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Childhood Disintegrative Disorder
   
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Childhood Disintegrative Disorder

Judy Chapman
2006


Definition of Childhood Disintegrative Disorder

            Childhood disintegrative disorder is a pervasive developmental disorder characterized by normal development for at least the first two years of a child’s life, followed by a marked regression in multiple areas of functioning before the age of ten, resulting in the deficits and behaviors associated with autistic disorder. The initial dramatic regression most often occurs at around three years of age, after which there is generally no further deterioration or progress (Volkmar, Koenig, & State, 2005).

            First reported in 1908, childhood disintegrative disorder has previously been named Heller’s syndrome, dementia infantalis, disintegrative psychosis, and disintegrative disorder. It was not included in the Diagnostic and Statistical Manual of Mental Disorders (DSM) until the 1994 publication of the fourth edition, DSM-IV (American Psychiatric Association [APA]).
 

          The official definition in the DSM-IV (APA, 1994) includes the following four criteria: (1) there must have been apparently normal development for at least the first 2 years after birth, with age-appropriate communication, social relationships, play, and adaptive behavior; (2) the child, before the age of 10 years, must have sustained a clinically significant loss of previously acquired skills in at least two areas including  language, social skills, toileting skills, play, or motor skills; (3) there are abnormalities of functioning in at least two of the three problematic areas that define autism (impaired social interaction, impaired communication, and restricted or repetitive patterns of behavior or activities); and (4) the disturbance is not better accounted for by another specific pervasive developmental disorder or by schizophrenia.       

Signs and Symptoms of Childhood Disintegrative Disorder

            Generally, no particular physical abnormalities characterize childhood disintegrative disorder, but occasionally neurologic examination will find mild macrocephaly, microcephaly, motor incoordination, or electroencephalograph abnormalities (Bernstein, 2006). People with autism tend to have larger heads than the population in general, and it has been suggested that sudden, rapid head growth in an infant may be an early warning signal (National Institute of Mental Health, n.d.). However, on average, their heads are no larger than those of their unaffected siblings and parents (Biever, 2005). Behavioral –  rather than physical – changes are the very evident signs of this disorder.

            The onset of childhood disintegrative disorder may be insidious or abrupt, as the child generally becomes hyperactive and resistant to change, and begins to display affective symptoms (Bates, 2002). He regresses in his communicative, social, and emotional development. A child previously able to speak in phrases loses the ability to use words, and a previously affectionate child may lose the ability to be consoled, and may even reject human contact. Motor function may become impaired, causing loss of previously acquired skills such as drawing and pedaling a tricycle, as well as possible poor coordination and an awkward gait (Bernstein, 2006). Social interaction becomes problematic, perhaps complicated by tantrums, aggression, and withdrawal. Interests become restricted as the behavior and activities exhibit repetitive or stereotyped patterns. Biological rhymicity may be disrupted, including difficulty awakening from sleep. There is often a striking deterioration in self-help skills such as toileting, and there may be various affective responses that appear inexplicable at the time of onset (Volkmar, Koenig, & State, 2005).

            After losing previously attained skills, most children function at a level of moderate to severe mental retardation, and then typically maintain that status quo for the rest of a normal lifespan (Volkmar, Koenig, & State, 2005), although very occasionally some individuals exhibit some improvement. After the deterioration plateaus, the individual with childhood disintegrative disorder, by definition, exhibits the characteristics of autism.           

            The qualitative impairments in communication may include a delay or lack of spoken language, an inability to initiate or sustain a conversation, stereotyped and repetitive use of language, and lack of varied make-believe play (APA, 1994). Often there is an inability to understand body language or tone of voice. Some individuals are mute or speak only single words or display echolalia. The facial expressions, body language, and tone of voice may be inappropriate. The inability to express needs can result in the frustration that triggers inappropriate behaviors such as tantrums or aggression (National Institute of Mental Health, n.d.).

            Manifestations of restricted, repetitive, and stereotyped patterns of behavior, interests, and activities may include motor stereotypies and mannerisms (APA, 1994). There may be hyperactivity or extreme under-activity, or uneven gross or fine motor skills (Autism Society of America, n.d.b). There may be odd, repetitive motions, such as flapping the arms or walking on the toes, or sudden freezing in position. There may be obsessive attachment to one particular toy or object. A child might endlessly line up toys in a certain way, rather than use them for pretend play, and become tremendously upset if someone else moves one of the toys. Requiring total consistency in their environment, they can become frantic as a result of a slight change in their routine, according to the National Institute of Mental Health (n.d.).

            According to the DSM-IV (APA, 1994), the qualitative impairment in social interaction exhibited by an individual with childhood disintegrative disorder may include impaired nonverbal behaviors, failure to develop peer relationships, and lack of social or emotional reciprocity. The National Institute of Mental Health (n.d.) states that some individuals don’t smile. Many have difficulty regulating their emotions, and might be disruptive or aggressive at times, damaging themselves or others, and making social interaction even more problematic. Other possible socially inappropriate behaviors mentioned by the Autism Society of America (n.d.b) include laughing or crying or showing distress for no apparent reason, an aloof manner and preference to be alone, tantrums, difficulty in mixing with others, not wanting to cuddle or be cuddled, reduced eye contact, and lack of response to verbal cues – acting deaf, despite normal hearing.

