and often occur in association with lymphedema and fibrous bands of the affected limb as well as other abnormalities, including rudimentary digits and clubfeet. The mechanism of injury in HTTS begins with obstruction of lymphatic drainage by the constricting ligature, followed by developing lymphedema that, in turn, obstructs venous drainage and outflow and, eventually, arterial inflow. Ischemia, necrosis, and 254 Pediatrics in Review Vol.32 No.6 June 2011
Differential Diagnosis The differential diagnosis of HTTS includes a missed diagnosis of congenital annular bands and ainhum. Ainhum is the spontaneous dactylitis and autoamputation (dactolysis) of a digit, usually of the fifth toe bilaterally. The cause of ainhum is unknown, and the condition occurs predominantly in darker-pigmented individuals living in tropical regions. Ainhum is uncommon in the United States.
Management The treatment of HTTS involves searching thoroughly for the offending constricting ligature, followed by prompt removal once found. Adequate lighting and loupe magnification can help in iden-
Figure 3. Healing fourth toe with scab tissue.
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visual diagnosis
tifying and dividing the constricting hair or thread. The constricting band must be removed completely to restore adequate perfusion. If a remaining band or band segment is suspected, surgical exploration is advised. If the constricting band is removed early, local care of the affected appendage should be sufficient for complete resolution.
Patient Course The hair strand was cut with a small pair of scissors and the hair removed. The hair strand was noted to be the same color as the mother’s long hair and, thus, it was presumed that the tourniquet was shed maternal hair. Shortly after removing the hair strand, the color of the distal toe improved. A local wound dressing was applied to the toe with a topical antibiotic medication, and because the baby was no longer in any apparent distress, he was discharged from the hospital. A few days later in clinic, his toe was noted to be healing well. Two weeks, later the toe appeared almost normal, with just minimal erythema and scab tissue noted (Fig. 3).
Summary • HTTS is well described in the medical literature. If not recognized and treated promptly, HTTS can lead to a catastrophic event such as necrosis and autoamputation of the involved appendage. • Early recognition and treatment of HTTS usually leads to little or no sequelae. • Recognition and treatment depend on increased physician awareness plus performing a thorough and complete physical examination of any child (whether fussy or not) who presents to the physician. • Prevention includes educating parents about HTTS so they seek medical attention when their child becomes unexplainably fussy or develops a swollen, red appendage.
References 1. Barton DJ, Sloan GM, Nichter LS, et al. Hair-thread tourniquet syndrome. Pediatrics. 1988;82:925–928
2. Johnson CF. Intentional banding. Pediatrics. 1989;83:1077–1078 3. Alverson B. A genital hair tourniquet in a 9-year-old girl. Pediatr Emerg Care. 2007;23:169 –170
Suggested Reading Gomez VR. Clubfeet in congenital annular constricting bands. Clin Orthop Relat Res. 1996;323:155–162 Peckler B, Hsu CK. Tourniquet syndrome: a review of constricting band removal. J Emerg Med. 2001;20:253–262
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Visual Diagnosis: Swelling and Redness of the Fourth Toe in a 3-month-old Infant Charles O. Onyeama, Karla Vitale, Kenneth Cochran and Ginikanwa L. Onyeama Pediatr. Rev. 2011;32;253-255 DOI: 10.1542/pir.32-6-253
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Index of Suspicion • Case 1: Status Epilepticus, Hypertension, and Tachycardia in a 5-year-old Boy • Case 2: Cardiopulmonary Arrest During Gymnastics Practice in a Teenage Girl • Case 3: Acute Renal Failure in a Teenage Boy Who Has Autism and Pica Corey Chartan, Elizabeth Aarons, Aliva De, Steven Fishberger, John Messina, Ifrah Abdirahman, Steven Arora, Maisa Dekna and Keith K. Lau Pediatr. Rev. 2011;32;257-263 DOI: 10.1542/pir.32-6-257
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/32/6/257
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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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index of suspicion
Case 1: Status Epilepticus, Hypertension, and Tachycardia in a 5-year-old Boy Case 2: Cardiopulmonary Arrest During Gymnastics Practice in a Teenage Girl Case 3: Acute Renal Failure in a Teenage Boy Who Has Autism and Pica 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 Chartan, Aarons, De, Fishberger, Messina, Abdirahman, Arora, Dekna, and Lau have disclosed no financial relationships relevant to these cases. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.
Case 1 Presentation
Case 2 Presentation
A 5-year-old boy is brought to the ED by emergency medical services in status epilepticus after a 3-day history of headaches. This morning he had a generalized tonic-clonic seizure, and paramedics administered lorazepam at his home. He continues to seize and requires a second dose of lorazepam on arrival to the ED. Once he is stabilized, a history is obtained from the parents. They describe the headaches as generalized, they start suddenly, and nothing seems to alleviate them. The headaches are not worse in the early morning and not associated with vomiting or vision changes. The boy has had no recent illnesses and has been eating well and acting well between the headaches. In the ED, his blood pressure is 137/106 mm Hg, heart rate is 109 beats/min, respiratory rate is 20 breaths/min, and temperature is 37.8°C. On physical examination, he is postictal but has no focal signs. All other physical findings, including on funduscopic examination, are normal. Results of laboratory evaluation, including CBC, basic metabolic panel, urinalysis, thyroid panel, complement assessment, antistreptolysin O titer, and cardiac enzymes, are within normal limits. CT scan of the brain also yields normal results, as does echocardiography. The patient is admitted to the intensive care unit. Further imaging studies reveal the diagnosis.
A 13-year-old previously healthy competitive gymnast collapses while climbing a rope during practice. She exhibits cyanosis and apnea, and cardiopulmonary resuscitation is started immediately. An automated external defibrillator is connected by emergency personnel. The monitor shows a shockable rhythm (Fig. 1), and she is defibrillated once. Thereafter, she develops agonal respirations and sinus tachycardia. She remains unresponsive, has a Glasgow Coma Scale score of 5, and is endotracheally intubated. She has no history of fainting in the past, and her family history is negative for any sudden cardiac deaths, arrhythmias, or structural heart disease. On arrival at the ED, her temperature is 35.4°C, heart rate is 99 beats/min, respiratory rate is 22 breaths/min, blood pressure is 119/ 49 mm Hg, and oxygen saturation is 100% in room air. Her weight is 40 kg. She is comatose but responsive to pain. Her pupils are equally reactive. Her breath sounds are clear bilaterally and heart sounds are normal, no murmurs are appreciated, and her pulses are equal in all extremities. There are no signs of injury or trauma. Laboratory evaluation shows normal serum electrolyte and cardiac enzyme values. Chest radiography and CT scan of brain and neck are negative for any injury, hemorrhage, or infarct. ECG shows transient ventricular bigeminy (Fig. 2), followed by normal sinus rhythm. EchocardiogPediatrics in Review Vol.32 No.6 June 2011 257
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●
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Figure 1. Automated external defibrillator rhythm strip shows ventricular fibrillation
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before delivery of shock. ●
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Figure 2. ECG tracing shows ventricular bigeminy. ●
raphy documents normal anatomy and function. A 24-hour cardiac monitor shows normal sinus rhythm and single atrial premature complexes. Cardiac MRI reveals no abnormalities. The girl is admitted to the intensive care unit. Her condition is managed based on a tentative diagnosis that is confirmed after further testing.
