Cognitive and Behavioral Manifestations of Lead

The link between exposure to lead and children’s cognitive problems was implied in the earliest medical reports of frank lead poisoning of young children in Australia in the 1800s (Lin-Fu 1992). Children with acute severe toxicity of lead (Pb) are now rarely seen in the United States. However, millions of children may have subclinical neurobehavioral disorders associated with chronic low-level exposure to lead, representing a major public health concern (Bellinger 2008a). Lead is a nonessential metal that is recognized as a source of toxic exposure, with the developing nervous system particularly vulnerable. Because of this, U.S. regulations limiting the lead content of gasoline and household paint have led to a gradual reduction of the average blood lead concentration of Americans over the last three decades. Average blood lead levels of children in the United States dropped an estimated 78% from 1976 to 1991 (Brody et al. 1994; Caldwell et al. 2009). Despite these reductions in exposure to lead, new advances in research techniques have documented harmful consequences associated with lower blood lead levels. This raises the possibility that there is no threshold for occurrence of lead-induced toxicity. Bellinger (2008a) refers to “the silent pandemic of neurodevelopmental disorders resulting from children’s continuing exposure to low levels of lead.” The developing brain may be more sensitive to exposure to lead than the adult. Since the pioneering work of Needleman and colleagues (1979), a large scientific literature has documented the deleterious effects of pre- and neonatal exposure to lead. Decrements in IQ scores have proven to be among the most sensitive and consistent consequences of a child’s exposure to lead, but other cognitive and behavioral changes have been described as well, including attention-deficit hyperactivity disorder (ADHD). Among the important current sources of children’s exposure to lead is household dust (Dixon et al. 2009) the lead content in old water pipes, batteries, and from contamination by numerous industrial processes. Pre and postnatal exposure to cigarette smoke is a cofactor with lead exposure in children’s conduct disorders (Braun et al. 2008). Diagnosis of lead-induced disorders involves the determination of exposure to lead and the atomic absorption assay of lead in whole blood.

The Behavioral and Cognitive Manifestations of Blindness in Children

Ground-breaking progress in the field of neurodevelopmental disorders has allowed us far more insight into blindness and visual impairment (VI). The field of cognitive neuroscience has now established itself solidly in the literature, combining the knowledge from cognitive psychology, clinical studies related to brain damage, and neuroscience to open the way to significant advances in understanding. In recent years, the optimism engendered from the adult studies has played a large part in providing the impetus for developmental studies and in particular developmental neuroscience (Johnson 2005; Tager-Flusberg 1999). It is from this developmental neuroscience perspective that we can begin to understand the cognitive and behavioral manifestations associated with blindness and VI; albeit with the proviso that children with VI present particularly heterogeneous developmental patterns when compared to typically developing children (Fraiberg 1971). In considering the effects of blindness and VI, this chapter will focus on social understanding, language, cognition, and motor development. However, it begins with brief introductions to epidemiology and the effects of blindness on the functional and structural organization of the brain, which it is hoped will provide a useful context in which to consider the development of children who cannot see. Today the number of blind people in the world stands at 45 million, even though up to 75% of blindness could be avoided either by treatment or by prevention. The number of people with avoidable blindness will have doubled from 1990 to 2020 unless there is rapid and effective intervention, and the total number of the blind is projected to be as many as 76 million by 2020. To prevent this scenario, the World Health Organization (WHO) and the International Agency for the Prevention of Blindness (IAPB) have jointly initiated Vision 2020, a project that aims to eliminate the main causes of avoidable blindness by the year 2020, with the ultimate long-term goal of a world in which all avoidable blindness is eliminated and in which everyone with unavoidable vision loss reaches their full potential. The top priority of Vision 2020 is the prevention of childhood blindness. At present there are 1.4 million children under the age of 15 who are blind.