            Some of the above traits may result from difficulties with sensory integration, as many people with autism and childhood disintegrative disorder are under-sensitive or over-sensitive to certain sounds, textures, tastes, or smells. A certain sound may cause the person to cover his ears and scream. Some cannot tolerate the feel of clothing touching their skin. On the other hand, some are oblivious to cold or pain, apparently feeling nothing even when the child breaks a bone or bashes his head against a wall (National Institute of Mental Health, n.d.).

            A characteristic of autism and childhood disintegrative disorder is the failure to develop theory-of-mind, the ability to attribute mental states to others, so the individual has difficulty interpreting what others are thinking and feeling, and does not understand that others have their own plans, thoughts, and opinions. This phenomenon appears to be unique to autism, as non-autistic children –  including those with mental retardation –  demonstrate greater theory-of-mind than even cognitively superior autistics (Edelson, n.d.). Furthermore, the deficit does not improve significantly with age. Theory-of-mind has received much attention and has been the subject of many studies, some of which are mentioned below with regard to causes of childhood disintegrative disorder. However, high-functioning autistic Eric Chen writes that theory-of-mind is misleading, and proposes a theory-of-self: autistic people lack a coherent sense of self apart from other people, so their own thoughts, sensations, and perceptions are mixed with those of other people (Chen, 2006). He states that an autistic does not understand the concept of self as an integrated combination of emotions, will, and intellect, but sees these as disconnected parts – and this causes the apparent failure to attribute mental states to others.

            Epilepsy is the medical condition most highly associated with autism and childhood disintegrative disorder. About 25% of individuals with autism have seizures, and various other electroencephalograph (EEG) abnormalities are found in another 25% (Volkmar, Koenig, & State, 2005). Prevalence of seizures in childhood disintegrative disorder is at least as high as that in autism (Kurita, Koyama, Setoya, & Osada, 2004). About 25% of autistic children begin having seizures during puberty (Edelson, n.d.). The cause is unknown, but hormonal changes may be implicated. Although in some cases the seizures may be noticeable, typically they are not evident. Some signs that suggest possible subclinical seizures include behavior problems, such as aggression, self-injury, or tantrumming; decline in academic performance; or loss of some behavioral or cognitive gains. If untreated, these seizures can have deleterious effects, according to Edelson (n.d.), who reports that he has known autistic individuals who were considered high-functioning prior to puberty, but who, after experiencing untreated seizures during puberty, were considered low functioning by their late teens.

            Some individuals with pervasive developmental disorders have gastrointestinal problems such as constipation, diarrhea, or irritable bowel syndrome. One study found that these conditions are associated with a high prevalence of elevated cytokine production against whole cow’s milk protein and its major components, indicative of a non-allergic food hypersensitivity (Jyonouchi, Geng, Ruby, Reddy, & Zimmerman-Bier, 2005).

            An attempt to identify a regressive phenotype for children with pervasive developmental disorders studied 351 children with the disorders (Richler, et al., 2006). Findings were that children who regressed had slightly lower verbal IQ and social reciprocity levels, later onset of symptoms, and more gastrointestinal symptoms than children with pervasive developmental disorders without regression.

Relationship between Childhood Disintegrative Disorder and Autism

            Childhood disintegrative disorder is quite rare, with an estimated incidence ranging from about 0.2 per 10,000 (Fombonne, 2003) to approaching 5 in 10,000 (Bernstein, 2006), compared with a prevalence for autism of 1 in 166 births (Autism Society of America, 2006).  As of 2005, just over 100 cases of childhood disintegrative disorder had been reported in the literature since the disorder was identified in 1908, probably reflecting both its true infrequency as well as the possibility that it is significantly underdiagnosed (Volkmar, Koenig, & State, 2005). As with autism, childhood disintegrative disorder afflicts males more frequently than females, with estimated prevalence ranging from slightly more males (Bernstein, 2006), to a ratio of 6 to 1 (Bates, 2002).

            Because childhood disintegrative disorder, once established, resembles autistic disorder, there has been considerable debate about whether to include childhood disintegrative disorder as a separate disorder in the DSM. It was included in the DSM-IV Field Trial for Autistic Disorder (Volkmar, 1995), and was determined to warrant differentiation from autistic disorder due to its different mode of presentation, both in age of onset – with at least two years of normal development –  and in pattern of onset – with a very dramatic loss of skills. Further support for its distinction from autism was its apparently worse prognosis, as the 16 patients with childhood disintegrative disorder in the field trial displayed significantly more autistic symptoms than the autistic group, and were more likely to be mute, have IQ scores of less than 40, and be in residential placement. While childhood disintegrative disorder nearly always results in moderate to profound mental retardation, cognitive functioning in autistic disorder spans the entire range, from severe retardation to superior intellect (Santangelo & Tsatsanis, 2005). The field trial found a median age at onset of 36 months; the criterion stipulating a 24-month minimum was arbitrary, as autistic regression can also occur at any time prior to 24 months, and the field study rejected a case in which the child’s regression began at 18 months. Volkmar, Koenig, & State (2005) point out that regression is poorly understood and in critical need of study. They suggest that some of the more dramatic cases of autistic regression may actually be some of the earliest cases of childhood disintegrative disorder.

