- Email: [email protected]
Child development
New Developments
Child Development James Coplan, M.D. The past 2 or 3 years have seen an explosion of information velopmental disabilities. Let’s hit some of the high points.
regarding
de-
Fragile-X Syndrome Fragile-X syndrome is the most common hereditary form of mental retardation, affecting approximately 1 in 1,000 individuals in the general population. Although the name “fragile-x” suggests a chromosomal disorder, in fact this condition is due to a single-gene defect that results in the typical dysmorphic features, developmental delays, and cytogenetic findings. The “classic” patient with fragile-X syndrome is male, with a broad forehead, large external ears, lax joints, large testes (if postpubertal), mental retardation, and perhaps some autistic features. The “classic” picture in a female is borderline to mild mental impairment with subtle abnormalities of facial phenotype. The inheritance pattern of fragile-X syndrome defies explanation through conventional mendelian genetics.‘,2 About 20% of males who carry the mutant gene are clinically unaffected. These individuals, referred to as “normal transmitting males,” pass the mutant gene to their daughters, most of whom are also clinically normal. Half of their sons, however, will be clinically affected by the fragile-X gene, often severely so. How can this be? The answer hinges on deactivation and reactivation of the X chromosome during oogenesis. The eggs in a female fetus are inactivated during early fetal life and are only reactivated decades later, at the time of ovulation. The genetic defect in fragile-X syndrome prevents normal reactivation of the X chromosome during the final preovulatory phase of oogenesis. DNA analysis of affected individuals reveals a specific region of the distal X chromosome containing an abnormal segment; the size of this abnormal segment appears to correlate with the degree of clinical expression of fragile-X syndrome, and may get larger from generation to generation, each time the X chromosome is deactivated and reactivated. The initial mutation in the grandparent causes no loss of genetic material or alteration of X chromosome function; the grandparent is clinically unaffected. As-the mutated X chromosome passes to the daughters of the carrier, the genetic mutation prevents the X chromosome from responding properly to its “wake-up call” at the time of oogenesis, so that her offspring (i.e., the grandchildren of the original carrier) are clinically affected. If the grandchild is a male, full clinical expression of fragile-X syndrome will ensue. If the grandchild is female, then the range of clinical expression will depend on lyonization of the abnormal versus normal X chromosome in the somatic cell lines of the female infant. (According to the Lyon hypothesis, in females one or the other X chromosome is inactivated in all cells,) Up until now, laboratory diagnosis of fragile-X has relied on the arduous task of examining chromosomes cytogenetically for the “fragile” site (the X chromosome does not really break, so the term “fragile” is a misnomer). Even in affected individuals, only about 5% to 15% of cells demonstrated the “fragility” James Coplan, MD, Science Center, Syracuse.
44
Current
Problems
in Pediatrics
is Associate
/ February
Professor
1993
of Pediatrics,
State
University
of New
York-Health
New Developments
that until now has been the defining laboratory feature. Now, however, a DNA probe for the fragile-X gene is available.3 This technique is commercially available, is easier to perform, and is more sensitive and specific than the cytogenetic methods analysis. Descriptions of fragile-X syndrome have suffered from ascertainment bias: In clinical settings, only the most severely impaired children have been submitted for fragile-X testing because cytogenetic analysis for fragile-X is so laborious. We have fallen into the trap of circular logic, failing to think of fragile-X in mildly affected persons of either sex. Given what is now known about the frequency of this gene in the general population, as well as its range of expression, clinicians would be well-advised to perform the DNA probe for the fragile-X gene on a// children with mental retardation, learning disabilities, developmental language disorder, or autism, unless some other proven etiology is at hand. Bear in mind also that all affected children have a carrier parent. If the affected child is a girl, she could have a “normal transmitting” father or an unaffected to mildly affected heterozygote mother. If the affected child is a boy, the only source for the abnormal X chromosome is an obligate carrier mother. Genetic counseling and DNA probe analysis of the parents are therefore indicated as well.
