Show Summary Details
Page of

Regression and Other Patterns of Onset 

Regression and Other Patterns of Onset

Chapter:
Regression and Other Patterns of Onset
Author(s):

Ozonoff Sally

, Heung Kelly

, and Thompson Meagan

DOI:
10.1093/med/9780195371826.003.0005
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2015. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).

Subscriber: null; date: 16 August 2017

Points of Interest

  • Dichotomous classification of onset (early onset, regression) is insufficient to describe the many ways that symptoms of autism emerge in early development.

  • Parent report methods for measuring regression may not be reliable.

  • Prospective investigations of high risk samples suggest that regression may be much more common in children with autism than previously thought.

  • Symptoms of autism appear to emerge slowly during the first year of life. Behavioral signs of autism are not present at or shortly after birth in most children, as Kanner once suggested.

Introduction

The onset of autism is usually described as occurring in one of two patterns. In one onset prototype, children show abnormalities in social and communicative development in the first 12 months of life. The most common initial symptom recognized by parents is delayed speech development (De Giacomo & Fombonne, 1998), but a growing body of literature suggests that social and nonverbal communicative delays predate the language abnormalities that typically lead to diagnosis. Behaviors that discriminate between young children with autism, developmental delays, and typical development are orienting to name, looking at the faces of others, joint attention, affect sharing, and imitation (Baranek, 1999; Osterling & Dawson, 1994; Stone et al., 1994, 1999; Werner, Dawson, Osterling, & Dinno, 2000; Wetherby et al., 2004). A few studies suggest that symptoms can be detected before the first birthday in some children (Baranek, 1999; Werner et al., 2000), but these very early differences appear to be nonspecific (e.g., sleeping, eating, temperament patterns) and do not differentiate children with developmental delays from those with autism (Werner et al., 2005). Group differences are more reliably present and consistently found across studies in the second year of life (Palomo et al., 2006). This so-called early onset pattern is thought to occur in the majority of individuals with autism.

In the second pattern of onset, regressive autism, children appear to be developing typically for the first year or two of life. Between the first and second birthday, they lose skills that they had previously acquired, accompanied by the onset of autistic symptoms. The earliest literature on autism made no mention of this onset pattern. Kanner (1943), for example, did not report any loss of previously acquired skills in the 11 cases he described initially. The phenomenon was first reported in the 1970s by researchers in Japan (as cited in Kobayashi & Murata, 1998) and further described in the following decade (Hoshino et al., 1987; Kurita, 1985; Volkmar & Cohen, 1989).

Domains of Loss

The developmental areas most affected by regression are communication and social abilities. Much less frequently, adaptive and motor losses are reported (Davidovitch et al., 2000; Ozonoff et al., 2005; Siperstein & Volkmar, 2004). Several studies have found loss of language skills to be the most common type of regression reported by parents (Goldberg et al., 2003; Siperstein & Volkmar, 2004), possibly because speech is so eagerly awaited and salient to parents. Regression typically also involves loss of social interest and behaviors. As described by Rogers and DiLalla (1990), “the onset of their children’s symptoms began with a change in or loss of the child’s previous apparently normal social behavior. A loss of interest in others, the loss of eye contact, increasing isolation, the loss of interpersonal initiative including normal play were among the behaviors that the parents reported” (p. 866). Almost all parents who reported loss of words also described loss of social skills (Goldberg et al., 2003; Lord et al., 2004). Ozonoff and colleagues (2005) found loss of eye contact to be the most frequently reported change in social behavior, with 90% of parents of children with regression reporting such a loss. The second most frequently lost social behavior was a loss of social interest, which was reported in 61% of children with regressive autism (Ozonoff et al., 2005).

Timing of Loss

Regression is most often observed between the first and second birthday, with mean or median ages of regression reported across different samples between 16 and 20 months (Goldberg et al., 2003; Kurita, 1985; Ozonoff et al., 2005; Shinnar et al., 2001). In a large epidemiological sample, parents of children with regression first became concerned about development at a mean age of 19.8 months (Fombonne & Chakrabarti, 2001), which is consistent with the smaller studies.