            Some researchers question the categorization of childhood disintegrative disorder apart from autism (Hendry, 2000; Kurita, Koyama, & Osada, 2005), or suggest that childhood disintegrative disorder as a distinct category may disappear once the etiology is known (Mercadante, Van der Gaag, & Schwartzman, 2006). A study testing the clinical validity of childhood disintegrative disorder slightly supported its distinction (Kurita, Koyama, Setoya, & Osada, 2004). Compared with matched autistic children with speech loss an average of 6 years after the speech loss, 10 children with childhood disintegrative disorder displayed significantly more epilepsy and stereotypy and had significantly less uneven intellectual functioning. There was also significantly more fearfulness reported for childhood disintegrative disordered children during the period of speech loss. However, there was no significant difference in retardation level, which suggests no worse short-term outcome in childhood disintegrative disorder, and the researchers concluded that there is need for a long-term study of the validity of childhood disintegrative disorder as a separate disorder. The largest follow-up study to date, involving 39 cases of childhood disintegrative disorder matched with autistic controls, found that those with childhood disintegrative disorder had lower overall functioning, were more aloof, and had a greater incidence of co-morbid epilepsy (Mouridsen, 2003).

            An indication that childhood disintegrative disorder and autistic disorder may share a genetic mechanism of transmission is the occurrence of autism and childhood disintegrative disorder in two half brothers (Zwaigenbaum et al., 2000). A study of phenotypic characteristics of autistic regression included 486 individuals with a pervasive developmental disorder, not limited to autistic disorder (Parr, Baird, Le Couteur, Rutter, & Bailey, 2004). The 486 subjects were from 239 multiplex families. The study found that regression usually affected only one of the two relatives with a pervasive developmental disorder, suggesting that regression is an intrinsic feature of genetic susceptibility, but it may or may not be manifested. Another finding was that the individuals who lost meaningful language had on average acquired first words much earlier (21 months) than their non-regressive relative (34 months), but after regression they had significantly lower IQ scores and Vineland Domain scores, and the scores were lowest for those who regressed and did not regain their language skills.

             Because of the infrequency of childhood disintegrative disorder, there appears to be no research devoted exclusively to its study (Kupper, 2004); however, it is of special interest to researchers due to its potential to further the understanding of the pathogenesis of autism.

            For purposes of this discussion, the causes of childhood disintegrative disorder will be assumed to be intimately related to the causes of autism, as appears to be the assumption of many of the referenced studies, while none of the studies indicates that they are not closely related or identical. It seems likely that the two disorders probably share a similar pathophysiology and genetic mechanism of transference. Recent advances in understanding the complex genetics of autism suggest that it might consist of not just one, but multiple related subtypes with more or less similar sets of symptoms (Biever, 2005; Schellenberg, et al., 2006; University of California, Davis, 2006).

Causes of Childhood Disintegrative Disorder

            The pathophysiology of childhood disintegrative disorder is unknown. Although autism is considered a neurodevelopmental disorder of genetic origins, environment must also be highly influential, as evidenced by the lack of complete concordance in monozygotic twins, and the wide variance of phenotypic expression, even within monozygotic twins (Santangelo & Tsatsanis, 2005). Many researchers hypothesize that childhood disintegrative disorder and autism result from a genetic predisposition which may be triggered by environmental stressors such as birth trauma or prenatal or postnatal virus exposure (Bernstein, 2006). Metaphorically, genetics may place the child at the edge of a cliff, and an environmental insult may push him over.


           
Very rarely, an environmental trigger for the onset of childhood disintegrative disorder can be identified. Medical conditions which have apparently triggered childhood disintegrative disorder include infections, degenerative or demyelinating conditions of the brain (Malhotra, Chakrabarti, Gupta, Kumar, & Gill, 2003), as well as tuberose sclerosis, metachromatic leukodystrophy and Addison-Schilder’s disease, and subacute sclerosing panencephalitis; however, associated conditions are generally not found (Volkmar, Koenig, & State, 2005).

            Although psychological factors such as a ‘refrigerator mother’ were at one time believed to cause autism, it is now emphasized that physiological – rather than psychological – factors are involved (Autism Society of America, n.d.d)

            Research into the cause of autism has investigated a wide array of possible factors, many of which appear to be implicated in at least some cases of autism and childhood disintegrative disorder. A few of the most widely held hypotheses will be mentioned here.     

            There is general agreement that autism and childhood disintegrative disorder are primarily of genetic origin. However, the study of genetics of childhood disintegrative disorder is hampered by its infrequency and the lack of families with multiple occurrences. Gross chromosomal abnormalities have not yet been found, but childhood disintegrative disorder is not believed to be inherited in dominant fashion, as its incidence is sporadic; there are no reports of families with multiple occurrences of childhood disintegrative disorder (Volkmar, Koenig, and State, 2005).