Asthma and Cystic Fibrosis

Asthma and cystic fibrosis (CF) are examples of childhood pulmonary illnesses with significant psychological impacts. These disorders have in common an induced difficulty with a primal drive, the drive to breathe. Acute impairment with the drive to breathe is highly anxiety provoking, and chronic impairment is life-altering. Pulmonary illnesses like asthma and CF can have direct impacts on brain functioning through systemic hypoxia (low blood oxygen [O2] level) or hypercapnia (high blood carbon dioxide [CO2] level) due to poor respiratory gas exchange. With chronic respiratory problems in children, hypoxia is the more clinically pertinent issue in that hypoxia seems to produce developmental impacts. Studies that have looked at the outcomes of pulmonary hypoxia have found associations with adverse effects even from oxygen levels that were just slightly below the normal range (Bass et al. 2004). A drop of only 4% O2 saturation from baseline is associated with attentiondeficit hyperactivity (ADHD)-like symptoms. Persistent oxygen saturation levels that are even lower than this have been associated with decreased IQ and delays in motor development (Bass et al. 2004). Negative neurobehavioral effects of the hypercapnia side of impaired respiratory status are less well documented. In fact, hypercapnia, besides triggering an increase in cerebral blood flow and driving a sense of air hunger particularly in people with trait anxiety, seems to have no lasting neurocognitive impact (Wan et al. 2008). Research on the use of intentional ‘‘permissive’’ hypercapnia when using mechanical ventilation assistance (allowing higher blood carbon dioxide levels to minimize barotrauma from the assist device) has shown no common neurocognitive complications from this strategy. There are even suggestions of some improved neurocognitive outcomes for neonates managed in this manner (Miller and Carlo 2007). These results are tempered by a higher reported frequency of intraventricular hemorrhage in hypercapnic very-low-birth-weight infants, and there is at least one case report of subarachnoid hemorrhage in a child ventilated with permissive hypercapnia for an asthma episode (Edmunds and Harrison 2003; Kaiser et al. 2006). The severe hypercapnia of complete respiratory failure goes hand in hand with hypoxia, so the effects of each in that potentially fatal scenario are difficult to separate.

Neurocognitive Effects of Solid Organ Transplantation

The first successful organ transplant was a kidney transplant performed between identical twins in 1954. Since that time, major medical advances have been made to help improve survival rates for transplant recipients. In 2008, there were 1,964 solid organ transplants performed for children under age 18 (2007 Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients [OPTN/SRTR] Annual Report 1997–2006). Currently, approximately 1,830 pediatric patients are awaiting some type of solid organ transplant (2007 OPTN/SRTR Annual Report 1997–2006). Organ transplantation in children is relatively recent compared to other treatments for children with chronic illnesses. The focus over the first few decades has been on medical advances and improving survival rates for transplant patients. In the recent years, increasing attention has been given to the developmental, neurocognitive, and psychosocial outcomes prior to transplant and in the short-term period post transplant. Most chronic illnesses and acute traumatic medical events have implications for neurocognitive outcomes. End-stage disease of the liver, kidney, heart, and lung are all believed to affect intellectual, academic, and neurocognitive functions. Gross neurodevelopmental deficits have become less common due to early medical intervention (e.g., improved nutrition, surgical intervention, reduced exposure to aluminum (Warady 2002). Organ transplantation is believed to ameliorate the deleterious long-term developmental and neurocognitive effects, but this topic has received little attention in the literature, and the available results with regard to intellectual, academic, and neurodevelopmental results have been mixed. In a combined sample of solid organ transplant patients, 40% had clinically significant cognitive delays (Brosig et al. 2006). Examining the impact of different underlying disease processes and transplantation of each solid organ separately is critical. Thus, we discuss the neurocognitive outcomes of each organ group separately in this chapter. Neurocognitive outcomes can be assessed in a variety of ways depending upon the age of the child. Among infants and toddlers, neurocognitive functioning is measured by an assessment of motor function, social and environmental interaction, and language development. Assessment of older children may involve the evaluation of intelligence, academic achievement, emotional and behavioral functioning, and adaptive skills.

Neurocognitive Outcomes in Childhood Cancer: Effects of Disease and Treatment on Brain Development and Learning

Childhood cancer is a rare disease, accounting for only 1% of all malignancies in humans of all ages. In 2007, approximately 10,400 new cases of cancer were diagnosed in children 14 years of age and younger (American Cancer Society 2007). Significant advances in diagnostic techniques and tailored treatments during the past three decades have increased the 5-year survival rate for all cancers to over 80% (Twombly 2007). For acute lymphoblastic leukemia (ALL), the most common form of childhood cancer, the current survival rate is approaching 90% (Pui and Howard 2008). Better survival has led to increased awareness and focus on the consequences of cancer treatment, called late effects. The Children’s Oncology Group has developed and published guidelines for monitoring childhood cancer survivors for late effects in nearly every organ system (Landier et al. 2004), with a recent growing interest in those affecting cognitive, academic, social, and behavioral function (Nathan et al. 2007), which are the focus of this chapter. It was long assumed that a cancer diagnosis and the severe toxicity associated with treatment was such a traumatic event that significant adverse psychological consequences were inevitable. Recent, large reports from the Childhood Cancer Survivorship Study and reviews of smaller studies suggest that this is not the case for the majority of children and adolescents treated for and surviving cancer (Eiser, Hill, and Vance 2000; Zebrack et al. 2002; Zeltzer et al. 2009). With the exception of children who experience central nervous system (CNS) cancer or cancer treatment (Zebrack et al. 2004), most childhood cancer survivors are not significantly different from the general population on measures of depression (Phipps and Srivastava 1999), selfesteem (Noll et al. 1999), hopefulness (Ritchie 2001), or posttraumatic stress disorder (PTSD). Some children experience symptoms of posttraumatic stress during acute treatment, but these symptoms diminish over time (Phipps et al. 2006). For children with CNS cancer or who receive treatment that affects the CNS, the picture is somewhat different, with poorer emotional and social functioning, neurocognitive function, and overall health-related quality of life (HRQL) reported in this subpopulation (Calaminus et al. 2000; Vannatta et al. 2007).

