Agenesis of the Corpus Callosum: A Literature Review

C H A P T E R S E V E N

Agenesis of the Corpus Callosum: A Literature Review Shihfen Tu, Donna Doherty, Kathryn J. Schilmoeller, and Gary L. Schilmoeller* Contents 1. Introduction 1.1. Prenatal development 1.2. Disorders of the corpus callosum 1.3. Causes and diagnosis 1.4. Prevalence 1.5. Associated conditions 2. Physical/Health-Related Issues 2.1. Concurrent medical conditions 2.2. Sensory abnormalities 2.3. Daily living 2.4. Developmental outcomes 3. Social/Emotional/Behavioral Traits 3.1. General descriptions 3.2. Other behavioral or emotional disorders 4. Language/Communication/Cognitive Characteristics 4.1. Language development 4.2. Pragmatics/social communication 4.3. Cognition 5. Therapeutic Interventions for Individuals with ACC 5.1. Common themes 6. Conclusion and Future Directions 6.1. Summary 6.2. Future directions References

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In this chapter, we will review recent literature on the condition of agenesis of the corpus callosum (ACC), in an effort to promote general understanding of this condition as well as to provide relevant findings most applicable to *

College of Education and Human Development, The University of Maine, Orono, Maine

International Review of Research in Mental Retardation, Volume 38 ISSN 0074-7750, DOI 10.1016/S0074-7750(08)38007-0

Ó 2009 Elsevier Inc. All rights reserved.

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educational and service providers. We begin with a brief overview of the condition, its biological basis, types, and potential health-related consequences before turning to a discussion of its broad developmental and intellectual impact. We will summarize the current understanding of the effect of these callosal conditions on communication, cognition, and behavior. In addition, we will discuss the challenge of determining the most appropriate services and supports for early intervention, special education, and lifelong assistance. Finally, we will call attention to questions related to our current understanding and treatment for persons with ACC and identify important areas for future study.

1. Introduction

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The corpus callosum is the major structure of the human brain that connects the two cerebral hemispheres. It is a broadband of more than 200 million nerve fibers that provide the main route for transfer and integration of information between the two hemispheres (Kamnasaran, 2005; Shonkoff & Marshall, 2000; Windhorst, 1996). Please see Fig. 7.1 for an illustration of the

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Figure 7.1 Medial view of a halved human brain. From http://en.wikipedia.org/wiki/ File:Gehirn,__medial__-__beschriftet__lat.svg (Permission to copy granted under the terms of GNU Free Documentation License. This file is licensed under the Creative Commons Attribution ShareAlike 3.0 License.)

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structure. Studies of brain lateralization suggest that each hemisphere of the brain performs specialized functions. The corpus callosum provides the means for integrating the information from each hemisphere in order to perceive, comprehend, and act fully upon sensory input. Although there are other smaller commissures (cross-hemisphere connections) in the brain, those are comprised of significantly fewer nerve fibers than the corpus callosum. Thus, absence of the corpus callosum is considered a major brain anomaly (Mercer, 1998; Shonkoff & Marshal, 2000; Windhorst, 1996).

1.1. Prenatal development Typically the corpus callosum begins to develop very early in prenatal life. The lamina reuniens, which serves as a precursor to the corpus callosum, forms as early as the sixth to eighth week of pregnancy (Kamnasaran, 2005; Shonkoff & Marshall, 2000; Windhorst, 1996; Wisniewski & Jeret, 1994). Sometime around the 10th or 11th week of gestation, callosal nerve fibers begin to cross the midline to connect the cerebral hemispheres. These connections appear in the anterior portion of the brain first, forming the genu, with the body and splenium of the corpus callosum developing later, from the front to back. At about 18–20 weeks gestation, the most anterior portion of the corpus callosum, the rostrum, develops, finalizing the formation of the structure (Kamnasaran, 2005; Lassonde, Sauerwein, & Lepore, 2003). Once in place, these fibers continue to mature throughout pregnancy. Full maturation and myelination of callosal fibers continue throughout childhood and adolescence (Kamnasaran, 2005; Ramaekers, 1991; Shonkoff & Marshall, 2000; Windhorst, 1996).

1.2. Disorders of the corpus callosum Any disruption to the typical sequence of growth of these nerve fibers or their precursors can lead to a failure of the corpus callosum to develop normally (Kamnasaran, 2005; Njiokiktjien, 1991). Depending on the timing and cause of the disruption, the structural abnormality may be partial (p-ACC) or complete (c-ACC). In some cases, the corpus callosum is present, front to back, but abnormally thin. This is sometimes referred to as hypoplasia. Researchers are working to better understand the similarities and differences in outcomes based on the type of callosal condition. Individuals with congenital absence of the corpus callosum appear to be affected differently than those whose corpus callosum is severed in an attempt to control intractable seizures (i.e., commissurotomy, see Lassonde et al., 2003; Paul et al., 2007). While patients who undergo commissurotomies often exhibit a “disconnection syndrome” characterized by the inhibition of sensory information being transferred across hemispheres and the impediment of some bimanual motor tasks, individuals with ACC perform better on tasks related to interhemispheric integration. It is possible that individuals with a

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congenital absence of the corpus callosum may benefit from early neural plasticity, which allows alternate neural pathways to develop, although the extent of this compensation is limited (Paul et al., 2007).