            The prevalence rate of autism in siblings of autistics is much higher than the rate in the general population, but much lower than in single-gene diseases according to Muhle, Trentacoste, & Rapin (2004).The heritability of autism is about 60% to 92%, depending upon how one defines the autistic phenotype. Twin studies find a 60% concordance rate in monozygotic twins, and no concordance in dizygotic twins. Extending the autistic phenotype to include communication and social disorders increased the concordance rates to 92% for monozygotic twins and 10% for dizygotic twins. Another study compared the level of subsyndromal autistic social impairment in nonautistic brothers of children from three distinct groups of pathology, and found the greatest impairment in brothers from families with multiple incidence of autism (Constantino et al., 2006). Of the other two groups, brothers of children with any pervasive developmental disorder also showed substantial impairment, unlike siblings of probands with psychopathology unrelated to autism. These and other studies strongly suggest that genetic inheritance is the primary cause of pervasive developmental disorders, and other factors may contribute to variable expression of the related traits.

            Many investigations of the genetics of pervasive developmental disorders suggest the interaction of numerous genes. Research involving multiplex families  indicates that at least 10 genes interact in causing autism and some researchers believe there may be more than 15 involved (Santangelo & Tsatsanis, 2005). Results of linkage and association studies have implicated nearly every chromosome in the human genome, but some have been more consistently linked to autism than others. A very recent study (Schellenberg, et al., 2006), using genome-wide linkage scans, found the linked genes for families in which only males were autistic differed somewhat from the linked genes for families in which at least one female was autistic. The researchers state that they have found evidence for genetic subtypes of autism involving sex (male versus female) and timing of onset (early versus late). They find an autism locus on chromosome 7q, which has been linked with autism in other studies, as well as evidence for influence of several other genes in particular, although they suggest that there could be 20 to 30 other genes involved to a lesser extent.  

            Studies have found an association between autism and a family history of autoimmune disorders. In a study of three well-defined groups of 101 families each, autoimmune disorders were, not surprisingly, more common in the group of families having a child with autoimmune disorder than in families of a healthy control child (Sweeten, Bowyer, Posey, Halberstadt, & McDougal, 2003). However, the frequency of autoimmune disorders was yet higher in a third group consisting of families having a child with a pervasive developmental disorder. Molloy et al. (2006) found that familial autoimmunity is also associated with autistic regression. Although autoimmune disorders in general were significantly associated with regression, thyroid disease was the only particular autoimmune disorder that was significantly associated with regression.

            The hypothesis of an autoimmune cause for autism is supported by a study  that found antibodies to myelin basic protein in the sera of 58% of autistic children but in only 22% of normal children (Singh, Warren, Odell, Warren, & Cole, 1993). Any relationship between antibodies to myelin basic protein and autism is not currently understood, but the immune response may be the basis of autoimmune pathogenesis in some cases of autism, which might lead to abnormal development or function of the nerve fiber myelin (Healing Center On-Line, n.d.). In a later study, Singh, Lin, & Yang (1998) examined the associations between virus serology and autoantibody by comparing incidence of antibody for measles and human herpesvirus-6 and brain autoantibody. They found that 90% of serum containing measles-antibody was also contained brain autoantibody, and 84% of serum that was herpesvirus-6-positive was also brain-antibody positive. Singh concluded that the data supported the hypothesis that a measles virus-induced autoimmune response is a causal factor, and a herpesvirus-6 co-infection could contribute to the pathophysiology. The theory remains unproven, although oft-quoted (Healing Center On-Line, n.d.).

            A review by Cohly and Panja (2005) reports that the two primary types of immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Studies showing elevated brain specific antibodies support an autoimmune mechanism, and proinflammatory chemokines and an anti-inflammatory and modulatory cytokine are consistently elevated in autistic brains. Currently it appears that mercury or an infectious agent such as the measles virus are the most likely triggers for the immune dysfunction, but it is the subsequent activation of cytokines that is believed to be damaging. Measles-mumps-rubella antibodies are significantly higher in autistic children than in normal children. An autoimmune mechanism in autism might be triggered by maternal antibodies.

            Researchers at the University of California, Davis (2005) compared immune cells obtained from 30 children with autism and 26 unaffected children. The immune cells were exposed to bacteria and viruses to activate T-cells, B-cells, and macrophage cell populations, which provoke a cytokine response. They found a marked difference in response between the two groups.           

            A recent study  compared levels of brain derived neurotrophic factor (BDNF) in children with various pervasive developmental disorders or epilepsy with levels in unaffected children (Conolly et al., 2006). BDNF, when elevated in the serum of a newborn infant, predicts intellectual and social developmental abnormalities. Elevated mean BDNF and BDNF autoantibodies were found in children with autism and childhood disintegrative disorder, suggesting previous interaction between BDNF and the immune systems.

            Singer et al. (2006) recently investigated serum autoantibodies to the human brain and found that children with autism and their siblings, compared to control subjects, exhibit differences in autoimmune reactivity in the cerebellum and cingulate gyrus. The autistic children also displayed differences in the caudate, putamen, and prefrontal cortex.  