Side Effects of Anticonvulsant
Drugs
Inform&ion continues to accumulate regarding the cognitive and behavioral side effects of phenobarbital. A prospective study of 217 children between 8 and 36 months old randomly assigned subjects to phenobarbital or placebo for the treatment of complex febrile convulsions4 Treatment was terminated at the age of 24 months. Developmental testing at the ages of 24 and 30 months showed an approximate 5-point difference in IQ, in favor of the placebo group. This study can be criticized on a variety of methodologic grounds. Furthermore, the reader should be aware of the “correction” published in the New England Journal of Medicine.5 Nonetheless, the trend is clear: Phenobarbital is not good for cognitive development in toddlers. There is also evidence regarding the ability of phenobarbital to precipitate long-lasting depressive disorder.6 If you have a patient who has been well controlled on phenobarbital for years and is cognitively and emotionally normal, you might be reluctant to meddle (“If it ain’t broke, don’t fix it!“). On the other hand, if you are about to put a patient on anticonvulsant medication or if you have a patient with cognitive or behavioral problems who is taking phenobarbital, you should give strong consideration to something else (valproic acid, carbamazepine, or another agent, depending on the seizure type).
Fetal Alcohol Syndrome The incidence of fetal alcohol syndrome (FAS) has been reported variously as 1 in 1,000 to as high as 1 in 100, depending on the risk group studied. The diagnosis of FAS or the more subtle fetal alcohol effects (FAE) remains exclusively clinical. Physical findings are suggestive but not pathognomonic.7 Drinks per day and maximum number of drinks on any one occasion during the 12 months prior to the pregnancy correlate with outcome.7 (One glass of wine, one beer, or one mixed drink counts as “one drink.“) Once women realize they are pregnant, they change their drinking habits, their drinking history, or both. The more severe a woman’s drinking problem, the greater the likelihood that she will significantly underestimate her alcohol consumption during pregnancy.’ Don’t be shy and don’t count on the obstetrician to do your work for you. Regrettably, even
Current
Problems
in Pediatrics
I February
1993
45
New Developments
when the obstetrician has documented alcoholism in the mother’s record, the pediatrician often fails to take note of this information or reflect the diagnosis of FAS in the newborn’s chart9 Now we find two interesting studies of alcohol in breast milk. Newborn infants sucked more frequently but consumed less milk after lactating adult volunteers consumed 1 oz of ethanol.” Moderate drinking in a population of nonalcoholic but lactating and breast-feeding women was associated with a statistically significant 7-point decrement in the infants’ performance on the Bayley Psychomotor Developmental Index (PDI).” The authors of this study acknowledged that a 7-point decline on the PDI “probably” is not clinically significant in any given child. Nonetheless, the public health implications of this finding are substantial. If the entire developmental curve is shifted 7 points to the left, then we can expect a much greater number of children at the lower end, with a substantial increase in the number of FAS infants with clinically significant delay. The failure to recognize FAS or the more subtle FAE is in the same league as the failure to diagnose a genetic or chromosomal disorder: The recurrence risk for FAE in subsequent offspring may be as high as 50%. Developmentally delayed children with FAE being reared by an alcoholic mother are certainly at an increased risk for abuse. The best way to make the diagnosis is to ask. Do it.
Human lmmunodeficiency
Virus
Developmental delay is the sole presenting feature in some children with congenital human immunodeficiency virus (HIV). Developmental symptoms run the gamut from mild to severe, including speech delay, gross-motor delay, short attention span, clumsiness, poor school performance, dysarthria, dysphagia, ataxia, spasticity, dementia, and occasionally seizures. Severe disability is usually accompanied by changes on computed tomography (CT) (cerebral atrophy, ventriculomegaly, calcifications in the basal ganglia) or magnetic resonance imaging (MRI) (hyperintense white matter lesions in the white matter on T2 weighting), and abnormalities of the cerebrospinal fluid (CSF) and electroencephalograms (EEG).12 Disability may be static or progressive. Clinical signs of neurologic degeneration plus associated laboratory or imaging abnormalities are the defining features of HIV encephalopathy. Most (but not all) overtly encephalopathic children also manifest opportunistic infection or other clinical evidence of systemic HIV involvement. However, this is not always the case. Scott and colleagues13 reported a series of 172 congenitally infected infants, 12% of whom presented with HIV encephalopathy as their sole initial symptom of congenital infection. Congenitally infected infants show a bimodal pattern of clinical expression: An early-onset group is symptomatic in the first year or two of life and most are dead by age 4 to 5 years if untreated; a late-onset group is asymptomatic in the first year or two and thereafter runs about a 5% to 10% risk per year of becoming symptomatic. The early-onset group has been estimated variously to comprise 20% to 80% of all congenitally infected infants,‘3-‘g with the balance falling into the late-onset group. These varying estimates may represent selection bias (short follow-up interval introduces bias toward children with early-onset disease), timing of infection (fetal versus perinatal), or other factors. Much of the literature on congenital HIV reflects outcome for the early-onset group; our image of the “typical” child with HIV is colored by our exposure to children with early-onset disease. The epidemiologic significance of a large pool of children with silent congenital HIV is disquieting and diagnostically more troublesome than the overtly ill infant with full-blown acquired immunodeficiency syndrome (AIDS).