Prevalence of Regression

Fombonne and Chakrabarti (2001) reviewed six early studies that reported regression rates in the range of 22% to 50%. Similar rates have been found in other studies. Rogers and DiLalla (1990) and Tuchman and Rapin (1997) reported approximately 30% of their samples displayed a loss of skills. Kurita (1985) reported that 37% of his sample showed speech loss. In these and other similar studies, which do not use epidemiological or community-based samples, sample sizes are typically small and cases may be ascertained in a manner that is biased toward greater severity (e.g., through clinics or hospitals). Samples from epidemiological studies provide better estimates of prevalence. In one such study, Taylor et al. (2002) reported a 25% rate of developmental regression in a large cohort of children with autism born between 1979 and 1998 in London. Another epidemiological study undertaken in California found that 34.7% of 277 children with autism had histories of regression (Byrd et al., 2002). Thus, both epidemiological and individual sample studies indicate that regression in autism occurs in a substantial minority of cases and is not a rare form of onset.

Later Outcomes

Several studies have compared the later outcomes of children with regression to those of their peers with early onset autism, with varying results. Hoshino et al. (1987) reported more severe speech and behavioral problems, as well as lower adaptive levels, in children with regression. Rogers and DiLalla (1990) found that children with regression had significantly lower IQs than those who did not lose speech. However, Short and Schopler (1988) found no statistically significant differences in IQ between early onset and regression cases, and one early study actually found a better prognosis for children who had experienced a regression (Harper & Williams, 1975). In most studies, the results have been mixed. Richler et al. (2006) reported on a large (n = 351) multisite sample (mean age 9 years) and found that children with regressive autism displayed significantly lower social reciprocity and verbal IQ than children with autism without regression, but found no differences on twelve other measures of intelligence, autism severity, and adaptive skills. Other studies (Brown & Prelock, 1995; Kobayashi & Murata, 1998; Meilleur & Fombonne, 2009; Wiggins, Rice, & Baio, 2009) have reported similarly mixed results, with some skills lower in children who regressed, but other skills no different from children with early onset autism. These studies assessed outcome at a variety of ages and many were based on small samples. A recent study examined two different cohorts of children with autism (ages 6–9 years and 16–19 years at data collection) from a large community-based sample, comparing functioning in children with and without regression. No differences were found between the onset groups in autism severity, intellectual function, or social, communicative, and adaptive outcomes. Similarly, no significant differences were found between the onset groups in any of the potential etiological factors examined, such as rate of seizures, MMR vaccination history, gastrointestinal symptoms, prenatal or neonatal risk factors, and family history (Heung, 2008). Similar findings of virtually no group differences between children with and without regression on a range of outcome measures have been reported by others (e.g., Hansen et al., 2008; Werner, Dawson, Munson, & Osterling, 2005). Hansen et al.’s investigation examined a large sample and had excellent statistical power to detect group differences, but nevertheless found very few. Thus, while some earlier studies suggested otherwise, large-scale investigations, some of which followed children for years after onset, indicate that regression histories are not necessarily associated with poorer developmental outcomes.

Potential Etiologies of Regression

The mechanisms underlying autistic regression (or for that matter, early onset autism) are unknown. Accelerated rates of head growth have been reported in several studies of young children with autism, suggesting that processes of synaptic growth and pruning may go awry and lead to autism. However, no differences in head circumference trajectories were found between children with signs of autism early in life and those with regression in one recent study (Webb et al., 2007); head growth was accelerated in both groups.

The possibility that seizures or other electrophysiological disruptions contribute to regression has also been suggested (Mantovani, 2000), in part due to the apparent reversibility of “autistic-like” features with anticonvulsant treatment found in a small subset of individuals with another regressive condition, Landau-Kleffner syndrome (Deonna, Ziegler, Maeder, Ansermet, & Roulet, 1995; Nass, Gross, Wisoff, & Devinsky, 1999; Neville et al., 1997). Kobayashi and Murata (1998) found epilepsy to be twice as frequent in children with a history of regression than in children without such a history (31% versus 15%). Hoshino et al. (1987) also found a higher incidence of epileptic seizures and febrile convulsions in children who had experienced regression (23% versus 5%). However, this finding is not universal. Among their sample of children on the autism spectrum, Tuchman and Rapin (1997) found no difference in the frequency of reported epilepsy between children with autistic regression and those without (12% and 11%, respectively). Similarly, Shinnar et al. (2001) found that regression was actually more common in children with autism without seizures. Neither Hansen et al. (2008), Baird et al. (2008), or Heung (2008) found differences in rates of epilepsy between regression and no regression groups.