            There have been numerous studies and much debate over the role of the measles, mumps, and rubella vaccine (MMR) in triggering autism or autistic regression. Autistic children have significantly higher MMR antibodies than normal children, which implicates the MMR in autism (Cohly and Panja, 2005). However, several epidemiological studies have not found a correlation between the MMR and the risk of autism (Mutter, Nauman Schneider, Walach, & Haley, 2005). A study of regression in Japan, where the MMR was used only between 1989 and 1993, compared vaccinated and non-vaccinated children and found no significant difference in the proportion or incidence of regression (Uchiyama, Kurosawa, & Inaba, in press). Nor was there a significant change in the incidence of regression across the periods before, during, and after the use of the MMR. Another Japanese study of an area with a population of 300,000 found a dramatic rise in the incidence of pervasive developmental disorders beginning some years after the discontinuation of the MMR (Honda, Shimizu, and Rutter, 2005).

            Although epidemiological studies apparently indemnify the MMR as a cause of pervasive development disorders, the MMR involves two factors – mercury and the autoimmune system –  which continue to be suspect. Thimerosol, the preservative added to MMR vaccines, is mercury-based. Some studies have found that autistic children have lower than normal levels of mercury in their hair and higher than normal levels in their baby teeth, which prompted the highly controversial theory that autistic children have an impaired ability to excrete mercury (Biever, 2005).  Mutter, Naumann, Schneider, Walach, and Haley (2005) reviewed the evidence linking mercury to autism, and concluded that it may be a causal factor. Autistic children were found to have had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunogobulin shots. The levels of mercury and thimerosal found in vitro several days after vaccination inhibited half of the methionine synthatase, which is crucial for brain development and production of glutathione. Autistic children have been found to have significantly decreased glutathione. In autoimmune susceptible mice, similar conditions in vitro led to neurobehavioral deterioration.

             Studies associating autism with month of birth have had mixed results. Most recently, a historical, population-based cohort study looked at over 311,169 people, but found no link between the month or season of birth and the risk of autism (Kolevzon, Weiser, Gross, Lubin, Knobler, et al., 2006).

            Apart from the genetic and environmental factors that interact in the pathogenesis of autism and childhood disintegrative disorder, a plethora of studies in the past few years have found that the disorders are associated with numerous neurobiological abnormalities, which appear to cause at least some of the troublesome symptoms. Penn (2006) reviewed the research and found converging evidence that autism involves abnormalities in brain volume, certain brain structures, neurotransmitter systems, and neuronal growth. Postmortem and imaging studies of autistic persons have implicated many major brain structures, including the cerebellum, cerebral cortex, limbic system, corpus callosum, basal ganglia, and brain stem (National Institute of Mental Health, n.d.). Other research is focusing on the roles of neurotransmitters, especially serotonin.

            The mirror neuron system has very recently been the subject of many studies, as its dysfunction has been associated with the lack of empathy and imitative skills which marks autism (Kiderra, 2005). One study used EEG recordings of mu waves to study the activity of mirror neurons located in the premotor cortex of the frontal lobes (Oberman, et al., 2005). Activity of mirror neurons correlates with mu rhythm suppression, which occurs in the premotor cortex when the brain is engaged in doing, seeing, or imagining action. Normally, the mu wave is suppressed in response to one’s own movement or the observed movement of others. However, in autistic subjects, mu waves and mirror neurons responded to only the subject’s own movement. The failure of motor neurons to respond to the behaviors of others may contribute to the autistic difficulties in comprehending others and responding appropriately.

            Using functional imaging, Dapretto et al. (2006) studied activity of mirror neurons in the inferior frontal gyrus of high-functioning autistic and nonautistic children as they observed and imitated emotional expressions. This activity stimulated the mirror neurons of nonautistic children, but did not activate those of autistic children. Although autistic children performed the tasks well, the inferior frontal gyrus displayed a level of overall activity directly related to the child’s level of social functioning.

            Williams, et al. (2006) studied imitative impairment and mirror neurons, focusing on the right parietal lobe of 16 autistic adolescent males of normal intelligence as compared with matched nonautistic controls. Autistic individuals showed less extensive activity, and the differences between the two groups were most evident at the right temporo-parietal junction associated with theory-of-mind. Researchers also noted that during imitation, autistic subjects did not show modulation of left amygdala activity that was evident in controls.

            The findings of another study of mirror neuron activity as indexed by mu wave suppression may be related to the far greater prevalence of autism and childhood disintegrative disorder among males (Cheng, Tzeng, Decety, Imada, & Hsieh, 2006). Nonautistic subjects observed videotaped hand actions and a moving dot. Females showed greater mu suppression – indicating greater mirror neuron activity – for hand action, while men responded more strongly to the moving dot.

            The mirror neuron systems of high-functioning adults with pervasive developmental disorders differ from matched controls anatomically, according to a study which analyzed the thickness of the cerebral cortex in areas belonging to the mirror neuron system (Hadjikhani, Joseph, Snyder, & Tager-Flusberg, 2006). Researchers found localized decreases of grey matter in subjects with pervasive developmental disorder, and the thinning of the mirror neuron system correlated with pervasive developmental disorder symptom severity.