Frequently Used Abbreviations ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR: GI: GU: Hct: Hgb: MRI: WBC:
alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal fluid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate gastrointestinal genitourinary hematocrit hemoglobin magnetic resonance imaging white blood cell
258 Pediatrics in Review Vol.32 No.6 June 2011
Case 3 Presentation A 13-year-old boy who has autism and pica presents with colicky abdominal pain, vomiting, and constipation for 1 month. He vomits three to four times a day and has not passed stool for 2 weeks. He has a poor appetite and has shown a progressive decrease in physical activities. He continues to have good urine output. The only medication he takes is lorazepam. Physical examination reveals a thin, nondistressed boy who has experienced a 7-kg weight loss over the past 3 months and whose height has been at the 25th percentile since age 4 years. He is afebrile, his heart rate is 97 beats/min, respiratory rate is 18 breaths/min, and blood pressure is 100/66 mm Hg. His abdomen is distended and demonstrates diffuse tenderness. Following manual disimpaction, fecal matter shows plasticine, clothing remnants, and hair. The family states that the plasticine was imported from China. Laboratory results are: ● ●
Hgb, 13.6 g/dL (136 g/L) WBC count, 10.5⫻103/L (1.5⫻ 109/L)
Platelet count, 274⫻103/L (274⫻ 109/L) ESR, 46 mm/hr Serum creatinine, 6.2 mg/dL (548 mol/L) BUN, 50 mg/dL (17.9 mmol/L) Bicarbonate, 17 mEq/L (17 mmol/ L) Anion gap, 18 mEq/L (18 mmol/ L) Serum glucose, 84.7 mg/dL (4.7 mmol/L) Serum albumin, 4.3 g/dL (43 g/L) Antistreptolysin O titer, 415 kIU/L (normal, ⬍200 kIU/L) Serum complement 3, 1.56 g/L (normal, 0.73 to 1.73 g/L) Heavy metal screening, negative
Serum calcium, phosphorus, and parathyroid hormone values are normal. Urinalysis shows: ● ● ● ● ● ● ●
● ●
Specific gravity, 1.025 pH, 5.5 Glucose, 1⫹ Ketones, 1⫹ Blood, 2⫹ Protein, 2⫹ 3 to 5 red blood cells/high power field (hpf) 3 to 5 WBCs/hpf 6 to 10 granular casts/hpf
Ultrasonography of the kidneys and bladder yields normal results. Additional evaluation reveals the diagnosis.
Case 1 Discussion Ultrasonography of the abdomen detected a hypoechoic, well-circumscribed mass close to the superior pole of the right kidney. Abdominal CT scan and subsequent MRI scan confirmed a right-sided, 3-cm, low-density suprarenal mass (Fig. 3). Concentrations of catecholamines and metanephrine in urine collected over 24 hours as well as fractionated plasma free metanephrine
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family history of any of these disorders should consider undergoing genetic testing.
Clinical Presentation
Figure 3. MRI scan shows a 3-cm lowdensity suprarenal mass on the right side.
all were elevated, suggesting the diagnosis of pheochromocytoma.
The Condition Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells located in the adrenal medulla. These uncommon tumors occur in fewer than 0.2% of patients who have hypertension, and only 10% of the tumors are found in children. In fact, pheochromocytomas are known as the “10% tumor” because in adults, approximately 10% of tumors are bilateral, 10% are located outside of the adrenal glands, 10% are familial, and 10% are malignant. Compared with adults, children have a higher incidence of bilateral, extra-adrenal, and familial tumors. Some studies also suggest a possible higher incidence of malignancy in children. The most common extra-adrenal sites include locations anywhere along the abdominal sympathetic chain, the periadrenal area, and even the urinary bladder. The familial tumors may be associated with multiple endocrine neoplasia syndrome type 2A and type 2B, von Hippel-Lindau disease, and neurofibromatosis type 1. An asymptomatic person who has a
The clinical features of pheochromocytoma result from excessive secretion of epinephrine and norepinephrine. The classic triad of symptoms consists of sweating, episodic headaches, and tachycardia. The tumor usually is associated with paroxysmal hypertension, although sustained hypertension is more common in children. Less frequently occurring signs and symptoms include pallor, nausea, vomiting, weakness, abdominal pain, and orthostatic hypotension. Malignant hypertension can occur, and the patient may present with increased intracranial pressure or encephalopathy associated with seizures. On examination, patients may appear anxious and pale while experiencing palpitations and tachycardia. There may be evidence of cardiomyopathy, arrhythmias, or papilledema.
Differential Diagnosis Various disorders must be considered in children who present with persistent hypertension, especially those who also have evidence of end-organ damage. Of these, renal or renovascular diseases, including glomerulonephritis and renal vein thrombosis, are at the top of the list. A common cardiac cause for hypertension is coarctation of the aorta. Endocrinopathies such as hyperthyroidism and Cushing syndrome also should be considered and ruled out. Patients who take an overdose of tricyclic antidepressants or abuse cocaine also may present with hypertension. Neuroblastomas and ganglioneuroblastomas secrete vasoactive intestinal peptides, and affected patients may present with hypertension.
Diagnosis Because pheochromocytomas secrete catecholamines, the laboratory study to establish the diagnosis is measurement of catecholamines and their metabolites. These chemicals include homovanillic acid, vanillylmandelic acid, and metanephrine, which are metabolites of dopamine, norepinephrine, and epinephrine, respectively. Such substances can be measured in a 24-hour urine specimen, which always should be analyzed for urinary creatinine to establish adequacy of collection. In addition, fractionated metanephrines in the plasma is a sensitive test. Measurements of catecholamines and metabolites in plasma or urine are highly sensitive and specific in patients who have symptoms. Abnormal urine or plasma test results should be followed by imaging studies. CT scan or MRI usually localizes tumors in the adrenal area. If these studies are negative in the presence of clinical evidence of pheochromocytoma, 123-I-metaiodobenzylguanidine (MIBG) scintigraphy can be performed. MIBG structurally resembles norepinephrine and, therefore, is taken up actively by neuroendocrine cells and stored in the neurosecretory granules. Such storage results in a higher concentration of MIBG in neuroendocrine cells compared with other tissues and, thus, is helpful in locating and diagnosing pheochromocytomas.