46
Current
Problems
in Pediatrics
/ February
1993
New Developments
Chronic subclinical encephalopathy can erode cognitive ability, even though intelligence remains in the normal range. Pizzo and colleagues*‘, *’ compared 13 overtly encephalopathic subjects and 5 apparently nonencephalopathic subjects, all of whom received zidovudine (ZDV, AZT). The mean age was 5 years, 11 months (range, 14 months-l 1 years, 8 months). At entry, overtly encephalopathic subjects had a mean IQ of approximately 65; apparently nonencephalopathic subjects had a mean IQ of 93. Subjects in both groups enjoyed about a 15-point rise in IQ following treatment with ZDV. Therefore, even the apparently unimpaired subjects had HIV encephalopathy, despite initial IQ values comfortably within the normal range. Cohen and coauthors’g reported on 15 children, aged 4 to 8 years, who had been infected as neonates via transfusion of HIV-contaminated blood. All had intelligence in the normal range; all were medically asymptomatic. Nonetheless, defects on fine motor, sustained attention, or abstract concept formation tasks were present in HIVpositive subjects, compared to matched controls. The proportion of children in the late-onset group with subclinical encephalopathy as their sole manifestation of HIV may be considerably higher than the 12% rate of isolated severe encephalopathy in the early-onset group. Young or subclinically involved children may have the most to gain from ZDV.*‘, ** Physicians are thus in a “need to know” situation regarding any developmentally delayed child’s HIV status. What does one do when confronted by a child with speech delay, borderline cognitive development, attention deficit/hyperactivity disorder, or mild mental retardation? These conditions are ubiquitous and not specific for HIV infection. Should all such children be tested for HIV? I am leaning in this direction but have not yet taken this step. I do routinely ask parents of a developmentally delayed child if they have any specific reason to be concerned about HIV infection. If risk factors are present, or if risk status is unknown (for example, if the child is adopted), I will screen for HIV by enzyme-linked immunosorbent assay (ELISA). Tests such as CT, MRI, lymphocyte subsets, or quantitative immunoglobulins may increase one’s suspicion, while other tests such as western blot or PCR may provide specific evidence for HIV infection. It is not clear how far to pursue such studies, in the face of a negative ELISA. How often a child should be retested by ELISA is likewise unclear.
Autism You have seen facilitated communication (FC) on TV. What is it, and what does it mean for persons with autism? FC was developed by Rosemary Crossley, an Australian educator. FC was originally developed as hand or arm support by a therapist (facilitator) to train persons with a physical disability, such as cerebral palsy, to gain greater control over their own bodily activities, including typing. Similar techniques were then attempted with autistic persons, with surprising results: Although autistic persons initially required hand-over-hand guidance to use the keyboard (as with physically disabled persons), eventually this guidance could be reduced or eliminated almost altogether. Ultimately, the facilitator might have to do nothing more than rest his or her hand on the autistic person’s shoulder, while the person with autism types. Using FC, persons with autism produce text that is socially appropriate (often reflective or introspective) and often intellectually appropriate for age level, frequently even persons who had previously been labeled as severely mentally retarded.23 All of this sounds too good to be true, and at the moment there are no Lentrolled data to support the claims being made by proponents of FC. Many therapies for developmental disability enjoy brief moments of popularity, only to be
Current
Problems
in Pediatrics
/ February
1993
47
New Developments
relegated to a footnote in history. FC, however, may be different. Autism has long been conceptualized as a severe communicative disorder.24 Perhaps autism is some type of disconnection syndrome, like conduction aphasia or corpus callosotomy. If this is so, then autistic persons may indeed have latent capabilities that have heretofore been incapable of reaching the surface. (Biklen’s choice of the term “praxis” may or may not be correct; many autistic children have well-developed praxic abilities-dismantling mechanical objects, for example-in the face of severe communication abnormalities.) Much remains to be learned. The danger exists that FC will be oversold, with an unfortunate backlash. Research is needed, by persons who are neither proponents nor detractors of FC. If FC works for some autistic persons, will it work for all? Can FC work with “ordinary” mental retardation (for example, Down syndrome). If so, how? If not, why not? FC may have as much to tell us about the neurology of language as did Broca or Wernicke’s discoveries of the last century, but we must have data.