Phenylketonuria

Phenylketonuria (PKU) is the most frequent disorder of amino acid metabolism. First described by Fölling in 1934, PKU is an autosomal recessive disorder involving mutations in the phenylalanine hydroxylase (PAH) gene, which inhibits the normal metabolism of phenylalanine, an amino acid found in all proteins (Scriver et al. 2001). As a result, phenylalanine cannot be converted into tyrosine and accumulates in the blood and other tissues in untreated patients on a normal diet (Huijbregts et al. 2003; Pietz et al. 1998). The degree of impairment varies significantly among patients, resulting in a broad continuum of phenotypes (NIH Consensus Development Conference Report 2001). Phenylketonuria is the most common biochemical cause of mental retardation (Scriver et al. 1995). When untreated, increased phenylalanine concentrations in blood and tissues and low to normal tyrosine concentrations result in severe mental and neurological retardation (Scriver et al. 1995). In 1953, a treatment was discovered by Horst Bickel and his colleagues in England (Bickel et al. 1953). The treatment has become a standard of care and is based on a phenylalanine-restricted diet that consists of severe restriction of natural protein supplemented with all amino acids, except phenylalanine, to compensate for the shortage of amino acids through regular protein intake (Huijbregts et al. 2003). The work of Bickel and his colleagues proved that excessive phenylalanine resulted in neurological problems and that dietary treatment was beneficial. Patients with both classical and less severe forms of PKU require dietary protein restriction to prevent neurological sequelae and to ensure normal cognitive development. The first newborn screening program began in 1961 and initial results were reported by Guthrie and Susi (1963). The Guthrie bacterial assay for the filter paper blood test made it possible to identify PKU from a drop of blood from the heel of a newborn within the first days of life. It was then possible to begin treatment and thereby prevent mental retardation. Today, laws mandating newborn screening are in place in North American and Europe.

Klinefelter Syndrome

Klinefelter syndrome (KS) was first identified by Dr. Harry Klinefelter in 1942 (Klinefelter, Reifenstein, and Albright 1942) in a report of nine tall men with hypogonadism, sparse body hair, gynecomastia, and infertility. The associated chromosome disorder 47XXY was identified several years later (Jacobs and Strong 1959). The full phenotype consists of hypogonadism, low testosterone levels, infertility, gynecomastia, sparse body hair, eunuchoid body habitus, long legs and arm span, and above-average height. However, except for hypogonadism (small testes), which is present in nearly all individuals with XXY, the physical phenotype may be quite variable. In live-born males, KS has an incidence of 1:500 to 1:1,000 (Bojesen, Juul, and Gravholt 2003; Hamerton, Canning, Ray, and Smith 1975; Ratcliffe, Bancroft, Axworthy, and McLaren 1982; Rovet, Netley, Keenan, Bailey, and Stewart 1996), with a further incidence of 1:300 in spontaneous abortions (Hassold and Jacobs 1984). Klinefelter syndrome is the most common of the sex chromosome abnormalities and the second most common chromosomal disorder after Down syndrome. The possibility that incidence is increasing has also been raised (Morris, Alberman, Scott, and Jacobs 2008). Despite this, possibly as a consequence of poor identification, the syndrome has been studied less extensively than, for example, Turner syndrome (45XO) and many other developmental disorders. Boys with KS are generally tall and long-limbed but with increasing height in the population, these characteristics alone are not necessarily distinguishing. Individuals with KS are generally not immediately identifiable, and many cases of KS remain unidentified throughout life. Up to two-thirds of cases may never be identified clinically (Lanfranco, Kamischke, Zitzmann, and Nieschlag 2004). There is no clearly identifiable facial appearance, although mandibular prognathism (a prominent lower jaw and extended chin) is reported on group analysis using radiographic cephalometry (Brown, Alvesalo, and Townsend 1993). Increased genetic screening now means that 10% of cases in the United Kingdom are diagnosed prenatally on the basis of karyotype, with a further 25% of cases diagnosed during childhood (Abramsky and Chapple 1997). However, this means that 65% of cases reach puberty undiagnosed. In Belgium, fewer than 10% of expected cases are diagnosed before puberty (Bojesen et al. 2003).