Management Surgical removal of the tumor usually is curative but is associated with risks. The procedure should be performed only after adequate preoperative medical therapy. Alpha-adrenergic blockade with phenoxybenzamine is the first-line therapy. The dose may be increased every few days until the symptoms resolve and blood pressure normalizes. After adequate alpha blockade is achieved, beta blockade Pediatrics in Review Vol.32 No.6 June 2011 259
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may be started a few days before surgery. Beta blockade never should be started before alpha blockade because unopposed alpha-receptor stimulation results in significant hypertension. Great care must be taken during surgery because manipulation of the tumor intraoperatively may result in marked secretion of catecholamines, causing severe hypertension. Hypotensive crisis may occur because of a postoperative drop in catecholamine concentrations. When bilateral pheochromocytomas are present, bilateral adrenalectomy may be necessary, although it is sometimes possible to preserve some adrenal cortex and avoid permanent adrenal insufficiency. After tumor removal, catecholamine values usually fall to normal in approximately 1 week. Longterm follow-up should be pursued in all patients because there is a risk of both recurrent disease and malignant transformation, even years after initial presentation. This patient was started on phenoxybenzamine, followed by labetalol for 14 days. Two days before surgery, he received intravenous alpha and beta blockade. He underwent exploratory laparotomy and resection of the adrenal pheochromocytoma. Postoperatively, his blood pressure remained stable. Four days later, he was discharged, having had no complications or recurrent hypertension.
Lessons for the Clinician ●
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Hypertension in children and adolescents warrants a thorough investigation. Hypertension in children has many causes, and a systematic approach is necessary to identify the cause for hypertension. Treatment of patients who have pheochromocytomas should be undertaken by physicians experienced in management of these tumors.
260 Pediatrics in Review Vol.32 No.6 June 2011
(Corey Chartan, MD, Elizabeth Aarons, MD, Chris Evert Children’s Hospital, Broward General, Fort Lauderdale, FL)
Case 2 Discussion Sudden cardiac death is defined as an unexpected death due to cardiac causes occurring in a short time period (generally within 1 hour of symptom onset). If an intervention restores circulation, the patient is said to have survived sudden cardiac death. About 10% of pediatric deaths after 1 year of age are sudden, and the individual risk is estimated to be about 1 in 20,000 to 1 in 50,000 per year. Causes may be cardiac, noncardiac (respiratory, infectious, drowning, epilepsy, intracranial hemorrhage), or unknown (no identifiable cause at necropsy). A systematic approach to evaluation for identifiable underlying cardiac problems is essential. Structural defects in the heart may range from known congenital heart disease to hypertrophic cardiomyopathy, anomalous origin of the left coronary artery, myocarditis, arrhythmogenic right ventricular dysplasia, and coronary artery disease. Secondary or primary pulmonary hypertension can cause sudden death. In the absence of structural heart disease, conditions predisposing to malignant arrhythmias, such as WolffParkinson-White (WPW) syndrome, long or short QT syndrome, Brugada syndrome, or catecholamine-induced polymorphic ventricular tachycardia (CPVT) should be considered. In this patient, echocardiography, continuous cardiac monitoring, and cardiac MRI showed no abnormalities. Her ECG showed no evidence of QT prolongation, ventricular pre-excitation, or ST- or T-wave abnormalities. Thus, there appeared to be no evidence of any structural
heart disease or of any electrocardiographic abnormalities consistent with QT prolongation, WPW, or Brugada syndrome. The presumptive diagnosis was CPVT. The girl underwent implantable cardioverter-defibrillator (ICD) placement, with the pacemaker set at a low rate of 40 beats/min and set for defibrillation shock to occur at rates greater than 205 beats/min. During her hospital stay, she had a brief period of short-term memory loss and confusion following extubation. However, neurologic examination and EEG findings were normal. She subsequently recovered normal neurologic function. She was discharged from the hospital, treated with atenolol, and advised against participating in competitive gymnastics. Genetic testing was positive for CPVT with a deleterious mutation of RYR2 Arg 420 Trp. Her brother and mother subsequently were found to have the same mutation.
The Condition CPVT is a recently described clinical entity characterized by exercise- or stress-induced syncope or cardiac arrest due to ventricular tachyarrhythmias in the absence of QT prolongation or organic heart disease. The clinical hallmark is normal electrocardiographic findings at rest and a reproducible form of polymorphic ventricular tachycardia (VT) that can degenerate into ventricular fibrillation (Fig. 4) with exercise, isoproterenol infusion, or other forms of adrenergic stimulation. This entity was described initially in 1975. (1) An extensive report on the follow-up evaluation of 21 patients who had CPVT was published in 1995. (2) With mortality rates of 30% to 50% by age 35 years, it is one of the most malignant channelopathies. Two forms of CPVT have been identified. Mutations in the cardiac
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index of suspicion
competitive gymnastics but participates in modified track.
Lessons for the Clinician ●
●
Figure 4. ECG tracing shows catecholamine-induced polymorphic ventricular tachy-
cardia.
ryanodine receptor channel (RYR2) gene account for the autosomal dominant form, known as CPVT 1, which is present in 50% to 65% of cases. Mutations in the cardiac calsequestrin (CASQ2) gene are responsible for the rare autosomal recessive form, CPVT 2.
Clinical Presentation The prevalence of CPVT in the population is not known but has been estimated to be around 1 in 10,000. The clinical presentation includes syncope or sudden cardiac arrest triggered by physical exercise, swimming, or emotional stress. The mean age of onset of symptoms is between 7 and 9 years. If the patient develops hypoxic seizures, there may be a delay in identification of the condition. Cases also are detected during routine screening of family members of the index case. Diagnosis is made by exercise stress test resulting in the characteristic arrhythmia, which follows the sequence of junctional tachycardia; ventricular premature contractions with quadrigeminy, trigeminy, and bigeminy; short or long salvoes of bidirectional tachycardia; and bursts of rapid, irregular, polymorphic tachycardia. The findings disappear in the reverse order. This arrhythmia can be reproduced predictably by exercise as well as isoproterenol infusion.
Management Conventionally, the therapeutic approach has been the use of beta blockers because of the catecholaminergic mechanism of the arrhythmia. The most widely used beta blockers have been nadolol and propranolol. However, their efficacy over long-term follow-up has been questioned. (3)(4) Some studies have shown that verapamil may be an effective alternative, and a recent report has suggested the use of verapamil in combination with beta blockers to decrease the prevalence of ventricular arrhythmias in CPVT. (5) Given the lack of absolute efficacy of any pharmaceutical regimen, ICD placement should be considered in addition to the use of beta blockers for prevention of sudden cardiac death in all affected patients who are survivors of cardiac arrest, continue to experience syncope, or have documented sustained VT despite betablocker therapy. (6) The maximum tolerated dose of beta blockers should be prescribed to patients who have CPVT and an ICD placed to prevent episodes of VT or ventricular fibrillation and to avoid inappropriate shocks due to sinus tachycardia. Sports and all forms of vigorous physical activities are contraindicated despite therapy. This patient has not had any arrhythmic events while receiving betablocker therapy. She has discontinued
●
It is critical to recognize and appropriately manage CPVT because of its malignant potential. CPVT should be looked for in children presenting with convulsions or syncope after exercise or emotion. Genetic testing should be considered for confirmation and refinement of clinical diagnosis as well as to identify asymptomatic high-risk individuals who will benefit from lifestyle modification, drug therapy, and possibly prophylactic ICD implantation.