            There have been several post-mortem studies of autistic brains, all of which found abnormalities in the limbic system, cerebellum, and related inferior olive, according to a review by Bauman and Kemper (2005). Limbic system anomalies appeared to reflect arrested development, as they involved small cell size and increased cell packing density in the hippocampus, amygdala, and entorhinal cortex. In the cerebellum, which is vital to motor coordination, all studies found significantly reduced numbers of Purkinje cells, the largest neurons of the cerebellar cortex. In the cerebellar nuclei, as well as the inferior olive and vertical limb of the band of broca, studies found apparently age-related changes, from abundant, abnormally enlarged neurons in young brains, to more sparse, small, pale neurons in the adult autistic brains. These changes suggest an ongoing process of neuropathology in autism.

            There is also evidence of age-related changes in the amygdala, indicative of an abnormal pattern of development in autism. A magnetic resonance imaging study found that the amygdalas of autistic children of 7.5 to 12.5 years of age were enlarged, whereas those of autistic adolescents aged 12.75 to 18.5 years were of normal volume (Schuman et al, 2004). This indicates that autistic amygdalas are enlarged early in development, but do not later undergo the increase in volume which characterizes the development of amygdalas in normal adolescents. A very recent post-mortem stereological study compared the amygdalas of nine autistic males with those of ten age-matched male controls (Schumann and Amaral, 2006). The analysis found no difference in volume of the amygdala or cell size, but the autistic amygdala and its lateral nucleus contained significantly fewer neurons. The researchers concluded that their findings, combined with the findings of enlarged amygdalas in young autistic children, indicate that the postnatal development of the neurons in the autistic amygdala includes early enlargement, and eventually a reduction in number.

            Evidence of the influence of amygdalar development in pervasive developmental disorders was provided by a longitudinal study of 45 affected children (Munson et al., 2006). At ages 3 and 4, the right amygdala was enlarged and predicted poorer social and communication abilities at the age of 6 years. No predictive relationship at this age was found for the left amygdala, hippocampus, or total cerebral volume. However, another magnetic resonance imaging study found that the hippocampus is abnormally large in autistic brains of both children and adolescents (Schumann et al, 2004).

            A magnetic resonance imaging study found evidence that physical differences in the orbitofrontal cortex are implicated in the social deficits in autism (Girgis et al, 2006). Autistic children were found to have decreased grey matter volume in the right orbitofrontal cortex, as well as correlations between social deficits and white matter structures of the orbitofrontal cortex.

            A study of recorded EEGs of 86 autistic patients found that 43% had epileptic discharges, and 76% of the discharge foci were in the frontal region (Hashimoto, et al., 2001). The researchers concluded that the mechanism of autistic symptoms includes dysfunctions of the frontal region, which they note is related to theory-of-mind.

            A wide array of neurotransmitters have been studied for an association with autism, with inconclusive results thus far. A very recent review considers a possible connection between the findings that among autistic individuals, immune abnormalities are common, and about 33% have elevated levels of whole blood serotonin (5-HT) levels (Burgess, Sweeten, McMahon, & Fujinami, 2006). Because 5-HT acts as an immunomodulator, they recommend further research into a possible interaction between serotonin and immune abnormalities in autism. It has also been suggested that evidence for a possible association between autism and serotonin or genes which influence the serotonin system is provided by the fact that drugs that act selectively on the serotonin system are some of the most effective treatments for the dysfunctional behaviors of the disorder (Weiss et al., 2006).

            In their review of the literature, Lam, Aman, & Arnold (2006) conclude that there is little or no evidence supporting a role for dopamine, norepinephrine, or endogenous opioids, and serotonin appears to be the most likely candidate for a role in autism, but more research is required. They suggest that promising new areas of study should consider possible dysfunction of the cholinergic system, oxytocin, and amino acid neurotransmitters. A recent study concluded that an abnormality in glutamatergic neurotransmission may be involved in the pathophysiology of autism (Shinohe, et al., in press). Serum levels of glutamate – which is crucial in brain development – were significantly higher in patients with autism than in controls. However, the levels of other amino acids –  including glutamine, glycine, d-serine, and l-serine –  did not differ from the levels of normal controls.

            In a review of evidence from various labs, Sabbagh (2004) finds that theory-of-mind reasoning may consist of at least two distinct neural circuits. The left medial frontal region may reason about the mental states of others, while the orbitofrontal/medial temporal circuit in the right hemisphere apparently decodes others’ mental states from cues such as facial expressions. Sabbagh found that the evidence suggests that abnormal functioning of the orbitofrontal/medial temporal circuit may produce the abnormal development of social-cognitive skills characteristic of autism. A more recent functional imaging study by Vollm et al. (2006) supports this hypothesis, finding that theory-of-mind stimuli increased activity in the medial prefrontal cortex, lateral orbitofrontal cortex, temporal poles, superior temporal gyrus, middle frontal gyrus, cuneus, superior temporal gyrus, and temporoparietal junction.