1.3. Causes and diagnosis It is often difficult to pinpoint with certainty the exact cause for a callosal abnormality, but early prenatal insults or injuries, such as maternal infections, toxins, or asphyxia are sometimes suspected (e.g., Jeret, Serur, Wisniewski, & Lubin, 1987; Shevell, 2002; Wisniewski & Jeret, 1994). In certain cases, prenatal or postnatal genetic testing can identify a chromosome abnormality (Fratelli et al., 2007; Paul et al., 2007; Serur, Jeret, & Wisniewski, 1988). Agenesis of the corpus callosum sometimes occurs in association with fetal alcohol syndrome or underlying metabolic disease in the developing fetus (Jeret et al., 1987; Marszal et al., 2000; Prasad et al., 2007; Wisniewski & Jeret, 1994). In one recent study, researchers found that mothers over 40 years of age were found to be at increased risk for having children with a callosal condition in association with a chromosomal abnormality such as Patau syndrome, Edward syndrome, and Down syndrome (Glass, Shaw, Chen, & Sherr, 2008). See Table 7.1 for a summary of risk factors. Callosal disorders are diagnosed by ultrasonography, computerized tomography (CT), or magnetic resonance imaging (MRI). Currently, radiologists and neurologists consider MRI the most accurate and reliable diagnostic technology in detecting callosal disorders because it provides the most information about the corpus callosum (Fratelli et al., 2007; Glenn et al., 2005; Hetts, Sherr, Chao, Gobuty, & Barkovich, 2006). Today, prenatal specialists can diagnose a fetus with a callosal abnormality as early as 20–22 weeks gestation (Fratelli et al., 2007; Glenn et al., 2005; Moutard et al., 2003). Callosal abnormalities are not always identified prenatally, however, and some newborns and young infants are diagnosed after birth during assessments for other visible or suspected birth defects (e.g., Table 7.1 Risk factors for agenesis of the corpus callosum

Risk factor

Example

Environmental factors

Maternal infections, toxic exposures (e.g., fetal alcohol exposure), asphyxia Trisomy 13, 15, 18; Andermann syndrome, Aicardi syndrome

Chromosome abnormalities/ genetic syndromes Inborn errors of metabolism Increased maternal age

Nonketotic hyperglycinemia, mucolipidosis Over 40 years

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hydrocephaly), medical complications (e.g., seizure activity), or developmental delays. Children and adults have also been identified later in life, especially during diagnostic procedures for head injuries, headaches, seizure activity, or other medical, neurological, or behavioral concerns (Schilmoeller & Schilmoeller, 2000; Shevell, 2002; Sorensen, 1997; Taylor & David, 1998).

1.4. Prevalence The reported prevalence of callosal conditions varies depending on the population studied and technology available at the time. Historically, the prevalence has been reported as high as 3–7 per 1,000 in the general population and 2–3 per 100 among individuals with developmental disabilities (Jeret et al., 1987; Wisniewski & Jeret, 1994). However, the estimated prevalence rates from more recent studies are lower. For example, based on a review of the recent neonatal and prenatal imaging studies, ACC appeared to occur in 1 in 4,000 live births (Paul et al., 2007). However, results from a study utilizing the California birth defect registry from 1983 to 2003 indicated a lower overall birth prevalence of callosal malformations as 1.8 per 10,000 live births (Glass et al., 2008). Yet, these more recent studies do not reflect those cases diagnosed after the first year of life, pregnancies that were interrupted due to stillbirth or termination, or those individuals that are not diagnosed. It is not clear how many children and adults with callosal abnormalities go undiagnosed or misdiagnosed, but one study suggests that these underdiagnoses may be common. In a retrospective study of 90 children with idiopathic developmental delay at the Hospital for Sick Children in Toronto, 40 (44%) were identified with undiagnosed callosal abnormalities revealed during diagnostic brain imaging (Widjajay, Nilsson, Blaser, & Raybaud, 2008). Notably, in 2003 a subcommittee of the American Academy of Neurology recommended that neuroimaging, such as MRI, be included as part of the evaluation of children with global developmental delays when certain criteria are met (Shevell et al., 2003). It is likely that the more common use of diagnostic technologies will help answer the question of prevalence and may lead to early and more frequent identification of children with callosal conditions. See Table 7.2 for a summary of prevalence estimates.

1.5. Associated conditions Although ACC can occur as an isolated condition (sometimes referred to as “primary ACC” or “isolated ACC”), it is frequently associated with other brain or central nervous system abnormalities and genetic or medical conditions that also affect health and development (e.g., Doherty, Tu, Schilmoeller, & Schilmoeller, 2006; Glass et al., 2008; Jeret et al., 1987; Shevell, 2002; Wisniewski & Jeret, 1994). Based on a review of the literature, some researchers suggested that 30–45% of those with ACC have identifiable chromosome abnormalities or genetic syndromes, which

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Table 7.2 Prevalence reported by various studies with the rates per 10,000 included in parentheses

Study

MR/DD population

General population

2.2–2.4% (220–240)

1–3 per 1,000 (10–30) 0.0005–0.7% (0.05–70)

Jeret et al. (1987) Wisniewski & Jeret (1994) Paul et al. (2007)

1 per 4,000 (2.5) 1.8 per 10,000 (1.8)

Glass et al. (2008)