(Aliva De, MD, Steven Fishberger, MD, John Messina, MD, St Joseph’s Children’s Hospital, Paterson, NJ)
References 1. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J. 1975;37:339 –344 2. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995; 91:1512–1519 3. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106:69 –74 4. Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart. 2003; 89:66 –70 5. Rosso R, Kalman JM, Rogowski O, et al. Calcium channel blockers and beta-blockers versus beta-blockers alone for preventing exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2007;4:1149 –1154 6. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden Pediatrics in Review Vol.32 No.6 June 2011 261
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cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e385– e484
Case 3 Discussion Ultrasonographic-guided percutaneous renal biopsy was performed, and the findings were consistent with the diagnosis of acute interstitial nephritis (AIN). Infiltrates consisting of lymphocytes and eosinophils as well as edema were noted in the interstitium, but no glomerular or vascular pathology was detected. Acute renal failure accounts for 5% of all pediatric hospitalizations. Timely diagnosis and proper management are necessary to prevent permanent renal injury. This patient presented to the medical team with the acute onset of renal failure. The potential causes of acute renal failure can be divided broadly into prerenal, renal, and postrenal disorders. The most common causes of acute renal failure are those related to prerenal injury. If not aggressively managed, parenchymal damage may be irreversible. This patient’s recent poor oral intake and repeated vomiting may have led to hypovolemia and reduced renal perfusion, leading to prerenal failure. The presence of recent weight loss and mild tachycardia also corroborate a prerenal cause for his renal insufficiency. However, his physical findings did not suggest the presence of severe hypovolemia, and his good urine output also pointed to the possibility of other causes of his renal dysfunction, such as a renal disorder. Proteinuria can occur in both glomerular 262 Pediatrics in Review Vol.32 No.6 June 2011
and tubular injury, but glucosuria (in the absence of hyperglycemia) is more consistent with tubular damage. Although granular casts can be a normal finding in healthy individuals, they are seen more commonly in patients experiencing dehydration, tubulointerstitial diseases, and lead intoxication. Heavy metal exposure was highly likely in this patient and may have contributed to his symptoms, but results of screening tests for heavy metal poisoning were negative. Although his antistreptolysin O titer was elevated, the absence of hypertension, gross hematuria, and a normal serum complement 3 value made poststreptococcal glomerulonephritis unlikely. The absence of hematuria and oliguria also made acute tubular necrosis less probable. Also, a postrenal cause of acute renal injury, such as obstruction, was ruled out by normal renal ultrasonography findings. Hence, despite substantial clinical clues that this patient had a renal cause for his renal failure, prerenal causes could not be excluded totally. With AIN confirmed, identifying an inciting agent as the cause of his nephritis remained difficult. A careful search for all possible causes of his interstitial nephritis revealed no apparent source. The additives in the plasticine possibly were offending agents, although, given his pica, he may have ingested some other unknown substance. His exposure to this adulterant may have been prolonged due to his chronic constipation. Retrospectively, his recent vomiting and anorexia may have been due to the azotemia rather than the cause of his renal failure. His serum creatinine concentration remained the same after bowel cleaning. As a result, he was started on corticosteroids, and his serum creatinine returned to 1.1 mg/dL (97.2 mol/L) in 3 weeks.
The Condition AIN is responsible for 1% to 3% of cases of acute renal failure. Since the first description of interstitial nephritis as a postinfectious acute inflammatory disease in patients suffering from diphtheria and scarlet fever by Councilman in late 19th century, other associations have been recognized over the years. Although drugs and toxins are the most frequent causes of AIN in the modern era, a definite causative agent is not always identifiable. However, herbal medicine as a cause of AIN has gained considerable attention recently. The diagnosis may be missed if the history of usage is not sought specifically. The first case of aristocholic acid-induced AIN was reported in early 1990. Since then, AIN has been described in association with numerous other herbal medicines. The onset of AIN can occur from hours to months after beginning to take the inciting agent. The features of drug-induced AIN are acute deterioration of renal function, mild-to-moderate proteinuria, glucosuria, and hematuria. Along with the clinical manifestations of acute renal failure, affected patients also may present with the classic symptoms of skin rashes, low-grade fever, mild arthralgia, and eosinophils in the urine. However, these signs are not pathognomonic and may not be present in all patients. If in doubt, the diagnosis always should be confirmed by renal biopsy. The hallmark of AIN is the infiltration of inflammatory cells within the renal interstitium with associated edema. The inflammatory cells typically are mononuclear cells, with a variable number of plasma cells and eosinophils.
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index of suspicion
Management The mainstay of treatment of drug- or toxin-induced AIN is removing the cause, although some individuals continue to deteriorate even after the toxins are removed. It is unclear whether corticosteroids decrease the risk of chronic renal failure. Although no randomized, controlled trial has been published, investigators have reported a faster clinical improvement in patients treated with corticosteroids, especially when started within 2 weeks of the onset of the symptoms.
Lessons for the Clinician ●
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Although AIN is not the most common cause of acute renal failure in children, pediatric clinicians must be aware of this disorder. Even in the absence of an obvious inciting cause, this diagnosis should be considered under certain circumstances, especially when features of tubulopathy, such as glucosuria and proteinuria, are present. It is important to obtain a full drug history, including prescribed and over-the-counter medications, folk remedies, and illicit drugs, in
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patients who present with signs and symptoms of acute renal failure. Pica is not a benign behavioral problem; under certain circumstances, serious medical consequences, such as organ failure, may occur.
(Ifrah Abdirahman, MD, Steven Arora, MD, Maisa Dekna, MD, Keith K. Lau, MD, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada) To view Suggested Reading lists for these cases, visit pedsinreview. aappublications.org and click on Index of Suspicion.