References 1. Russeau F, Heitz D, Biancalana V, et al: Direct diagnosis by DNA analysis of the fragile-X syndrome of mental retardation. N Engl J Med 1991; 325: 1673- 1681, 2. Shapiro LR: The fragile-X syndrome: A peculiar pattern of inheritance. N Engl J Med 1991; 325:17361737. 3. Oberle I, Russo F, Heitz D, et al: Instability of a 550 base paired DNA segment and abnormal methylation in fragile-X syndrome. Science 1991; 252: 1097- 1102. 4. Far-well JR, Lee YJ, Hertz DG, et al: Phenobarbital for febrile seizures-Effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322:364-369. 5. Correction. N Engl J Med 1992; 326:144. 6. Brent DA, Crumrine PK, Varma R, et al: Phenobarbital treatment and major depressive disorder in children with epilepsy: A naturalistic follow-up. Pediatrics 1990; 85:10861091. 7. Day NL, Jasperse D, Richardson G, et al: Prenatal exposure to alcohol: Effect on infant growth and morphologic characteristics. Pediatrics 1989; 84:536-541, 8. Morrow-Tlucak M, Ernhart CB, Sokol RJ, et al: Underreporting of alcohol use in pregnancy: Relation to alcohol problem history. Alcohol C/in Exp Res 1989; 13:399-401, 9 Little BB, Snell LM, Rosenfeld CR, et al: Failure to recognize fetal alcohol syndrome in newborn Infants. Am J Dis Child 1990; 144: 1142- 1146. 10. Mennella JA, Beauchamp GK: The transfer of alcohol to human milk-Effects on flavor and the infant’s behavior. N Engl d Med 1991; 325:981-985. 11. Little RE, Anderson KW, Ervin CH, et al: Maternal alcohol use during breast feeding and infant mental and motor development at one year. N Engl J Med 1989; 321:425-430. 12. Falloon J, Eddy J, Wiener L, et al: Human immunodeficiency virus infection in children. J Pediatr 1989; 114:1-30. 13. Scott GB, Hutto C, Makuch RW: Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. N Engl J Med 1989; 321: 1791- 1796. 14. Auger I, Thomas P, De Gruttola V, et al: Incubation period for paediatric AIDS patients. Nature 1988; 33615755577. 15. Blanche S, Rouzioux C, Moscato M-LG, et al: A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N Engl J Med 1989; 320:16431648. 16 Johnson JP, Nair P, Hines SE, et al: Natural history and serologic diagnosis of infants born to human immunodeficiency virus-infected women. Am J Dis Child 1989; 143:1147-l 153. 17. Hutto C, Parks WP, Lai S. et al: A hospital-based prospective study of pennatal rnfectron with human immunodeficiency virus type 1. J Pediatr 1991; 118:347-353. 18. Mayers MM, Davenny K, Schoenbaum EE. et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drug-using sex partners, in the Bronx, New York City. Pediatrics 1991; 88:1248-1256. 19. Cohen SE, Mundy T, Karassik B, et al: Neuropsychological functioning in human immunodeficiency virus type 1 seropositive children infected through neonatal blood transfusion. Pediatrics 1991; 88:58-68. 20. Brouwers P, Moss H, Walters P, et al: Effect of continuous-infusion zidovudine therapy on neu-
48
Current
Problems
in Pediatrics
/ February
1993
New Developments
21. 22. 23. 24.
ropsychologic functioning in children with symptomatic human immunodeficiency virus infection. J Pediafr 1990; 117:980-985. Pizzo PA, Eddy J, Falloon J, et al: Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988; 319:889-896. McKinney RE, Maha MA, Connor EM, et al: A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. A! Engl J Med 1991; 324:1018-1025. Biklen D: Communication unbound: Autrsm and praxis. Harvard Educ Rev 1990; 60:291-314. Tuchman RF, Fapin I, Shinnar S: Autistic and dysphasic children. I: Clinical characteristics, Pediatrics 1991; 88:1211-1218.