Fragile X: A Family of Disorders

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

Intrauterine and Postnatal Exposure to Tobacco and Secondhand Smoke and Child Cognitive and Behavioral Development

Children’s involuntary exposure to tobacco smoke is a common and substantial health problem that has been receiving increasing attention from the pediatric, public health and research communities. According to the 2006 Surgeon General’s Report, there is no safe level of tobacco smoke exposure, yet at least 30% of children in the United States live in households with at least one adult smoker, and nearly 60% have evidence of recent exposure (Machlin, Hill, and Liang 2006). Tobacco smoke exposure has been causally linked to numerous adverse health outcomes and is currently a leading preventable cause of both low birth weight and sudden infant death syndrome, and a major contributor to lower respiratory infections, otitis media, and increased asthma severity (American Academy of Pediatrics, Committee on Environmental Health 1997; Cook and Strachan 1999; DiFranza et al. 2004). Recently, associations between tobacco smoke exposure and other childhood health problems, such as increased rates of dental caries (Aligne et al. 2003; Iida et al. 2007), food insecurity (Cutler et al. in press), and the metabolic syndrome (Weitzman et al. 2005) have been identified. As discussed in this chapter, a growing human and animal literature, which expands upon a more than 25-year-old body of work, also indicates that involuntary exposure to tobacco smoke during the pre- and/or postnatal periods is associated with adverse cognitive and behavioral outcomes in children. Tobacco smoke exposure has been associated with decrements in IQ, problems with learning and memory, difficulty with auditory processing, neonatal hyperactivity, attention-deficit hyperactivity disorder (ADHD), internalizing and externalizing behavioral problems, and conduct disorder. Animal models have provided evidence that tobacco is toxic to the developing brain, and there are plausible biologic pathways that appear to mediate these effects. Exciting new studies have begun to identify specific genes that play a role in the relationship between tobacco smoke exposure and adverse cognitive and behavioral outcomes in children. The term “secondhand smoke” (SHS), also referred to as “environmental tobacco smoke” (ETS), refers to the smoke that is exhaled from a smoker’s lungs, as well as the smoke from the smoldering end of a cigarette.

Neuropsychological Consequences of Sleep-Disordered Breathing

Pediatric sleep disorders have been gaining awareness among practitioners due to their potential for cognitive, behavioral, and somatic effects (Gozal 2008; Moore et al. 2006). Sleep-disordered breathing (SDB) is commonly seen in children and encompasses a range of disorders, in primary snoring to obstructive sleep apnea (Marcus 2000). Sleep-disordered breathing is characterized by partial or complete upper airway obstruction during sleep due to collapse or narrowing of the pharynx. This can result in sleep fragmentation due to brief arousals during the night, as well as disruption or cessation of airflow (Blunden and Beebe 2006; Halbower and Mahone 2006). This chapter describes the neuropsychological and behavioral consequences of SDB, comorbid disorders, and effects of treatment. Sleep-disordered breathing is considered a spectrum of airflow limitation, from mild to severe. For instance, primary snoring (PS), defined as snoring without oxygen desaturation or sleep arousals, is at the mild end of the spectrum. Upper airway resistance syndrome (UARS), in the middle of the spectrum, is characterized by increased negative intrathoracic pressure with sleep arousals and sleep fragmentation but no oxygen desaturations (Bao and Guilleminault 2004; Garetz 2008; Lumeng and Chervin 2008). In obstructive sleep apnea (OSA), at the severe end of the spectrum, there are repeated episodes of blockage of the airway with changes in oxygenation. Obstructive sleep apnea results from a combination of factors, including anatomical obstruction from adenoids, tonsils, or a narrow pharynx, and decreased neuromuscular tone required to maintain airway patency (Arens and Marcus 2004). An overnight polysomnogram (PSG) completed in a sleep laboratory and measuring sleep–wake states, respiration, movement, blood levels of oxygen and carbon dioxide, and cardiac activity, is considered the “gold standard” for the diagnosis of OSA (American Academy of Pediatrics 2002). The PSG is used to diagnose respiratory events, cardiac changes, and arousals from different sleep states. Respiratory events include obstructive apneas and hypopneas. Obstructive apnea events are episodes of complete airway obstruction, while hypopneas are partial obstructions or airflow limitations (Garetz 2008; Redline et al. 2007).