Widjajay et al. (2008)

Live births

44 per 100 (4400)

may be an inherited trait or a new mutation (Paul et al., 2007). Several syndromes, such as Aicardi, Andermann, and Shapiro, are often associated with ACC; however, ACC also occurs infrequently with many more syndromes such as Chiari’s syndrome, Dandy–Walker’s syndrome, Apert syndrome, neurofibromatosis, and fetal alcohol syndrome (see Lassonde & Jeeves, 1994 or Paul et al., 2007 for discussions). The effect of these syndromes on individuals ranges from mild to severe depending on the constellation of features associated with the particular syndrome. Additional brain abnormalities are also common in individuals with a callosal disorder. Hydrocephaly and microcephaly are reported frequently (Glass et al., 2008; Goodyear, Bannister, Russell, & Rimmer, 2001; Jeret et al., 1987; Shevell, 2002; Wisniewski & Jeret, 1994). Other abnormalities (e.g., cortical malformations, posterior fossa abnormalities) that may affect health and intellect are also described (Glass et al., 2008; Hetts et al., 2006). Mental retardation often is reported, but the prevalence varies widely depending on the population studied, which can include individuals with “isolated ACC” as well as those with ACC and additional brain abnormalities or syndromes (e.g., Doherty et al., 2006; Goodyear et al., 2001; Serur et al., 1988).

2. Physical/Health-Related Issues 2.1. Concurrent medical conditions Compared to the general population, persons with ACC are more likely to have physical and structural abnormalities outside the central nervous system.

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Head and oral–facial defects, such as cleft lip or palate and facial asymmetries, are sometimes present, although the reported prevalence varies broadly (Doherty et al., 2006; Goodyear et al., 2001; Jeret et al., 1987; Marszal et al., 2000; Serur et al., 1988; Shevell, 2002; Wisniewski & Jeret, 1994). Some individuals experience motor impairments such as hypotonia, spasticity and coordination problems, and cerebral palsy (Doherty et al., 2006; Schilmoeller & Schilmoeller, 2001; Serur et al., 1988; Shevell, 2002). Other less commonly associated conditions include cardiac and genitourinary anomalies (Bedeschi et al., 2006; Glass et al., 2008; Goodyear et al., 2001) and costo-vertebral defects such as spina bifida or scoliosis (Bedeschi et al., 2006; Doherty et al., 2006; Jeret et al., 1987; Wisniewski & Jeret, 1994). Epilepsy and seizures are more common in children and adults with callosal conditions, with the reported prevalence varying from 27.3 to 85.7% depending on the population studied (Doherty et al., 2006; Goodyear et al., 2001; Jeret et al., 1987; Serur et al., 1988; Shevell, 2002; Taylor & David, 1998; Wisniewski & Jeret, 1994). For example, in a survey of parents of children with ACC who contacted the ACC Network (an international support organization for families), 27.3% reported a seizure condition diagnosed by a medical professional (Doherty et al., 2006). A much higher prevalence (85.7%) was reported in a population of children with ACC from a pediatric neurology clinic (Marszal et al., 2000). This difference may be attributed to the fact that children with seizure disorders will more likely be under the care of a neurologist.

2.2. Sensory abnormalities Individuals with ACC often have sensory deficits or abnormalities, with vision issues being the most commonly reported (Doherty et al., 2006; Goodyear et al., 2001; Marszal et al., 2000; Schilmoeller & Schilmoeller, 2000, Serur et al., 1988). Specific vision problems include near- and farsightedness, strabismus, nystagmus, and problems with depth perception. Hearing deficits, both mild and profound, have also been reported, sometimes with atypical patterns over time (Doherty et al., 2006; O’Brien, 1994; Schilmoeller & Schilmoeller, 2000; Serur et al., 1988). In a longitudinal case study documenting the assessment and treatment of a young girl with ACC, she was initially diagnosed with severe hearing loss and vision impairments (Skinner & Hickson, 2002). Over a 4-year period, this child’s vision and hearing abilities matured to near-normal abilities. This phenomenon has been reported anecdotally in other infants and young children as well. Based on parental reports, some children with ACC have abnormal reactions to touch and pain (Doherty et al., 2006; Schilmoeller & Schilmoeller, 2001). In a survey of caregivers of 189 individuals with ACC and their siblings (Doherty et al., 2006), 46.7% of individuals with ACC were described to have tactile defensiveness and were “more” or “much more” sensitive to touch than would be expected. Interestingly, while those

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with ACC may be more sensitive to touch, they may also have a higher tolerance for pain. About 56.6% of the respondents in the same study indicated that their child with ACC had little or less pain perception than would be expected (Doherty et al., 2006). Parents of children with ACC also report this phenomenon anecdotally, including serious injuries (e.g., broken bones, burns) and illnesses (e.g., burst eardrums, appendicitis) that go undetected until much later than would be expected. Awareness of the potential for undetected conditions to occur is important and, as yet, largely unstudied.