Past research has occasionally suggested that psychosocial stressors might trigger regression in a vulnerable child. Kurita (1985) found that events such as the birth of siblings, parental discord, and change of residence were occasionally reported just before the regression. Rutter (1985) noted, however, that the specific life events that have been associated with developmental regression are relatively minor and common to many children, questioning their causal association. Clearly, the majority of children who experience such stressors do not suffer from regression.

Immunizations

Wakefield et al. (1998) linked autism to MMR vaccination in their study of 12 autistic children with gastrointestinal (GI) symptoms such as chronic constipation, pain, bloating, and esophageal reflux. The GI symptoms reportedly began around the same time that the children’s autistic symptoms appeared. Endoscopy revealed lymphonodular hyperplasia and macroscopic evidence of colitis. These findings led Wakefield and his colleagues to hypothesize that the children’s regressive autism was induced by the MMR vaccinations through a series of events involving mucosal damage, increased permeability of the intestines, and gastrointestinal absorption of toxic neuropeptides, causing central nervous system dysfunction and behavioral regression (Hansen & Ozonoff, 2003).

Wakefield et al.’s (1998) paper was later retracted by 10 of the study’s 13 authors (Murch et al., 2004), in part due to the paucity of epidemiological evidence supporting the theory (e.g., Dales, Hammer, & Smith, 2001; Farrington, Miller, & Taylor, 2001; Kaye, del Mar Melero-Montes, & Jick, 2001; Taylor et al., 2002; Uchiyama, Kurosawa, & Inaba, 2007). For example, Taylor et al. (1999) found no evidence of changes in incidence or age at diagnosis associated with the introduction of the MMR vaccine in the United Kingdom in 1988. A later study by this group (Taylor et al., 2002) compared three groups of children: (1) children who received the MMR vaccine before their parents became concerned about their development, (2) children who received the vaccine after such concern, and (3) children who had not received the vaccine at all. Findings showed no significant differences in incidence of regression between these three groups.

In addition to the lack of epidemiological evidence for MMR influence, there is also little support in the literature for a specific regressive phenotype of autism that Wakefield (1998) termed “autistic enterocolitis.” One large study found more GI symptoms in children with regression than those without regression (Richler et al., 2006), but this has not been reported in several other empirical studies. Fombonne and Chakrabarti (2001) analyzed one epidemiological sample and two clinical samples of children (total N = 262) and found no association between developmental regression and GI symptoms; only 2.1% of the samples experienced both problems, and this rate did not exceed chance expectations. In addition, this study compared children who were exposed to the MMR immunization with those who were not exposed and found no difference in the reported rates of regression between the two groups. These authors also found no evidence that children with regressive autism have symptom or severity profiles that are different from children with early onset autism (Fombonne & Chakrabarti, 2001). Similar lack of association between GI problems and regression has been reported by several other groups (Baird et al., 2008; Hansen et al., 2008; Heung, 2008; Taylor et al., 2002).

Concerns about MMR extended to other combinations of vaccines, to the increasing number of vaccines, and then to potentially toxic components of vaccines. One such component that attracted much attention was thimerosal, a mercury-containing preservative found in vaccines. James and colleagues (2004) found that, compared to controls, some children with autism have a severe deficiency of glutathione, which is required for heavy metal detoxification and excretion. Contrary to this hypothesis, however, increases (rather than decreases) in the incidence of autism following discontinuation of thimerosal-containing vaccines have been reported in Denmark (Madsen et al., 2003) and California (Schechter & Grether, 2008). Andrews et al. (2004) found no relationship between vaccine doses (and thus, levels of thimerosal exposure) and subsequent neurodevelopmental disorders including autism. Some have suggested that symptoms of autism are similar to those of mercury poisoning (e.g., Bernard et al., 2001; Blaxill, Redwood, & Bernard, 2004), but this was refuted by Nelson and Bauman (2003) who found no link between either the clinical manifestations or the neuropathology of autism and mercury poisoning. Thus, there is no direct support for the hypothesis that immunizations contribute to autism and/or developmental regression. Recently, research is focusing on whether certain medical conditions that can be associated with autism, such as mitochondrial disorders, may increase vulnerability to adverse effects of vaccines (Poling, 2006; Weissman et al., 2008).