Current Problems in Pediatrics / February 1993
49
Child Development James Coplan, M.D. The past 2 or 3 years have seen an explosion of information velopmental disabilities. Let’s hit some of the high points.
regarding
de-
Fragile-X Syndrome Fragile-X syndrome is the most common hereditary form of mental retardation, affecting approximately 1 in 1,000 individuals in the general population. Although the name “fragile-x” suggests a chromosomal disorder, in fact this condition is due to a single-gene defect that results in the typical dysmorphic features, developmental delays, and cytogenetic findings. The “classic” patient with fragile-X syndrome is male, with a broad forehead, large external ears, lax joints, large testes (if postpubertal), mental retardation, and perhaps some autistic features. The “classic” picture in a female is borderline to mild mental impairment with subtle abnormalities of facial phenotype. The inheritance pattern of fragile-X syndrome defies explanation through conventional mendelian genetics.‘,2 About 20% of males who carry the mutant gene are clinically unaffected. These individuals, referred to as “normal transmitting males,” pass the mutant gene to their daughters, most of whom are also clinically normal. Half of their sons, however, will be clinically affected by the fragile-X gene, often severely so. How can this be? The answer hinges on deactivation and reactivation of the X chromosome during oogenesis. The eggs in a female fetus are inactivated during early fetal life and are only reactivated decades later, at the time of ovulation. The genetic defect in fragile-X syndrome prevents normal reactivation of the X chromosome during the final preovulatory phase of oogenesis. DNA analysis of affected individuals reveals a specific region of the distal X chromosome containing an abnormal segment; the size of this abnormal segment appears to correlate with the degree of clinical expression of fragile-X syndrome, and may get larger from generation to generation, each time the X chromosome is deactivated and reactivated. The initial mutation in the grandparent causes no loss of genetic material or alteration of X chromosome function; the grandparent is clinically unaffected. As-the mutated X chromosome passes to the daughters of the carrier, the genetic mutation prevents the X chromosome from responding properly to its “wake-up call” at the time of oogenesis, so that her offspring (i.e., the grandchildren of the original carrier) are clinically affected. If the grandchild is a male, full clinical expression of fragile-X syndrome will ensue. If the grandchild is female, then the range of clinical expression will depend on lyonization of the abnormal versus normal X chromosome in the somatic cell lines of the female infant. (According to the Lyon hypothesis, in females one or the other X chromosome is inactivated in all cells,) Up until now, laboratory diagnosis of fragile-X has relied on the arduous task of examining chromosomes cytogenetically for the “fragile” site (the X chromosome does not really break, so the term “fragile” is a misnomer). Even in affected individuals, only about 5% to 15% of cells demonstrated the “fragility” James Coplan, MD, Science Center, Syracuse.
44
Current
Problems
in Pediatrics
is Associate
/ February
Professor
1993
of Pediatrics,
State
University
of New
York-Health
New Developments
that until now has been the defining laboratory feature. Now, however, a DNA probe for the fragile-X gene is available.3 This technique is commercially available, is easier to perform, and is more sensitive and specific than the cytogenetic methods analysis. Descriptions of fragile-X syndrome have suffered from ascertainment bias: In clinical settings, only the most severely impaired children have been submitted for fragile-X testing because cytogenetic analysis for fragile-X is so laborious. We have fallen into the trap of circular logic, failing to think of fragile-X in mildly affected persons of either sex. Given what is now known about the frequency of this gene in the general population, as well as its range of expression, clinicians would be well-advised to perform the DNA probe for the fragile-X gene on a// children with mental retardation, learning disabilities, developmental language disorder, or autism, unless some other proven etiology is at hand. Bear in mind also that all affected children have a carrier parent. If the affected child is a girl, she could have a “normal transmitting” father or an unaffected to mildly affected heterozygote mother. If the affected child is a boy, the only source for the abnormal X chromosome is an obligate carrier mother. Genetic counseling and DNA probe analysis of the parents are therefore indicated as well.