2.3. Daily living Other developmental and health-related issues also affect the daily living of children with ACC. Researchers report early sucking, chewing, and swallowing difficulties, and esophageal reflux (Doherty et al., 2006; Ng, McCarthy, Tarby, & Bodensteiner, 2004; Sorensen, 1997; Stickles, Schilmoeller, & Schilmoeller, 2002). Children with ACC also often accomplish toilet training at a much later age than their typically developing siblings. In the previously noted survey of 189 caregivers of children with ACC (Doherty et al., 2006), 40.5% of those over the age of 5 years were not yet toilet trained, which can be problematic when they reach school age. In the same study, 45.5% of the children over the age of 5 years experienced bedwetting (enuresis) either occasionally or frequently. Individuals with ACC often experience sleep problems as well, including difficulty getting to sleep and frequent nighttime waking (Doherty et al., 2006; O’Brien, 1994; Schilmoeller & Schilmoeller, 2000). Lack of restorative sleep or interrupted sleep may be of particular interest since recent literature suggests an association between disordered sleep and behavioral problems or learning difficulties (Anstead, 2000).

2.4. Developmental outcomes When assessing newborns and children for developmental progress, healthcare providers should be aware of the potential for delays in this population so that needed evaluations and services can be provided. Developmental delays are quite common among children with ACC, with the reported prevalence ranging from 60.8 to 80.7% of those studied (e.g., Doherty et al., 2006; Goodyear et al., 2001; Schilmoeller & Schilmoeller, 2000; Shevell, 2002). Some researchers suggest children with isolated ACC have better developmental outcomes than those with ACC and additional conditions (Francesco, Maria-Edgarda, Giovanni, Dandolo, & Giulio, 2006; Moutard et al., 2003; Ramelli, Zanda, Wyttenbach, Bronz, & Schnider, 2006). Yet a retrospective study of prenatally diagnosed children with ACC (n = 117) found that 36% of those diagnosed with isolated ACC exhibited significant developmental delays (Fratelli et al., 2007).

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Researchers rarely address specific domains of developmental delay, but some provide clues. For example, motor skills frequently are delayed or impaired in children with ACC (Goodyear et al., 2001; O’Brien, 1994). Some children may be delayed in achieving such developmental milestones as walking and in manual dexterity, like using a pencil (O’Brien, 1994). We will address language and cognitive development and other social and behavioral outcomes in later sections. Finally, many researchers agree that it is difficult to predict developmental outcomes in infants and children with ACC; close monitoring and screening for emerging developmental and educational needs is recommended (Chadie et al., 2008; Fratelli et al., 2007; Moutard et al., 2003; Ramelli et al., 2006). For health-related issues and associated conditions, see Table 7.3. Table 7.3 Health-related issues and other conditions associated with agenesis of the corpus callosum

Concurrent medial conditions

Sensory abnormalities

Motor impairments Eating/feeding impairments Elimination Sleep issues Developmental delays

Chromosomal abnormalities and syndromes – Aicardi syndrome, Andermann syndrome Central nervous system abnormalities – hydrocephaly, microcephaly, cortical malformations Mental retardation Epilepsy/seizures Costo-vertebral defects – spina bifida, scoliosis Head and oral-facial defects – cleft lip and palate Cardiac anomalies Genitourinary anomalies Visual disturbances – near/far sightedness, strabismus, nystagmus, depth perception issues Hearing deficits—mild to profound Increased sensitivity to touch Unusual tolerance to painful stimuli Hypotonia, spasticity, coordination problems, cerebral palsy Early feeding problems, esophageal reflux, swallowing difficulties Late toilet training, enuresis, constipation Difficulty falling asleep, frequent nighttime waking Delays in meeting motor milestones, speech delays, cognitive delays

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3. Social/Emotional/Behavioral Traits 3.1. General descriptions Some researchers have described individuals with ACC as happy, friendly, and sometimes immature for their age (e.g., Brown & Paul, 2000; Stickles et al., 2002). Parents and researchers have also observed children, adolescents, and adults with ACC as having difficulties in social and emotional development (Badaruddin et al., 2007; Schilmoeller & Schilmoeller, 2000). Although they enjoy being with others, persons with ACC may have particular trouble in developing and sustaining close friendships with peers of the same age and may prefer interacting with younger children (Badaruddin et al., 2007; Sorensen, 1997; Stickles et al., 2002). Such poor peer relations may reflect an inability to process and interpret social and emotional signals, a pattern observed in psychological testing and consistent with what some parents have reported as trouble discerning their children’s feelings (Brown & Paul, 2000; O’Brien, 1994; Paul, Van LanckerSidtis, Schieffer, Dietrich & Brown, 2003). For example, in one study where two adolescent males with ACC were administered a battery of cognitive and psychosocial tests, compared to the control group, both scored the lowest on the Thematic Apperception Test (Brown & Paul, 2000). They were shown six cards based on which they were asked to tell a story with a beginning, a middle, and an end. The two young men were also told to explain the thoughts, feelings, and actions of the characters. The investigators reported that the two adolescents gave inadequate logic for their stories and showed little complexity of social understanding. The adolescents also failed to mention the content that is usually brought out by the cards and tended to overlook the emotional content and social implications of the testing materials. The researchers also observed that these two young men were somewhat unsophisticated in their self-awareness and were socially na¨ıve. The authors suggested that individuals with ACC may be more successful in routine social exchanges and interactions, but have more difficulties in new situations, where complex or abstract thought processes are important. Some researchers have observed subtle behavioral characteristics, such as the tendency to perseverate, exhibited by individuals with ACC (Brown & Paul, 2000; Schilmoeller & Schilmoeller, 2001). In a survey of parents of individuals with ACC and their siblings (n = 118 pairs), caregivers rated persons with ACC (compared to their siblings) as more likely to perseverate (Tu, Schilmoeller, Schilmoeller, Doherty, & Moes, 2008). In addition, they reported that it was more difficult to read the emotional state of the individuals with ACC, who were also rated as more likely to show unusual facial expressions, to make unusual gestures, and to have more difficulty using appropriate personal space.