Genetics

It has been suggested that autism with regression may represent a different genetic subtype. One study (Xi et al., 2007) examined a group of 31 boys with autism and speech loss for mutations in MeCP2, the gene that causes Rett syndrome, another condition involving developmental regression. Only one sequence variant was found, leading the authors to conclude that mutations in the coding region of the MeCP2 gene are not common causes of regression in autism.

Both Schellenberg et al. (2006) and Molloy et al. (2005) conducted linkage analyses in large cohorts of siblings with autism and found different linkage signals for pairs with and without regression, suggesting a possible genetic susceptibility to the regressive form of onset. The association found by Molloy et al.’s group was not replicated in the International Molecular Genetic Study of Autism Consortium (IMGSAC) cohort of affected siblings (Parr et al., 2006), however. The methods of the two studies differed in that the Molloy et al. study examined only siblings concordant for regression (n = 34 pairs), while the IMGSAC study included all pairs in which at least one sibling had experienced language loss (n = 58), of which only 12 were concordant for regression. Therefore, these linkage findings require further investigation and replication. The low rate of concordance for regression (20.7%) in the IMGSAC sample is, in and of itself, an important finding, suggesting that the regression phenotype is likely to be etiologically heterogeneous and multifactorial.

The liability to autism includes not only the full autism syndrome but also qualitatively similar but milder deficits (e.g., shyness, intense interests, speech delays, or other communication difficulties). This subclinical set of social and language differences seen in nonautistic relatives of individuals with autism is called the broader autism phenotype (BAP) and is found in 12 to 50% of relatives of those with autism (Lainhart et al., 2002). The BAP is considered an index of genetic vulnerability to autism (Piven, 2001).

Lainhart et al. (2002) compared the BAP in relatives of children with early onset and regressive autism. In a sample of 88 children, they found that parents of children with and without regression showed similar rates of the BAP (27.8% versus 32.9%, p = 0.33). Both groups had significantly higher rates of the BAP when compared to parents of children without autism (3.6%; p ≤ 0.01). The authors argued that these findings suggest that environmental factors are unlikely to be the sole cause of regressive autism. That is, if regressive autism were caused solely by nongenetic factors, such as immunizations, one would instead expect to find similar rates of the BAP in relatives of children with regressive autism and the general population, both of which would be significantly lower than relatives of children with early onset autism (Lainhart et al., 2002).

Case Studies of Onset Types

We end this section with two case studies that illustrate the traditionally defined patterns of onset described so far in this chapter. These case descriptions were reconstructed from both parent responses on the Autism Diagnostic Interview–Revised (ADI-R; Lord et al., 1994; Rutter et al., 2003) and family videos collected as part of an IRB-approved home movie study (Ozonoff et al., 2008). Unique to these case studies, family home movies were systematically analyzed by coders unaware of the child’s diagnosis or the purposes of the study, trained to reliability on an objective coding system (Werner & Dawson, 2005). Coded data was divided into four developmental periods, each 4 months long. To account for differences in the amount of footage available in each period, raw duration and frequency scores were converted to proportion and rate scores, respectively. Means for each period were calculated and graphs of the developmental trajectories are presented in Figure 4-1. The rates of key social-communicative behaviors are thus objectively quantified during the window of development when autism symptoms emerge, illustrating the two prototypical patterns of onset described in this chapter. Informed consent was obtained from parents prior to participation in the research project, as well as prior to the writing of these descriptions (which use pseudonyms and disguise identifying characteristics).

Figure 4–1. Developmental trajectories of key behaviors coded from home video.