Side Effects of Anticonvulsant
Drugs
Inform&ion continues to accumulate regarding the cognitive and behavioral side effects of phenobarbital. A prospective study of 217 children between 8 and 36 months old randomly assigned subjects to phenobarbital or placebo for the treatment of complex febrile convulsions4 Treatment was terminated at the age of 24 months. Developmental testing at the ages of 24 and 30 months showed an approximate 5-point difference in IQ, in favor of the placebo group. This study can be criticized on a variety of methodologic grounds. Furthermore, the reader should be aware of the “correction” published in the New England Journal of Medicine.5 Nonetheless, the trend is clear: Phenobarbital is not good for cognitive development in toddlers. There is also evidence regarding the ability of phenobarbital to precipitate long-lasting depressive disorder.6 If you have a patient who has been well controlled on phenobarbital for years and is cognitively and emotionally normal, you might be reluctant to meddle (“If it ain’t broke, don’t fix it!“). On the other hand, if you are about to put a patient on anticonvulsant medication or if you have a patient with cognitive or behavioral problems who is taking phenobarbital, you should give strong consideration to something else (valproic acid, carbamazepine, or another agent, depending on the seizure type).
Fetal Alcohol Syndrome The incidence of fetal alcohol syndrome (FAS) has been reported variously as 1 in 1,000 to as high as 1 in 100, depending on the risk group studied. The diagnosis of FAS or the more subtle fetal alcohol effects (FAE) remains exclusively clinical. Physical findings are suggestive but not pathognomonic.7 Drinks per day and maximum number of drinks on any one occasion during the 12 months prior to the pregnancy correlate with outcome.7 (One glass of wine, one beer, or one mixed drink counts as “one drink.“) Once women realize they are pregnant, they change their drinking habits, their drinking history, or both. The more severe a woman’s drinking problem, the greater the likelihood that she will significantly underestimate her alcohol consumption during pregnancy.’ Don’t be shy and don’t count on the obstetrician to do your work for you. Regrettably, even
Current
Problems
in Pediatrics
I February
1993
45
New Developments
when the obstetrician has documented alcoholism in the mother’s record, the pediatrician often fails to take note of this information or reflect the diagnosis of FAS in the newborn’s chart9 Now we find two interesting studies of alcohol in breast milk. Newborn infants sucked more frequently but consumed less milk after lactating adult volunteers consumed 1 oz of ethanol.” Moderate drinking in a population of nonalcoholic but lactating and breast-feeding women was associated with a statistically significant 7-point decrement in the infants’ performance on the Bayley Psychomotor Developmental Index (PDI).” The authors of this study acknowledged that a 7-point decline on the PDI “probably” is not clinically significant in any given child. Nonetheless, the public health implications of this finding are substantial. If the entire developmental curve is shifted 7 points to the left, then we can expect a much greater number of children at the lower end, with a substantial increase in the number of FAS infants with clinically significant delay. The failure to recognize FAS or the more subtle FAE is in the same league as the failure to diagnose a genetic or chromosomal disorder: The recurrence risk for FAE in subsequent offspring may be as high as 50%. Developmentally delayed children with FAE being reared by an alcoholic mother are certainly at an increased risk for abuse. The best way to make the diagnosis is to ask. Do it.
Human lmmunodeficiency
Virus
Developmental delay is the sole presenting feature in some children with congenital human immunodeficiency virus (HIV). Developmental symptoms run the gamut from mild to severe, including speech delay, gross-motor delay, short attention span, clumsiness, poor school performance, dysarthria, dysphagia, ataxia, spasticity, dementia, and occasionally seizures. Severe disability is usually accompanied by changes on computed tomography (CT) (cerebral atrophy, ventriculomegaly, calcifications in the basal ganglia) or magnetic resonance imaging (MRI) (hyperintense white matter lesions in the white matter on T2 weighting), and abnormalities of the cerebrospinal fluid (CSF) and electroencephalograms (EEG).12 Disability may be static or progressive. Clinical signs of neurologic degeneration plus associated laboratory or imaging abnormalities are the defining features of HIV encephalopathy. Most (but not all) overtly encephalopathic children also manifest opportunistic infection or other clinical evidence of systemic HIV involvement. However, this is not always the case. Scott and colleagues13 reported a series of 172 congenitally infected infants, 12% of whom presented with HIV encephalopathy as their sole initial symptom of congenital infection. Congenitally infected infants show a bimodal pattern of clinical expression: An early-onset group is symptomatic in the first year or two of life and most are dead by age 4 to 5 years if untreated; a late-onset group is asymptomatic in the first year or two and thereafter runs about a 5% to 10% risk per year of becoming symptomatic. The early-onset group has been estimated variously to comprise 20% to 80% of all congenitally infected infants,‘3-‘g with the balance falling into the late-onset group. These varying estimates may represent selection bias (short follow-up interval introduces bias toward children with early-onset disease), timing of infection (fetal versus perinatal), or other factors. Much of the literature on congenital HIV reflects outcome for the early-onset group; our image of the “typical” child with HIV is colored by our exposure to children with early-onset disease. The epidemiologic significance of a large pool of children with silent congenital HIV is disquieting and diagnostically more troublesome than the overtly ill infant with full-blown acquired immunodeficiency syndrome (AIDS).