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3.2. Other behavioral or emotional disorders Extreme emotional or behavioral disorders are rarely reported among individuals with ACC; however, conditions such as depression or anxiety disorders have been observed (P´arraga, P´arraga, & Jensen, 2003; Taylor & David, 1998). In one case study, an 11-year-old boy with ACC reportedly showed aggression and suicidal ideation, with prior diagnoses of depression, attention deficit/hyperactive disorder, and oppositional defiant disorder (Panos, Porter, Panos, Gaines, & Erdberg, 2001). In contrast to severe problems, individuals with ACC are more likely to show emotional and behavioral problems that are of lesser severity (Doherty et al., 2006; O’Brien, 1994; Schilmoeller & Schilmoeller, 2000). For example, some have temper tantrums (found in 23.4% of 47 individuals in O’Brien, 1994) and exhibit inflexibility handling change in routines (13.2% of 596 individuals in Schilmoeller & Schilmoeller, 2000). In addition, compared to their siblings, persons with ACC were rated as more likely to show rapid mood changes and stubbornness (Doherty et al., 2006). Even though a few studies indicated that some children with ACC exhibited autistic-like behaviors, it is rare that these children received a formal diagnosis of autism (Badaruddin et al., 2007; Doherty et al., 2006; O’Brien, 1994; Schilmoeller & Schilmoeller, 2000). In a study in which 61 children with ACC (ages 2–11) were compared to a group of 52 children with autism (ages 6–11), both groups had difficulties with social interactions and communication, but children with ACC did not frequently display the repetitive or restrictive behaviors (e.g., spinning, lack of interest in others) more commonly seen in children with autism (Badaruddin et al., 2007). Similarly, children with ACC usually do not receive a diagnosis of ADD, ADHD, or Asperger syndrome. However, compared to their siblings, they are more likely to be diagnosed as having a learning disability, developmental delay, or mental retardation (Doherty et al., 2006).

4. Language/Communication/Cognitive Characteristics 4.1. Language development Individuals with ACC typically have language delays and communication deficits (e.g., O’Brien, 1994; Sauerwein & Lassonde, 1994; Schilmoeller & Schilmoeller, 2000; Sorensen, 1997; Stickles et al., 2002). For example, in one study in which 20 prenatally diagnosed children with isolated ACC were followed for 3–16 years, investigators reported mild to severe speech delays, cognitive disorders, and abnormal neurodevelopmental testing results (Chadie et al., 2008).

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In one case study, a young girl’s development over a 10-year period was examined through observation and testing (Sorensen, 1997). Even with an ongoing intervention that began at the age of 2, the girl continued to exhibit language delay and communication deficits, primarily in her pragmatic skills. Interestingly, despite the delay in language development, the child managed to perform at the grade level in academic coursework, except for math. In another case study, Stickles et al. (2002) researchers reviewed the language development of a 23-year-old man with ACC. Despite normal intelligence and extensive intervention, this young man also exhibited language delays and deficits in social communication. Specifically, he showed an inability to take the perspective of his listener. The young man sometimes changed topics without providing the listener the reason for switching or spontaneously started a new conversation without any relevant context or reference to make his comments meaningful. However, the authors noted that his written language skills did improve over time with consistent practice. Parents and caregivers have also observed delays in language development and communication deficits in their children with ACC. In one survey mentioned earlier (Tu et al., 2008), parents indicated that almost all siblings understood messages at their corresponding age level, while less than half of the children with ACC were able to do so. These parents gave similar responses when asked about their children’s ability to engage in conversation.

4.2. Pragmatics/social communication Among some individuals with ACC, the communication deficits are primarily in the area of pragmatic skills, such as understanding jokes, nonverbal communication, and emotional communicativeness (e.g., Brown & Paul, 2000; O’Brien, 1994; Panos et al., 2001; Paul, Schieffer & Brown, 2004; Stickles et al., 2002). For example, Brown, Paul, Symington, and Dietrich (2005) compared 16 adults and adolescents (between 14 and 55 years of age) with complete ACC and normal intelligence to a control group of 31 adults and adolescents of similar age and IQ. Compared to the control group, the group with ACC had more trouble understanding the subtleties of jokes or social stories. The inability to understand subtleties is consistent with the finding that some individuals with ACC lack the comprehension of non-literal language. For instance, when a battery of language tests were administered to 10 male adults with complete ACC (ages 16–31) and a control group of 14 male adults (ages 15–28), all with IQ scores in the normal range, participants with ACC had difficulties recognizing proverb meaning and affective prosody (i.e., grasping non-literal language). However, there was no

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significant difference between the two groups with regard to comprehending literal items (Paul et al., 2003). In this case, an example of a non-literal sentence was “I’d like to give you a piece of my mind,” while “The dog’s trying to give her a ride on the wagon” was an example of a literal sentence (p. 317). While these deficits in social communication are likely to impact the peer interactions of adolescents and adults with ACC, parents have also reported that young children with ACC had difficulties initiating and sustaining conversation, and they did not understand social reciprocity and nonverbal communication of others (Badaruddin et al., 2007). Specifically, when 61 children with ACC were evaluated using DSM-IV diagnostic criteria for autism, 43% of these children were reported to have difficulty “showing social and emotional give-and-take,” while 36% had difficulty in “understanding nonverbal communication” (Badaruddin et al., 2007). In addition, investigators found other atypical communicative behaviors such as repetitive and/or meaningless talk among individuals with ACC (O’Brien, 1994; Panos et al., 2001).