Figure 4–1.
Developmental trajectories of key behaviors coded from home video.

Case 1: Isaac, Early Onset Autism

Isaac was the product of a full-term pregnancy with no reported complications. His medical history is unremarkable. He is the first child born to parents with no family history of autism. He has two younger sisters who are typically developing.

Birth to 5 months : On the ADI-R, Isaac’s parents reported that they had concerns about his development “from birth, coming home from the hospital” and said that they had noticed “no eye contact around two weeks.” Corroborating these reports, family home video taken at three months of age shows Isaac fixating on the ceiling fan while his grandfather attempts to engage him in a social game. Although his grandfather’s face is animated and just a few inches away, Isaac never looks at him. By three months of age, his parents had already become concerned specifically about the possibility that their son had autism, although they had little experience or knowledge of the condition.

6 to 10 months : During this time, Isaac continued to ignore the social approaches of others and demonstrated multiple unusual visual and repetitive behaviors. At 10 months he is observed on video repetitively flipping and rolling a marker across the floor. Coding of home videos shows that Isaac rarely oriented to his name, vocalized, or smiled at others during this period. He also shows an elevated level of unusual visual behavior, such as prolonged staring at objects (see Figure 4-1).

11 to 15 months : In home video from this period, Isaac continues to be socially isolated. At 12 months, he can be observed on camera failing to respond to his mother’s repeated attempts to engage him in a game of peek-a-boo. Instead, his attention remains focused on a large hairbrush that he is spinning on the tiled bathroom floor. At 11 months of age, his parents refer him to the first author for an autism diagnostic evaluation. He is diagnosed with Autistic Disorder at 13 months.

16 to 20 months: During this period, Isaac begins receiving intensive early behavioral intervention and speech therapy. Home video footage at this time shows Isaac repeatedly pushing a button on a musical toy and putting his face up close to the blinking lights that accompany the song. At 16 months, he fails to make eye contact or respond to his father’s verbal prompts when they are looking through a picture book together.

21 to 24 months: Footage from just prior to his second birthday shows Isaac repetitively waving a flashlight on the ceiling and examining it from the corner of his eyes. Coded data from this period show that he rarely responded to his name, smiled at others, or vocalized. He continued to meet full criteria for Autistic Disorder when retested as part of a research study at 24 months of age.

Case 2: Kyle, Autistic Regression

Kyle is the only child of parents with no family history of autism. He was born at full term; no complications were experienced during pregnancy, labor, or delivery. His medical history in the first year and a half of life revealed nothing significant. Onset of GI problems around 18 months of age was reported.

0 to 5 months: Parent report and observation of family home videos from this time period indicate that Kyle was socially well engaged, displaying frequent reciprocal smiles and babbling often. At 5 months, for example, he is seen on video playing peek-a-boo with his mother, laughing, and babbling reciprocally to continue the game.

6 to 10 months: Kyle continues to demonstrate high rates of warm positive affect, eye contact, and vocalizations throughout this period (see Figure 4-1). At 9 months he is observed on video imitating his mother blowing raspberries, laughing, and taking turns in this social game.

11 to 15 months: Both by parent report and as observed on home video, Kyle’s behavior becomes more variable, particularly toward the end of this period. Home video at 11 months captures several word approximations (“nye-nye,” “hi,” “yeah”), bright smiles toward others, and immediate orientation when his name is called. Between 13 and 15 months he begins to appear more interested in objects than people, displays less positive affect, and demonstrates a few repetitive behaviors, but these concerning behaviors are interspersed with some typical social interactions, moments of excellent eye contact, and clearly directed smiles on home video. For example, at 13 months Kyle is filmed pushing plastic balls around the edge of a table as he circles it multiple times. Although his mother is sitting a few feet away, he does not approach her or look in her direction, even when accidentally backing into her, but later turns to his father, who is filming, and gives a broad smile. Similarly, at 15 months, Kyle is seen running back and forth across the living room, flapping his hands and sporadically squealing in a high-pitched manner as he approaches people and smiles. Kyle’s parents reported on the ADI-R that they began to have concerns about Kyle’s development at 15 months, when he “lost interaction and connectedness and began to withdraw socially.”