46
Current
Problems
in Pediatrics
/ February
1993
New Developments
Chronic subclinical encephalopathy can erode cognitive ability, even though intelligence remains in the normal range. Pizzo and colleagues*‘, *’ compared 13 overtly encephalopathic subjects and 5 apparently nonencephalopathic subjects, all of whom received zidovudine (ZDV, AZT). The mean age was 5 years, 11 months (range, 14 months-l 1 years, 8 months). At entry, overtly encephalopathic subjects had a mean IQ of approximately 65; apparently nonencephalopathic subjects had a mean IQ of 93. Subjects in both groups enjoyed about a 15-point rise in IQ following treatment with ZDV. Therefore, even the apparently unimpaired subjects had HIV encephalopathy, despite initial IQ values comfortably within the normal range. Cohen and coauthors’g reported on 15 children, aged 4 to 8 years, who had been infected as neonates via transfusion of HIV-contaminated blood. All had intelligence in the normal range; all were medically asymptomatic. Nonetheless, defects on fine motor, sustained attention, or abstract concept formation tasks were present in HIVpositive subjects, compared to matched controls. The proportion of children in the late-onset group with subclinical encephalopathy as their sole manifestation of HIV may be considerably higher than the 12% rate of isolated severe encephalopathy in the early-onset group. Young or subclinically involved children may have the most to gain from ZDV.*‘, ** Physicians are thus in a “need to know” situation regarding any developmentally delayed child’s HIV status. What does one do when confronted by a child with speech delay, borderline cognitive development, attention deficit/hyperactivity disorder, or mild mental retardation? These conditions are ubiquitous and not specific for HIV infection. Should all such children be tested for HIV? I am leaning in this direction but have not yet taken this step. I do routinely ask parents of a developmentally delayed child if they have any specific reason to be concerned about HIV infection. If risk factors are present, or if risk status is unknown (for example, if the child is adopted), I will screen for HIV by enzyme-linked immunosorbent assay (ELISA). Tests such as CT, MRI, lymphocyte subsets, or quantitative immunoglobulins may increase one’s suspicion, while other tests such as western blot or PCR may provide specific evidence for HIV infection. It is not clear how far to pursue such studies, in the face of a negative ELISA. How often a child should be retested by ELISA is likewise unclear.
Autism You have seen facilitated communication (FC) on TV. What is it, and what does it mean for persons with autism? FC was developed by Rosemary Crossley, an Australian educator. FC was originally developed as hand or arm support by a therapist (facilitator) to train persons with a physical disability, such as cerebral palsy, to gain greater control over their own bodily activities, including typing. Similar techniques were then attempted with autistic persons, with surprising results: Although autistic persons initially required hand-over-hand guidance to use the keyboard (as with physically disabled persons), eventually this guidance could be reduced or eliminated almost altogether. Ultimately, the facilitator might have to do nothing more than rest his or her hand on the autistic person’s shoulder, while the person with autism types. Using FC, persons with autism produce text that is socially appropriate (often reflective or introspective) and often intellectually appropriate for age level, frequently even persons who had previously been labeled as severely mentally retarded.23 All of this sounds too good to be true, and at the moment there are no Lentrolled data to support the claims being made by proponents of FC. Many therapies for developmental disability enjoy brief moments of popularity, only to be
Current
Problems
in Pediatrics
/ February
1993
47
New Developments
relegated to a footnote in history. FC, however, may be different. Autism has long been conceptualized as a severe communicative disorder.24 Perhaps autism is some type of disconnection syndrome, like conduction aphasia or corpus callosotomy. If this is so, then autistic persons may indeed have latent capabilities that have heretofore been incapable of reaching the surface. (Biklen’s choice of the term “praxis” may or may not be correct; many autistic children have well-developed praxic abilities-dismantling mechanical objects, for example-in the face of severe communication abnormalities.) Much remains to be learned. The danger exists that FC will be oversold, with an unfortunate backlash. Research is needed, by persons who are neither proponents nor detractors of FC. If FC works for some autistic persons, will it work for all? Can FC work with “ordinary” mental retardation (for example, Down syndrome). If so, how? If not, why not? FC may have as much to tell us about the neurology of language as did Broca or Wernicke’s discoveries of the last century, but we must have data.