4.3. Cognition As noted previously, some individuals with ACC have been observed to show difficulties in understanding complex social situations, social problem solving, and interpreting emotional content (Paul et al., 2003). These social difficulties may reflect the underlying deficits in complex reasoning and abstract thinking. In a study mentioned earlier (Brown & Paul, 2000), two individuals with ACC were given a battery of cognitive and psychosocial tests including the Categories Test, a concept formation task. To do well on this test, a person has to learn a theoretical principle successfully by trial and error. Both individuals had difficulties in recognizing abstract categories. They also performed poorly on Raven’s Colour Progressive Matrices, which is a measure of complex problem solving (Brown & Paul, 2000). Some researchers (e.g., Temple & Ilsley, 1994) also observed impairments in visual memory for complex spatial material such as the mental rotation task (Vandenberg & Kuse, 1978 When presented with two-dimensional pictures of arrays of cubes in different spatial orientations, children with ACC had trouble determining which pictures represented the same set of cubes viewed from different angles (Temple & Ilsley, 1994). Not surprisingly, individuals with ACC also face other challenges in the area of cognition. For instance, these children often experience problems with maintaining attention (e.g., Badaruddin et. al., 2007; Doherty et al., 2006; Moutard et al., 2003; Panos et al., 2001; Schilmoeller & Schilmoeller, 2000). As reported in some studies, they

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have trouble sitting still and are easily distracted and may experience academic difficulties and require additional services. In many of the published case studies, individuals with ACC may have normal intelligence, but often in the low to average range. Despite normal IQ scores, they frequently face academic challenges in subjects such as math and language performance (Finlay et al., 2000; Moutard et al., 2003; Sorensen, 1997; Stickles et al., 2002). For example, with the strong involvement and reinforcement of learning by the parents, the previously mentioned young girl with ACC and normal intelligence was able to achieve slow but steady academic progress over a 10-year period (Sorensen, 1997). Nevertheless, even though she successfully completed elementary school, the academic gap between her and her peers widened during the middle and high school years, particularly in the area of math. Other case studies have documented similar patterns (e.g., Stickles et al., 2002). These academic challenges typically accentuate during the adolescent years, presumably due to the heavy demand of attention and abstract reasoning required by coursework. Yet these challenges may also surface at an earlier age. In one study, 17 children prenatally diagnosed with isolated ACC were followed until 6 years of age (Moutard et al., 2003). Repeated intelligence testing during this period found no intellectual disability (i.e., mental retardation), but did reveal subtle speech delay and reasoning difficulties in some of the children by elementary school age. Overall, the IQ scores of most children in the study remained within the normal range, with a small decrease over time. Individuals with ACC sometimes show what has been called anosognosia—the virtual inability to recognize one’s own limitations. These individuals presume that they can accomplish things that are not within their skill abilities. In some cases, the anosognosia may put the individual in situations of danger to him or herself. For example, a young child assumes he can swim across a fast flowing river when he is incapable of swimming at all (K. Schilmoeller, personal communication, 2009). Some parents also report that their children with ACC engage in confabulation (Schilmoeller & Paul, 2003). These children tell incorrect or untrue stories but believe what they are saying is true. For instance, a child may accurately describe the scenery in a city (e.g., the location and surrounding of a sports stadium) and believe that he has been to the city, while in reality he has never traveled there and most likely has seen the scenery on a television program (K. Schilmoeller, personal communication, 2009). This pattern of telling incorrect information often is construed as lying by educators, parents, friends, or employers of the individuals with ACC and the consequences can be punishment or termination of employment. To date, no formal research has examined these phenomena.

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5. Therapeutic Interventions for Individuals with ACC Few researchers have investigated the types and effectiveness of therapies used with individuals with ACC. Indeed, given that ACC often occurs concurrently with other brain anomalies or other disorders, it is not possible to list specific therapeutic interventions applicable to all individuals. Some data do exist, however, that describe the specific therapies commonly used with these individuals (Schilmoeller & Schilmoeller, 2000, 2001) or track longitudinally the progress of single cases or small groups of individuals with ACC (Panos et al., 2001; Ritter, 1981, 1992; Sorensen, 1997; Stickles et al., 2002). Based on these data, several observations and suggestions regarding treatment choices and issues are relevant. In a survey of 596 families with a child with ACC that contacted an international family support network for ACC, parental reports indicated that 90% of the children received some form of therapy (Schilmoeller & Schilmoeller, 2000). The three most frequently reported therapies were physical therapy (63.6%), speech therapy (59.9%), and occupational therapy (56.3%). In a follow-up study of 678 families (Schilmoeller & Schilmoeller, 2001), parents corroborated these data, reporting that more than six in 10 children received one or more of these same therapies. Other commonly received therapies included early intervention, sensory integration therapy, and some form of academic (e.g., special education) counseling. Several researchers (Ritter, 1981, 1992; Sorensen, 1997; Stickles et al., 2002) followed the longitudinal course of academic and speech–language interventions with individual cases. The three individuals in these reports shared several common characteristics. Each had low average IQ scores on standardized tests. Each experienced language delays, especially in the area of pragmatics. With sustained intervention efforts, each was able to make academic progress (two were near the last years of high school and the third had graduated from high school and was taking college courses). Finally, all of the authors emphasized that therapeutic and intervention decisions were not driven primarily by results from standardized tests. Instead, interventions were required to fit the client’s needs based on specific academic and communicative challenges, each of which evolved over time.