            Underlying the dysfunction of the theory-of-mind circuit might be a deficit of communication between various brain areas. Scientists at the research network Collaborative Program of Excellence in Autism (CPEA) theorize that autism involves a failure of various parts of the brain to work together, or synchronize (Bock & Glass, 2004). With different brain areas working independently of each other, autistic persons have difficulty processing complex information, although they may excel at detail-oriented tasks.

This theory is compatible with the explanations given by Temple Grandin, a well-known high-functioning autistic, who has written several books. She emphasizes a primary difference between the autistic and nonautistic points of view: the autistic person focuses on details, unable to grasp the big picture, while the reverse is often true of nonautistics (Grandin & Johnson, 2005). The CPEA theory of underconnectivity is also compatible with the theory-of-self proposed by another high-functioning autistic, Eric Chen (2006), who believes that the root problem in autism is the lack of integration of the various aspects of a person into a coherent sense of self. The theory might also explain many of the other symptoms of autism, such as the problems with sensory integration, and the occasional autistic savant, who may work a particular area of the brain to an exceptionally high level individually, as it is deficient in interconnections with other parts of the brain.

            CPEA researchers have published the results of some of their studies suggesting that people with autism have a deficit at higher levels of analysis. One of the studies used functional imaging while autistic subjects and a control group performed tasks requiring memory of letters of the alphabet (Koshino et al., 2005). The volunteers with autism performed as well as controls, but showed more activation of the right hemisphere and less of the left, suggesting that they remember letters as shapes, using visual codes, while nonautistics remember them by name, using verbal codes. The autism group also showed less activation of the anterior portion of the brain, where higher-level thinking occurs, and more activation in the detail-perceiving posterior portion, including inferior temporal and occipital regions. Prefrontal activity was more correlated with left parietal activity in the control group, and with right parietal activity in the autism group. In addition, the different brain areas in autistic brains displayed less synchrony while recalling the letters.

            In another functional imaging study, CPEA researchers asked volunteer high-functioning autistics and matched controls a question about a simple sentence they had just read, and found the brains of autistic subjects had more activation in Wernicke’s area in the left laterosuperior temporal lobe, where individual words are comprehended, and less activation in Broca’s area in the left inferior frontal gyrus, where words of a sentence are integrated (Just, Cherkassky, Keller, & Minshew, 2004). Additionally, researchers found consistently lower functional connectivity – synchronization – between the participating cortical areas in autistic brains.

            A recent CPEA study scanned the brains of matched autistic and nonautistic subjects while they performed the Tower of London test, which measures the functioning of the prefrontal cortex (Just, Cherkassky, Keller, Kana, & Minshew, in press; Bock & Miller, 2006). In autistic participants, the prefrontal and parietal cortices functioned less synchronously than those of normal subjects. Furthermore, the researchers found that the corpus callosum was smaller in cross-sectional area in autistic brains than in normal brains, and the level of synchrony in the autistic brains correlated with the size of the corpus callosum. Another CPEA study found that the visual centers in the brains of autistic people were active not only when evaluating high imagery sentences, but also for low imagery sentences, while visual brain areas of matched normal participants were active only when evaluating high imagery sentences (Kana, Keller, Cherkassky, Minshew, & Just, in press; Bock & Miller, 2006). The researchers suggest that the autistic reliance on visualization may be a compensation for the diminished functioning of the frontal region. This study also confirmed that the prefrontal and parietal brain regions of the autistic brain worked less synchronously under task than those of normal subjects, and the level of synchrony was correlated with the size of the corpus callosum that connected them.

          Thus, the findings of these four CPEA studies of the autistic brain provide evidence supporting their theory of cortical underconnectivity, including underintegration of language and imagery, and a reliance on visualization to support language comprehension.

Treatment of Childhood Disintegrative Disorder

            There is no treatment known to cure childhood disintegrative disorder or autism. A multidisciplinary approach is advised, with parents, teachers, and therapists coordinating efforts to promote social adjustment and speech development. During the period of onset, the goal is to halt behavioral deterioration and improve remaining skills, generally using behavioral interventions.

            Once the deterioration plateaus, childhood disintegrative disorder is indistinguishable from autism, so treatment is the same as for autism. Therefore, the remainder of this discussion will refer to the treatments utilized for autism.

            Behavioral therapy is most often employed to treat autistic children, and many of the interventions used to treat autistic individuals are based on applied behavior analysis – the idea that behavior that is rewarded is more likely to be repeated (Autism Society of America, n.d.c). However, Eric Chen states that the goal of teaching an autistic social skills is misleading, as the root need is for the individual to integrate his various qualities and functions to create and recognize his own independent self (Chen, 2006). He argues that it is only by working at this fundamental problem that autistic people can be given the opportunity to enjoy a meaningful life.

            A well-known program to treat and serve autistics is TEACCH (Treatment and Education of Autistic and Related Communication Handicapped Children), which uses a structured teaching approach in an environment adapted to the child (Autism and PDD Support Network, n.d; Autism Society of America, n.d.). TEACCH is a behavioral management system which helps low functioning autistic children learn self-care skills.