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Index of Suspicion • Case 1: Status Epilepticus, Hypertension, and Tachycardia in a 5-year-old Boy • Case 2: Cardiopulmonary Arrest During Gymnastics Practice in a Teenage Girl • Case 3: Acute Renal Failure in a Teenage Boy Who Has Autism and Pica Corey Chartan, Elizabeth Aarons, Aliva De, Steven Fishberger, John Messina, Ifrah Abdirahman, Steven Arora, Maisa Dekna and Keith K. Lau Pediatr. Rev. 2011;32;257-263 DOI: 10.1542/pir.32-6-257
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Psychogenic Nonepileptic Seizures (Pseudoseizures) Hema Patel, David W. Dunn, Joan K. Austin, Julia L. Doss, W. Curt LaFrance, Jr, Sigita Plioplys and Rochelle Caplan Pediatr. Rev. 2011;32;e66-e72 DOI: 10.1542/pir.32-6-e66
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/32/6/e66
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 © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Article
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Psychogenic Nonepileptic Seizures (Pseudoseizures) Hema Patel, MD,* David W. Dunn, MD,*†, Joan K. Austin, PhD, RN,§ Julia L. Doss, PsyD,‡ W. Curt LaFrance, Jr, MD, MPH,** Sigita Plioplys, MD,§§ Rochelle Caplan, MD††
Author Disclosure
Objectives
After completing this article, readers should be able to:
1. Recognize the antecedent stressors associated with psychogenic nonepileptic seizures in children. 2. Identify pediatric nonepileptic seizures clinically. 3. Distinguish psychogenic nonepileptic seizures from epileptic seizures and other paroxysmal nonepileptic events. 4. Be aware of the comprehensive assessment needed to evaluate the child who has possible psychogenic nonepileptic seizures. 5. Become familiar with the management approaches used to treat psychogenic nonepileptic seizures in children.
Drs Patel, Dunn, Austin, Doss, LaFrance, Plioplys, and Caplan have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/
Definition Nonepileptic seizures are episodic behavioral events that mimic epileptic seizures but are not associated with abnormal cortical electrical discharges. Psychogenic nonepileptic seizures (PNES) are related to an underlying psychological stressor or conflict and differ from other paroxysmal nonepileptic events. A variety of terms have been used in the literature to describe these events, including hysterical epilepsy, hysteroepilepsy, psychogenic seizures, pseudoepileptic seizures, pseudoseizures, and nonphysiologic or functional seizures. The term psychogenic nonepileptic seizure is preferred because it is nonpejorative and neutral, although there is continuing discussion regarding the most appropriate terminology.
investigative use of a commercial product/
Demographics
device.
PNES are common. Although population data are limited, one report suggested a prevalence of 2 to 33 per 100,000, basing the estimate on an assumption that 10% to 20% of patients seen in an epilepsy center would be found to have PNES. (1) Reviewing video-electroencephalography (EEG) monitoring records, Patel and associates (2) and Wyllie and colleagues (3) found that 3.5% and 7% of children, respectively, seen in clinic for assessment of persistent seizures had PNES. PNES occur in both elementary-age children and in adolescents as well as in all age groups of adults. (2)(3)(4)(5)(6) A female preponderance has been reported but is more pronounced in adolescents than children. (2)(5) Overall, this sex-related trend is more marked among adults, occurring in 75% to 80% of the patients. (6) It is can be difficult to distinguish PNES from epileptic seizures based solely on clinical features. In children, diagnosis often is delayed for 6 months or more. (2)(4) Because epileptic seizures are more common and practitioners are more familiar with them, a large percentage of patients who exhibit PNES are treated initially with antiepileptic drugs. Children seen in the emergency department may be started on antiepileptic drugs by the treating physicians before complete evaluation, and when the diagnosis is unclear, physicians may start antiepileptic drugs because they worry about not giving medication to a child who might have epilepsy. *Section of Child Neurology, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN. † Section of Child Psychiatry, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN. § Indiana University School of Nursing, Indianapolis, IN. ‡ Minnesota Epilepsy Group, St. Paul, MN. **Department of Neuropsychiatry and Behavioral Neurology, Brown Medical School, Rhode Island Hospital, Providence, RI. §§ Department of Psychiatry and Behavioral Sciences, Northwestern University’s Feinberg School of Medicine, Chicago, IL. †† Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA.
e66 Pediatrics in Review Vol.32 No.6 June 2011
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The cost of misdiagnosing PNES as epileptic seizures is high from both a financial and psychosocial standpoint. Misdiagnosis can result in medical costs of inappropriate and often costly treatment, unnecessary hospitalizations and emergency department visits, and loss of work as well as increased strain on interpersonal relationships within the family. In addition, patients may be exposed to a variety of iatrogenic complications, such as invasive procedures in prolonged PNES (eg, psychogenic nonepileptic status or pseudostatus epilepticus) and adverse effects from unneeded antiepileptic drugs. Patients who have both PNES and epilepsy are at risk for invasive monitoring and evaluation for epilepsy surgery if they are misdiagnosed as having refractory epilepsy. Most importantly, misdiagnosis results in patients not receiving muchneeded appropriate psychiatric treatment. From a psychiatric standpoint, achieving symptom reduction may be more difficult, treatment of underlying psychological concerns may be delayed, and possibly the dynamics that are responsible for the symptoms may be perpetuated.
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Clinical Aspects Obtaining a thorough history is the critical part of the evaluation. (7)(8) Whenever possible, the episode should be described by an eyewitness. Having the family bring in a video of the events may be very beneficial. Adolescents and children should be asked about possible stressors without their parents present. Key elements that must be explored in the history include: 1. Description of the episode. PNES often are associated with certain physical manifestations that may help differentiate them from epileptic seizures (Table). PNES has been described extensively in adults, (6) but there are fewer reports in children, (2)(3)(4)(5) with the largest study thus far involving 59 patients. (2) These investigators reported a statistically significant difference in the clinical description of spells in young children compared with adolescents. PNES were more commonly manifested as subtle motor activity in children younger than 13 years of age, such as prolonged staring with unresponsiveness, isolated head shaking, eye fluttering, generalized limpness, and behavioral changes or combativeness. On the other hand, in the group of children 13
Differences in Physical Manifestations of Psychogenic Nonepileptic and Epileptic Seizures Table.