5.1. Common themes Informed by these studies, literature reviews, and personal conversations with parents and professionals, we summarize some common themes for families and professionals to consider.

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5.1.1. Physical delays Physical delays often are prevalent in the early years of life. Many children with ACC show delays in early milestones (rolling over, sitting up unassisted, walking, toilet training) but eventually gain proficiency in these areas. By the school years, many of these children show no significant delays compared with their typically developing peers. In these early years, physical therapy and occupational therapy, especially with attention to sensory integration issues, often are the therapies most indicated. 5.1.2. Nonverbal learning disabilities Some parents of children with ACC have found helpful the information on nonverbal learning disabilities (NLD; Rourke, 1995; Thompson, 1997). Others do not agree that issues for NLD completely match the learning experiences of those with ACC (e.g., Panos et al., 2001). However, even in the event that the match between NLD and ACC is not always congruent, many parents report that a list of suggestions that Rourke includes as an appendix in his book provides a good beginning point in terms of looking at educational issues for children with ACC. 5.1.3. Receptive versus expressive language People with ACC tend to absorb more information than they can demonstrate to others in educational settings that emphasize writing or verbal explanations. For example, in a case study mentioned earlier (Sorensen, 1997), the speech–language therapists working with the girl often reported that she appeared to know more than the formal tests revealed. Thus, teachers should be creative in finding ways for children to demonstrate their knowledge. The following anecdotal report by a parent is a good example in that regard (K. Schilmoeller, personal communication, 1999). A 5-year-old child with ACC was asked to draw a picture of a man. He took a crayon and scribbled across the page. The teacher concluded that the child had no concept of what a person looked like. However, shortly afterward when the child was provided different shapes of paper and pieces of masking tape, without prompting from an adult, that same child produced a face complete with eyes, nose, and mouth, and announced “This is me.” The child clearly understood what a face looked like. He simply could not manipulate a crayon well enough to demonstrate his knowledge. 5.1.4. Delays evident only at later ages Some families report that their children do not show any observable delays initially, commenting that their children with ACC are asymptomatic.

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However, often communicative, attention, and reasoning challenges are diagnosed for these same children when they are in formal educational settings (Moutard et al., 2003). This is especially the case in terms of abstract reasoning (e.g., math—Ritter, 1981, 1992; Sorensen, 1997; Stickles et al., 2002; certain types of more abstract humor such as irony or word play as well as social reasoning—Brown & Paul, 2000). Thus, early and close monitoring by both parents and professionals should be ongoing, even when the child with ACC shows no obvious delays. Perhaps the strongest recommendation regarding the selection of therapeutic interventions is to urge all teachers, therapists, and parents working with individuals with ACC to be diligent observers of the individual’s learning patterns. Rather than reaching for standardized curricula or models of therapy, let the uniqueness of the individual with ACC guide decisions about what works and what does not work.

6. Conclusion and Future Directions The precise impact of a disorder of the corpus callosum on the daily life and learning of a child or adult with the condition may be difficult to define. Yet, as researchers continue to untangle the mysteries of brain structure and function, we are learning more about the corpus callosum and the potential challenges for those living with the disorder. We should note that many of the psychosocial, communication, and cognitive studies on callosal disorders are case studies or studies with small samples drawn from clinical groups often without a comparison group. Even though these studies often documented subtle or significant developmental abnormalities, it has been suggested in some cases that ACC may be asymptomatic (Sauerwein & Lassonde, 1994; Wisniewski & Jeret, 1994), though some argued that more comprehensive studies need to be conducted in order to test this hypothesis (O’Brien, 1994). Given this lack of clarity, we therefore caution readers to take care in generalizing the findings summarized in this chapter when encountering cases of ACC.

6.1. Summary Not too long ago, the corpus callosum was believed to simply connect the two cerebral hemispheres. It was accepted that the effect of congenital absence or malformation of the corpus callosum on a person was the same as someone who had the corpus callosum severed later in life. It is now clear that such a belief is false (Lassonde et al., 2003; Paul et al., 2007). While we have learned a lot more about ACC in the past decades, much of this condition remains unknown.