References 1. Russeau F, Heitz D, Biancalana V, et al: Direct diagnosis by DNA analysis of the fragile-X syndrome of mental retardation. N Engl J Med 1991; 325: 1673- 1681, 2. Shapiro LR: The fragile-X syndrome: A peculiar pattern of inheritance. N Engl J Med 1991; 325:17361737. 3. Oberle I, Russo F, Heitz D, et al: Instability of a 550 base paired DNA segment and abnormal methylation in fragile-X syndrome. Science 1991; 252: 1097- 1102. 4. Far-well JR, Lee YJ, Hertz DG, et al: Phenobarbital for febrile seizures-Effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322:364-369. 5. Correction. N Engl J Med 1992; 326:144. 6. Brent DA, Crumrine PK, Varma R, et al: Phenobarbital treatment and major depressive disorder in children with epilepsy: A naturalistic follow-up. Pediatrics 1990; 85:10861091. 7. Day NL, Jasperse D, Richardson G, et al: Prenatal exposure to alcohol: Effect on infant growth and morphologic characteristics. Pediatrics 1989; 84:536-541, 8. Morrow-Tlucak M, Ernhart CB, Sokol RJ, et al: Underreporting of alcohol use in pregnancy: Relation to alcohol problem history. Alcohol C/in Exp Res 1989; 13:399-401, 9 Little BB, Snell LM, Rosenfeld CR, et al: Failure to recognize fetal alcohol syndrome in newborn Infants. Am J Dis Child 1990; 144: 1142- 1146. 10. Mennella JA, Beauchamp GK: The transfer of alcohol to human milk-Effects on flavor and the infant’s behavior. N Engl d Med 1991; 325:981-985. 11. Little RE, Anderson KW, Ervin CH, et al: Maternal alcohol use during breast feeding and infant mental and motor development at one year. N Engl J Med 1989; 321:425-430. 12. Falloon J, Eddy J, Wiener L, et al: Human immunodeficiency virus infection in children. J Pediatr 1989; 114:1-30. 13. Scott GB, Hutto C, Makuch RW: Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. N Engl J Med 1989; 321: 1791- 1796. 14. Auger I, Thomas P, De Gruttola V, et al: Incubation period for paediatric AIDS patients. Nature 1988; 33615755577. 15. Blanche S, Rouzioux C, Moscato M-LG, et al: A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N Engl J Med 1989; 320:16431648. 16 Johnson JP, Nair P, Hines SE, et al: Natural history and serologic diagnosis of infants born to human immunodeficiency virus-infected women. Am J Dis Child 1989; 143:1147-l 153. 17. Hutto C, Parks WP, Lai S. et al: A hospital-based prospective study of pennatal rnfectron with human immunodeficiency virus type 1. J Pediatr 1991; 118:347-353. 18. Mayers MM, Davenny K, Schoenbaum EE. et al: A prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history of intravenous drug use or of intravenous drug-using sex partners, in the Bronx, New York City. Pediatrics 1991; 88:1248-1256. 19. Cohen SE, Mundy T, Karassik B, et al: Neuropsychological functioning in human immunodeficiency virus type 1 seropositive children infected through neonatal blood transfusion. Pediatrics 1991; 88:58-68. 20. Brouwers P, Moss H, Walters P, et al: Effect of continuous-infusion zidovudine therapy on neu-
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21. 22. 23. 24.
ropsychologic functioning in children with symptomatic human immunodeficiency virus infection. J Pediafr 1990; 117:980-985. Pizzo PA, Eddy J, Falloon J, et al: Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 1988; 319:889-896. McKinney RE, Maha MA, Connor EM, et al: A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. A! Engl J Med 1991; 324:1018-1025. Biklen D: Communication unbound: Autrsm and praxis. Harvard Educ Rev 1990; 60:291-314. Tuchman RF, Fapin I, Shinnar S: Autistic and dysphasic children. I: Clinical characteristics, Pediatrics 1991; 88:1211-1218.
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