Factor
Psychogenic Nonepileptic Seizures
Epileptic Seizures
Duration Clinical features during episode Time of day
Prolonged Fluctuating Usually during wakefulness in the presence of an audience Preserved even with generalized motor activity
Briefer (usually <5 min) Stereotypic May occur in sleep whether or not anyone is present Usually altered (exception is supplementary motor area seizures) Abrupt
Consciousness Onset Head movements Extremity Vocalizations Eyes Pelvic thrusting Incontinence Related injury Tongue bite Postictal change
Gradual, with slow escalation in intensity More frequently side-to-side Out-of-phase movements, unusual posturing Emotional (crying) in the middle or end of episode Closed during the episode Forward direction Rare Inconsistent with fall Occasional (usually at the tip) None or brief, even after prolonged generalized convulsive event
Usually unilaterally turned, with staring expression In-phase movements, rhythmic muscle contractions Cry at the onset of episode May be open during the episode Retrograde direction May be present Consistent with fall Common (at the side) Prolonged, with confusion and exhaustion (although maybe absent after frontal lobe seizures)
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years and older, the clinical features were similar to those seen in adults, characterized more commonly by prominent motor activity with generalized arrhythmic jerking or flailing of extremities, side-to-side head movements, and forward pelvic thrusting. 2. Presence of precipitating factors. Do the episodes occur in a specific setting, such as at school or home or in the presence of a specific person? Particular attention should be placed on the timing and setting of the first episode. 3. History of traumatic events or stressors. Several risk factors have been found to be associated with an increased tendency for PNES. (2)(3)(7)(9) In children, the most commonly identified stressors include: • School difficulties, such as difficulty with learning, (2)(10) poor school performance, stress with school work, change in school environment, and behavioral problems at school with detention or suspensions. • Family discord, including parental or sibling hostility, parental divorce or separation, domestic physical abuse, and financial stress. • Interpersonal conflicts with teachers and social difficulties with peers or friends. • Sexual abuse, often difficult to discover in the initial acute setting, has been reported more frequently in adults who have PNES. (6) A history of sexual abuse is less frequent in children who have PNES, with ranges from 5% to 32%, (2)(3)(9) and further study is necessary to elucidate the true contribution. • Other stressors include bereavement, prior or concurrent somatic illness, and illness in the family. 4. History of coexistent psychiatric disorders. Many adults who have PNES have depression, anxiety disorders, or borderline personality disorders. (6) Children who have PNES also have more behavioral and emotional problems than children in the general population. Wyllie and associates (3) reported mood disorder in 32% and anxiety disorder in 24% of children exhibiting PNES, and Vincentiis and colleagues (9) reported mood/anxiety problems in 62%. Studies of the presence of severe psychopathology in children who have PNES present conflicting results. The prevalence is higher in adolescents than children. We found comorbid psychopathology in 16% of children younger than 13 years of age and 48.6% of adolescents who had PNES. (2) 5. History of epilepsy and other neurologic illness. A positive history of epilepsy or other neurologic illness should not exclude consideration of a comorbid diagnosis of PNES. Coexisting neurologic illness, include68 Pediatrics in Review Vol.32 No.6 June 2011
ing cognitive dysfunction such as learning disabilities, (10) headaches, and attention-deficit/hyperactivity disorder (ADHD), (2) have been reported in children who have PNES. Concurrent epilepsy was found in 12% of the affected children seen by Wyllie and colleagues, (3) 14% of patients studied by Kramer and coworkers, (5) and 44% of the children reported by Patel and associates. (2) Nonepileptic status may occur and is mistaken easily for epilepsy in children. 6. A family history of epilepsy (2)(4)(9) and somatization. These findings may serve as a behavioral model for children to shape the expression of their own symptoms.
Differential Diagnosis Other paroxysmal nonepileptic events are included in the differential diagnosis and can be mistaken for epileptic seizures or PNES. Particularly in younger children, many paroxysmal disorders can mimic seizures. Salient clinical features of some of the more common paroxysmal events can help differentiate them from PNES. Breath-holding spells occur at a peak age of 6 to 18 months, decreasing in frequency in the second postnatal year. Cyanotic episodes are more common than pallid episodes. These spells always are preceded by brief, vigorous crying for usually less than 15 seconds due to some emotional stimulus such as anger or frustration. The child then becomes silent, holds the breath in expiration, and develops cyanosis. There may be loss of consciousness with a brief period of limpness, followed by opisthotonic posturing, stiffening, or brief clonic movements. Recovery usually is within 1 minute, with a few gasps, followed by return to baseline. Parents should be reassured that these episodes are self-limited. Self-stimulation is masturbatory behavior that occurs in infants and young children. The episodes are characterized by stereotypic movements, usually involving the lower trunk, such as tightening of the thighs and gluteal muscles and rhythmic pelvic thrusting. These movements may continue for minutes to hours and may be associated with irregular breathing, flushing, and grunting. The episodes may be mistaken for bouts of abdominal pain, partial seizures, or movement disorders such as dystonia, resulting in unnecessary evaluation. The condition is benign and self-limited. Reassurance and counseling should be provided. The term “gratification behavior” may be more helpful because parents are occasionally taken aback by the term “masturbation.” Gastroesophageal reflux in babies and in children who have disabilities (eg, cerebral palsy) may be associated with back arching that occurs after feedings. Dyspeptic
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dystonia, or Sandifer syndrome, is a rare condition that is associated with gastroesophageal reflux or hiatal hernia. The condition occurs commonly in children 4 to 14 years of age, although such children often had feeding problems in infancy. The disorder is characterized by spastic torticollis and dystonic body movements, such as neck extension, head nodding, gurgling sounds, and writhing movements of the limbs. The child may appear quiet during the posturing. These behaviors can be differentiated from seizures by the signs generally appearing after feeding. Neurocardiogenic or vasovagal syncope commonly is confused with epilepsy. The syncope is precipitated by prolonged standing, change in posture, heat, fatigue, or hunger. The syncopal episode is characterized by a classic prodrome of lightheadedness, blurred vision, pallor, or sweating, followed by loss of consciousness from a few seconds up to 1 or 2 minutes. Convulsive syncope can result from cerebral ischemia and is not indicative of predisposition to epilepsy. Tonic posturing or brief jerking of the extremities and, rarely, even incontinence results from cerebral hypoxia. Following the episode, the patient appears pale and diaphoretic without clearly obvious disorientation. Other causes of syncope include cardiovascular-mediated syncope due to structural or conduction heart defects. If there is any question of an arrhythmia, it is prudent to obtain EEG. Some episodes of cardiovascular-mediated syncope are associated with a Valsalva-like maneuver, such as micturition, trumpet playing, and weight-lifting. Differentiation from epilepsy is based primarily on the clinical features. Tics are sudden, brief, repetitive, rapid involuntary movements of the face, neck, and shoulders. Motor tics can be simple or complex. Simple motor tics consist of isolated movements, such as head jerking, darting of the eyes, or twitching of the nose. Complex tics are characterized by more coordinated, sequential movements, such as head shaking associated with shoulder shrugging. Tics occur in clusters, are exacerbated by emotional stress and excitement, and are absent during sleep. Efforts to suppress the tics volitionally result in an increasing urge to perform them, with relief after doing so. Most tic behavior terminates spontaneously, although in some cases, the patient may progress into Tourette syndrome. Tics occasionally may be mistaken for myoclonic seizures, which also are characterized by brief isolated jerks of one or more extremities without associated change in responsiveness. Migraine has several manifestations. Migraine without aura is characterized by severe throbbing headache that is most frequently frontal or temporal; more fre-