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First of all, prevalence estimates of ACC vary greatly, ranging from 1.8 to 70 per 10,000 in the overall population. The rates are higher (220 or greater per 10,000) among the MR/DD population. Given that some individuals with ACC are undiagnosed, it is possible that the rates may be even higher. This is particularly relevant for those who have MR/DD, but with no discernable cause. Hopefully, with the increasing use of the imaging technologies and the advancement in the field, the condition may be more likely to be identified early and the question of prevalence may be better answered. Many individuals with ACC exhibit developmental delays and have other concurrent conditions. Consequently, the therapeutic and service needs of each individual change over time and vary from person to person. Depending on the person, the delays or abnormalities may be observed in areas such as behavior, cognition, speech/language, social, or motor development and may involve difficulties with daily living and school. For example, young children with ACC may be delayed in achieving some developmental milestones such as walking, speaking, and toilet training. Compared to their typically developing siblings, they may be more likely to have sleep problems (e.g., bedwetting, frequent nighttime waking) and have more temper tantrums and rapid mood changes. Children with ACC may also be more likely to show stubbornness and be less flexible in dealing with changes in routines. However, these children are generally described as friendly, happy, and enjoying interactions with others. Even though some may display certain autistic-like behaviors such as repetitiveness, the behaviors are of less severity and lower frequency than children with autism. Similarly, some children with ACC may have trouble paying attention or sitting still, but dual diagnosis with ADD or ADHD is not common. As a child with ACC enters elementary school, with proper monitoring and appropriate services (particularly in the areas of speech and language), he or she can usually meet academic expectations. However, some may have problems in pragmatic skills and may have “out of place” or “meaningless” talk. As they progress into middle and high schools, the difficulties may accentuate and so may the gaps between these children and their peers. These gaps can be social and academic. Some adolescents with ACC have impairments in complex and abstract reasoning and may experience difficulty with visual memory and spatial materials. These deficits may make learning subjects like math more challenging. Socially, some are described as unsophisticated and immature for their age and thus may have difficulties in establishing close friendship with same-age peers. There are also other sensory and cognitive abnormalities observed in individuals with ACC, most of which have not been studied extensively. For example, some infants with ACC exhibit delays in vision and auditory maturation. Case studies of these children revealed that they were initially

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diagnosed with severe hearing loss and vision impairment at birth, but developed normal hearing and vision within a few years. Other sensory abnormalities include an unusually high tolerance for pain among some individuals with ACC. The phenomenon of high pain tolerance seems particularly paradoxical in light of high sensitivity to touch among some children with ACC. It also raises concern for the physical safety of these children. In a similar sense, cognitive abnormalities like anosognosia can also cause concern for parents and caregivers of children with ACC. The virtual inability to recognize one’s own limitations can easily put oneself or others in physical danger. The phenomenon of confabulation suggests that individuals with ACC may have difficulties in sorting out the source of information they received. This abnormality may have some serious social and legal implications as individuals with ACC may be convinced that certain events are real when they are not. To outside observers, they may be viewed as being dishonest or untruthful. More research is needed to investigate these phenomena.

6.2. Future directions Regarding the directions for future research, we suggest the following areas. 6.2.1. Effectiveness of therapies and early intervention Given the limited data on the type and effectiveness of therapies for individuals with ACC, more research is needed. Very few studies (e.g.,, Panos et al., 2001) evaluate children with ACC using the model of NLD (Rourke, 1995; Thompson, 1997). Thus, the question remains as to whether the learning experiences of those with ACC match with the issues for NLD. It would be helpful for the parents and practitioners working with children with ACC if more information were available to determine the relationship between ACC and NLD, so that they may be able to utilize the educational resources and intervention strategies developed for those with NLD. The same holds true for other potentially relevant interventions. 6.2.2. Isolated ACC Given that many studies in the literature either use participants with comorbid conditions or are based on small samples with no comparison groups, it is difficult to tease out the unique effect of only missing the corpus callosum on brain function and development. Thus, more research with a focus on isolated ACC is needed to fully understand the impact of the disorder. Particularly with the advancement and increasing availability in imaging technology, more cases of callosal disorders are being diagnosed prenatally, some of which are isolated ACC. It is now possible to closely

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monitor these children and assess their development beginning in the early stages of their lives and, ideally, through adulthood. 6.2.3. Adult living As children with ACC develop into adulthood, other issues such as relationships, money management, and personal safety start to take center stage. Yet for many of these adults and their families, adult living is uncharted territory. Given that some individuals with ACC may be socially na¨ıve and unsophisticated in self-perception, and have problems with abstract reasoning, ansognosia, and confabulation (e.g., Brown & Paul, 2000; Ritter, 1992; Schilmoeller & Paul, 2003; Sorensen, 1997; Stickles et al., 2002), independent adult living may sometimes be hazardous. Families of some individuals with ACC face choices of whether to obtain legal guardianship or conservatorship of finances, and individuals with ACC may need support for obtaining and sustaining employment. Adults with ACC may face more challenges in forming intimate relationships, marrying, and being parents than do their peers. Studies are needed to examine how adults with ACC currently manage their daily living and how their experiences can serve as a roadmap for others in the future. There really is no single “best” way to support and/or educate individuals with ACC. For young children with the diagnosis, our recommendation to parents, educators, and service providers is to closely monitor the child, obtain appropriate evaluations, and start intervention services early. While some children with ACC exhibit impairments in certain areas at an early age, others may appear to develop typically until they reach school age. In addition to physical, occupational, speech and language therapies, social skills training may be beneficial in helping the child navigate the increasing challenges of school. The key is to monitor the child closely, even if he or she seems to initially be doing well, and to identify the problems early before the child falls too far behind academically or behavioral issues emerge.

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