            Pivotal Response Treatment is a method which, rather than targeting individual behaviors sequentially, uses naturalistic interventions to target crucial areas of a child’s development to encourage widespread improvements (Autism Society of America, n.d.c). Motivational strategies include child choice, task variation, interspersing maintenance tasks, rewarding attempts, and the use of direct and natural reinforcers.

            Children with severely impaired communication skills are sometimes helped by the Picture Exchange Communication System (PECS) (Autism and PDD Support Network, n.d.; Autism Society of America, n.d.c). Using applied behavioral analysis-based methods, individuals are taught to exchange a picture for the item or activity they want. In more advanced phases, the system teaches discrimination of symbols and then combinations of symbols.   

            Sensory integration therapy is usually done by occupational, physical or speech therapists. The senses which are problematic are gradually integrated through a process of sensitization or desensitization as needed, so that associated anxiety is reduced (Autism and PDD Support Network, n.d.; Autism Society of America, n.d.c).

            Using speech-language therapy, a speech therapist can help a person improve communication skills.  For a nonverbal individual, this may require alternatives such as signing, typing, or a picture board (Autism and PDD Support Network, n.d.).

            Although there are presently no drugs that significantly improve the underlying social and language deficits of autism, several drugs can induce some behavioral improvements (National Institute of Mental Health, n.d.). Selective serotonin reuptake inhibitors sometimes are associated with decreases in repetitive, ritualistic behavior, as well as improvements in eye contact and social contacts. Atypical antipsychotics  have been found to help with severe behavioral problems, but are used with caution, due to occasional mild side effects. Stimulants are occasionally used to reduce hyperactivity, but are rarely used with lower functioning autistic children. Seizures, which may afflict up to half of individuals with childhood disintegrative disorder, are reduced or eliminated by anticonvulsants. Parents of autistic children are advised to have an EEG performed on the child to check for any seizure activity, preferably for a period of 24 to 48 hours. (Bernstein, 2006; Edelson, n.d.).

            Vitamin and Mineral Therapy most often uses Vitamin B6, often in conjunction with magnesium. Vitamin B6 assists in the creation of enzymes needed by the brain. Although it remains somewhat controversial, numerous studies have reported positive results with use of Vitamin B6 and magnesium, so some authorities provide information regarding this supplement for autistic persons (Autism and PDD Support Network, n.d.; Autism Society of America, n.d.a). A recent 6-month study followed 33 children with pervasive developmental disorders as they received a Vitamin B6 and magnesium supplement (Mousain-Bosc et al., 2006). They sustained no adverse effects, but over half of the subjects showed significant improvement in symptoms of pervasive development disorder. When the supplementation was stopped, symptoms reappeared in a few weeks.

            Another popular supplement is dimethylglycine, a food substance found in brown rice and liver. There have been reports of improved speech, eye contact, social behavior, and attention span (Autism and PDD Support Network, n.d.).

            Various dietary interventions have been helpful for some individuals, particularly those with suspected food allergies. Gastrointestinal difficulties often afflict autistic people, providing additional motivation to experiment with the diet. Perhaps most popular among the diets which have been reported to be beneficial is one that is free of gluten and casein (Autism and PDD Support Network, n.d.; Autism Society of America, n.d.a). The Autism Research Institute has collected data from over 23,000 parents, who reported on their autistic child’s behavioral response to various drugs, supplements, and diets (Autism Research Institute, 2005). The gluten/casein-free diet was most successful, with 65% reporting improvement. Approximately half of the children were reported to improve with the candida diet, the Feingold diet, a rotation diet, or removal of chocolate, dairy products, sugar, or wheat.

            Mercury detoxification and chelation therapy – cleansing the body of heavy metals – have been reported to be of benefit for some autistic individuals. This intervention is controversial. However, parent ratings of this procedure have been overwhelmingly favorable, with 76% claiming improvement, according to the report of Autism Research Institute (2005).

            There are numerous alternative treatments which have reported some striking success stories, but are struggling for acceptance by the scientific community. In treating young children, an improvement of about 40% in 40 one-hour sessions of hyperbaric oxygen therapy has been claimed, and a similar improvement rate is reported for 20 one-hour sessions of neurofeedback (Othmer, 2005). Jaime Pineda, director of the Cognitive Neuroscience Laboratory at the University of California, San Diego, stated that biofeedback is a therapy suggested by the findings regarding mirror neurons and mu waves, as the mu rhythm is relatively amenable to learned control (Kiderra, 2005). Neurofeedback also has been found very effective in gaining control over seizures (Sterman, 2000) and in improving communication between various areas of the brain (Delorme & Makeig, 2003).

            Additional complementary approaches include art, music, or animal therapy, all of which have been found beneficial for some people (Autism and PDD Support Network, n.d.; Autism Society of America, n.d.c).

            According to Volkmar, Koenig, & State (2005), approximately 75% of children with childhood disintegrative disorder deteriorate to a much lower level than before onset of the disorder, and remain at that level, regardless of treatment. Rarely, the deterioration does not plateau, but continues and causes death. There have been several cases in which children have made a significant recovery from childhood disintegrative disorder, but generally any recovery is quite limited.

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