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quently bilateral; commonly associated with nausea, vomiting, photophobia, and phonophobia; and often relieved by sleep in a dark, quiet place. Migraine headache with aura is preceded by an aura such as blurred vision, brightly colored lights, scotomata, fortification figures, or distortion of body image (Alice in Wonderland syndrome). Other migraine syndromes, such as basilar, confusional, ophthalmoplegic, and hemiplegic migraine, which are associated with neurologic dysfunction and occasionally altered sensorium, now are included in the category of migraine with aura. Childhood “periodic syndromes,” such as cyclic vomiting syndrome, abdominal migraine, benign paroxysmal vertigo of childhood, and benign paroxysmal torticollis, are considered precursors of migraine. Further testing, including EEG and neuroimaging studies, may be indicated if structural abnormalities or epilepsy are in the differential diagnosis. Parasomnias are sleep-related phenomena that may occur during all the stages of sleep, including sleep onset (a rhythmic movement disorder characterized by gratification phenomena such as head banging or body rocking), nonrapid eye movement (REM) sleep (confusional arousals, night terrors, sleepwalking), and REM sleep (nightmares, REM sleep behavior disorder). A good clinical description by the parents and, if possible, a home video of the event help differentiate these episodes from seizures. Stereotypies are complex, repetitive, rhythmic, seemingly purposeful movements that are suppressible by distraction and do not affect daily activities. They occur in brief clusters, especially when the child is excited or stressed. Stereotypies most frequently involve the arms and head and present as arm flapping, hand rotation, or head nodding. They are seen in children who have normal development and also in children who have autistic spectrum disorder, learning disabilities, and ADHD. Such children usually have a chronic course, with complete resolution of stereotypies occurring in only about 5% by 11 to 12 years of age. Reviewing a home video of the event often helps differentiate these episodes from seizures. Paroxysmal movement disorders such as paroxysmal dystonic (nonkinesogenic) choreoathetosis and paroxysmal kinesogenic choreoathetosis constitute a group of sudden disturbances of neurologic function associated with a variety of unusual movements such as dystonia, chorea, or athetosis, many of which are related to channelopathies that can be mistaken for seizures. These conditions frequently are inherited. Paroxysmal dystonic choreoathetosis begins in early childhood and is characterized by episodes of dystonia and choreoathetosis inPediatrics in Review Vol.32 No.6 June 2011 e69
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volving the face, trunk, and extremities, often associated with dysarthria and dysphagia, that last from minutes to several hours and occur several times a week. The attacks start spontaneously at rest; after alcohol intake; or with stress, hunger, or excitement. This condition responds to clonazepam. The attacks of paroxysmal kinesogenic choreoathetosis are brief (usually ⬍1 or 2 minutes) and consist of dystonic or choreoathetotic movements affecting one or more extremities, occurring several times a day, and usually precipitated by sudden movement after rest. The movements respond to low doses of carbamazepine or phenytoin. Consciousness is retained in both of these disorders. PNES also should be differentiated from other behavioral nonepileptic disorders. Somatoform disorders, a group of conditions characterized by physical symptoms suggesting a medical disorder but representing a psychiatric condition, also may be considered. Malingering, the willful production of symptoms for gain, and factitious disorder, a need to assume the sick role, are seen predominantly in adults and rarely in children. Seizures are a frequent presenting complaint in factitious disorder by proxy. In this disorder, the caregiver falsely presents symptoms or signs of seizures in a child and assumes the sick role by proxy.
Evaluation Distinguishing between PNES and epileptic seizures can be one of the more challenging tasks facing the clinician. (6) Accurate diagnosis of PNES requires a high degree of suspicion. PNES should be suspected whenever: ●
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The events have atypical clinical features, such as occurring only in the presence of an audience or at unusual times. The PNES may be associated with certain stressors, although often the stressors are not readily apparent. The events occur frequently despite adequate concentrations of appropriate antiepileptic medication. There is a history of repeated hospitalizations or emergency department visits. There appears to be a lack of concern about psychosocial stresses in the child’s life and an excessive emotional response to the PNES episodes. (8) Several routine EEG tracings are normal.
Routine interictal EEG has some limitations. A random normal interictal EEG result neither rule outs epilepsy nor confirms the diagnosis of PNES. Similarly, an abnormal interictal EEG tracing with epileptic activity does not by itself confirm epilepsy. Interictal epileptiform activity, such as generalized spike-slow wave discharges, e70 Pediatrics in Review Vol.32 No.6 June 2011
may be seen in 2% to 3% of asymptomatic individuals. An abnormal EEG result may be seen in patients who have epilepsy, and if these patients also exhibit PNES, difficulty may arise in ascertaining the true nature of any given episode. Prolonged video-EEG monitoring remains the gold standard for definitively diagnosing PNES. Although this study is performed in an inpatient setting, thus separating the patient from routine environmental and social triggers, it has the benefit of simultaneous video recording and less artifact. Therefore, it is preferable to a 24-hour ambulatory EEG. By extending the recording time, prolonged video-EEG increases the likelihood of capturing the events of concern. A family member or friend who has witnessed the episode should be in the room at all times. If spontaneous spells do not occur, provocative procedures such as suggestion, hyperventilation, and photic stimulation may be used to elicit the event. Confirmation by the family that the recorded event is the “habitual event of clinical concern” is essential. If multiple types of episodes are reported, all the different episodes should be recorded. A definitive diagnosis of PNES is made only if the recorded event is confirmed to be the habitual event of clinical concern and is not associated with epileptiform activity on EEG. If typical episodes are not recorded, a conclusive diagnosis of PNES becomes more difficult. Lack of epileptiform changes on EEG during the episode does not indicate conclusively that the episode definitively is PNES. Clinically, frontal lobe seizures often are misdiagnosed as PNES. These spells commonly manifest with bizarre bilateral motor activity that may be clinically mistaken for PNES. In addition, the muscle and movement artifact associated with these seizures may obscure EEG activity, making it difficult to discern any ongoing ictal pattern. Also, some partial seizures associated with deep-seated foci may not produce an ictal pattern on routine surface EEG. For this reason, recording several of the events of clinical concern can be helpful in distinguishing between PNES and difficult-todiagnose epileptic seizures. Serum prolactin concentrations rise severalfold 5 to 20 minutes following a generalized tonic-clonic seizure of more than 30 seconds’ duration and decline to normal within 1 hour. This peak value can be compared with a sample obtained 90 to 120 minutes later. Patients who experience PNES do not demonstrate the expected rise in serum prolactin values. However, this technique has several limitations. There is a high false-negative rate in patients who have complex partial seizures, in which prolactin concentrations are raised in only 60% of cases,
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and the elevation is not as high as is seen following a generalized tonic-clonic seizure. Also, because of the rapidity with which the values peak and decline following a seizure, the timing for blood collection is critical. The data have been studied predominantly in adults, and the value of this testing in children and adolescents is uncertain. Therefore, this method is not used routinely.
Management It is important to convey the diagnosis of PNES to the patient and family in an appropriate, understanding, and nonjudgmental manner without making them feel that the child is “faking it,” “is crazy,” or that “it is all in his or her mind.” (7)(8) Clinicians should remind families that stress can precipitate a variety of symptoms, such as headaches, increased heart rate, and fatigue, and similarly can cause symptoms and signs of PNES. The video of the episodes should be reviewed with the family to help confirm that the episodes recorded are similar to those witnessed by the family and to educate the family about the episodes that clearly are PNES. Clarity in diagnosis is essential. If the episodes are referred to as seizures, the parents should be told that the events are not epileptic, ie, “there is no abnormal brain cell firing associated with the events.” Parents should understand that because EEG results are normal during the episode, these events are not epilepsy or caused by brain damage. Although videoEEG does not determine the cause of the episode, it is important that epilepsy be ruled out because antiepileptic drugs are ineffective for PNES. The clinician should explain that the spells may have emotional causes, of which the patient may not be aware, and that the patient may benefit from assessment and treatment by trained mental health personnel, such as a psychiatrist or psychologist. It is important to maintain physician-patient contact even after the referral to a mental health professional because of the need for a multidisciplinary management approach. (7) The objective of management is early diagnosis to prevent the episodes from becoming the patient’s primary coping mechanism for dealing with stress. (7)(8) In the outpatient setting, antiepileptic drugs are weaned very slowly, only after psychiatric care has been initiated and the patient and parents have accepted and understand the PNES diagnosis and treatment approaches. The child or adolescent is referred to a psychiatrist or psychologist who is knowledgeable about PNES for evaluation and treatment of the underlying psychopathology. In a small number of cases that have uncomplicated histories, the PNES stops after explanation and educa-
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tion about PNES. Treatment should center on teaching the patient new coping skills with stress management techniques. Good evidence indicates that cognitive behavioral therapy is beneficial for adults who experience PNES. (11) Family involvement is important to manage continued nonepileptic events using a behavioral approach and to ensure the success of the patient’s individual therapy. (7)(8) Psychopharmacologic agents may be indicated to treat associated psychiatric disorders such as anxiety, depression, or ADHD. Given the important role of learning and social difficulties in triggering PNES related to emotional causes, patients often need psychoeducational testing and intervention. School personnel also need to be guided on how to reintegrate the child into school, address possible learning or social difficulties, and respond to PNES that might occur at school. Children who have social problems also can benefit from social skills training.
Outcome Overall, children and adolescents who have PNES have a better prognosis than adults. (12) This difference may be related to earlier diagnosis and treatment of the previously described stressors or coping disorders in children. In adults, PNES occurs in the context of more chronic psychological maladjustment, such as chronic depression and personality disorders.
Summary • Based primarily on consensus due to lack of relevant clinical studies, it is difficult to distinguish PNES from epileptic seizures. Failure to make this distinction may result in lack of appropriate management and a decline in the quality of life for the child and family. • Based on some research evidence as well as consensus, common associated stressors in children include school difficulties, family discord, and interpersonal conflicts with peers and friends, with sexual abuse being less common than in adults. Anxiety and depression commonly are associated with PNES. (2)(3)(4) • PNES should be differentiated from other paroxysmal nonepileptic events. Based on strong research evidence, prolonged video-EEG monitoring is the gold standard in making a definitive diagnosis. (5)(6) • Based on some research evidence as well as consensus, early diagnosis and referral to a psychiatrist or psychologist for treatment of the underlying psychopathology with individual and family therapy are the mainstay of successful management of pediatric NES due to psychological causes. Children who have PNES have a better prognosis than adults. (3)(8)(11)(12)
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ACKNOWLEDGMENTS. The authors are members of the NES Task Force-Pediatric Workgroup sponsored by the American Epilepsy Society.
References 1. Benbadis SR, Hauser AW. An estimate of the prevalence of psychogenic non-epileptic seizures. Seizure. 2000;9:280 –281
2. Patel H, Scott E, Dunn D, Garg BP. Non-epileptic seizures in children. Epilepsia. 2007;48:2086 –2092
3. Wyllie E, Glazer JP, Benbadis S, Kotagal P, Wolgamuth B. Psychiatric features of children and adolescents with pseudoseizures. Arch Pediatr Adolesc Med. 1999;153:244 –248 4. Lancman ME, Asconape´ JJ, Graves S, Gibson PA. Psychogenic seizures in children: long-term analysis of 43 cases. J Child Neurol. 1994;9:404 – 407 5. Kramer U, Carmant L, Riviello JJ, et al. Psychogenic seizures: video telemetry observations in 27 patients. Pediatr Neurol. 1995; 12:39 – 41 6. Reuber M, Elger CE. Psychogenic nonepileptic seizures: review and update. Epilepsy Behav. 2003;4:205–216 7. Plioplys S, Asato MR, Bursch B, Salpekar JA, Shaw R, Caplan R. Multidisciplinary management of pediatric nonepileptic seizures. J Am Acad Child Adolesc Psychiatry. 2007;46:1491–1495 8. Caplan R, Plioplys S. Psychiatric features and management of children with nonepileptic seizures. In: Schachter SC, LaFrance WC, Jr, eds. Gates and Rowan’s Nonepileptic Seizures. 3rd ed. New York, NY: Cambridge University Press; 2010:163–178 9. Vincentiis S, Valente KD, Thome´-Souza S, Kuczinsky E, Fiore LA, Negra˜o N. Risk factors for psychogenic seizures in children and adolescents with epilepsy. Epilepsy Behav. 2006;8: 294 –298
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10. Hempel A, Doss J, Adams E. Neuropsychological and psychological aspects of children presenting with psychogenic nonepileptic seizures. In: Schachter SC, LaFrance WC, Jr, eds. Gates and Rowan’s Nonepileptic Seizures. 3rd ed. New York, NY: Cambridge University Press; 2010:179 –186 11. Goldstein LH, Childer T, Chigwedere C, et al. Cognitivebehavioral therapy for psychogenic nonepileptic seizures. A pilot RCT. Neurology. 2010;74:1986 –1994 12. Gudmundsson O, Prendergast M, Foreman D, Crowley S. Outcome of pseudoseizures in children and adolescents: a 6-year symptom survival analysis. Dev Med Child Neurol. 2001;43: 547–551
Suggested Reading Andriola MR, Ettinger AB. Pseudoseizures and other nonepileptic paroxysmal disorders in children and adolescents. Neurology. 1999;53(suppl 2):89 –95 Bowman ES. Nonepileptic seizures: psychiatric framework, treatment and outcome. Neurology. 1999;53(suppl 2):84 – 88 Krumholz A. Nonepileptic seizures: diagnosis and management. Neurology. 1999;53(suppl):76 – 83 LaFrance WC, Jr. Psychogenic nonepileptic “seizures” or “attacks”? It’s not just semantics: seizures. Neurology. 2010;75: 87– 88 LaFrance WC, Jr, Miller IW, Ryan CE, et al. Cognitive behavioral therapy for psychogenic nonepileptic seizures. Epilepsy Behav. 2009;14:591–596 Schachter SC, LaFrance WC, Jr, eds. Gates and Rowan’s Nonepileptic Seizures. 3rd ed. New York, NY: Cambridge University Press; 2010
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Psychogenic Nonepileptic Seizures (Pseudoseizures) Hema Patel, David W. Dunn, Joan K. Austin, Julia L. Doss, W. Curt LaFrance, Jr, Sigita Plioplys and Rochelle Caplan Pediatr. Rev. 2011;32;e66-e72 DOI: 10.1542/pir.32-6-e66
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