16 to 20 months : During this period, Kyle’s symptoms become much more pronounced on video and by parent report. At 20 months he is observed making repeated stereotyped vocalizations and failing to orient to his mother, who is just a few feet away. While playing outside, he is seen flapping his hands and sifting repetitively through a pile of rocks. He ignores others when they call or approach him. No word-like vocalizations are coded on video.

21 to 24 months : Home movies taken just before his second birthday show Kyle playing with a string of beads, repeatedly setting them on the edge of a table and closely watching as they slide over the side. He does not respond to the social overtures of others in any video clips. Kyle was diagnosed with Autistic Disorder at 27 months of age.

Problems with Traditional Views of Onset

Despite the prototypicality of these two case descriptions, as well as the progress that has been made in the last half century in describing the regression phenotype, a number of difficulties with traditionally held views about onset have become evident with time. One problem is that definitions of regression and methods of describing onset differ across studies and newer research has shown that results can be quite influenced by these measurement differences. A second issue is that recent research has not always upheld previous views or clinical intuitions about the central features of and differences between onset types. Finally, prospective studies provide new data that do not fully support the findings of onset investigations that used retrospective methods (parent recall or home video analysis). Therefore, we may need to revise current conceptualizations of how the symptoms of autism emerge in the first years of life. It is to these topics that we move in the following sections.

Definition and Measurement Issues

Until relatively recently, when prospective studies that follow children from infancy through the window of autism susceptibility have been conducted, the only methodologies to investigate the early autism phenotype and onset patterns were retrospective. One method is the analysis of home movies of children later diagnosed with autism spectrum disorders. While this reduces potential reporting biases of parent interviews, home movie methodology suffers from several biases (Palomo et al., 2006). There is tremendous variability across families in the amount, content, and quality of footage of early development that is captured on video. Many families do not tape their children early in life, so home movie studies are not representative of all children with autism. Many families turn off video cameras when children are not behaving as expected or in a positive manner. Finally, home movie analysis is a very time-intensive method of collecting information about early development that is not practical for routine research use. Thus, most studies of the early autism phenotype (and clinical practice) have employed parent report, a more efficient method of collecting early history. However, parent report can be biased by knowledge of the child’s eventual diagnosis, poor recall, or lack of sensitivity to developmental differences. Retrospective reports are subject to problems of memory and interpretation (Finney, 1981; Robbins, 1963) and need to be used with caution when examining hypotheses that demand precision in estimating event dates and frequencies (Henry, Moffitt, Caspi, Langley, & Silva, 1994). When people are asked to recall particular episodes, they often report them as having occurred more recently than they did, an error called “forward telescoping” (Loftus & Marburger, 1983). This phenomenon has been described specifically in investigations using parent report to study autism onset (Lord et al., 2004). Thus, it is critical to understand the degree of accuracy in parent reports of regression, particularly since other methods (e.g., video analysis) are labor intensive and require expert training.

One widely used instrument that collects detailed parent recollections of early development is the ADI-R, a “gold standard” research interview used in diagnosis (Lord et al., 1994; Rutter et al., 2003). This instrument has a section of 18 questions that collect detailed information about potential losses, including specific skills lost, duration of losses, and potential factors associated with the losses. It first asks about language losses (question 11, “Were you ever concerned that [your child] might have lost language skills during the first years of life?”). If the parent responds in the affirmative, the interviewer then probes for the number of words lost, how they were used prior to the loss, the duration of establishment of the skill, and the duration of loss of the skill. To meet ADI-R criteria for loss of language, at least five words must have been used spontaneously, meaningfully, and communicatively for at least three months before being lost for at least three months. If there are losses indicated by the parent that do not meet these criteria (e.g., words lost that fail to meet the quantity or duration criteria or other communicative losses, like loss of babbling or gesture use), they can be recorded on the form, but the child does not meet ADI-R criteria for word loss. There is no consensus in the field yet as to how to handle parent-reported losses that are subthreshold. Parents can give very convincing descriptions of 4 word losses or of losses of 5+ words that had not consistently been in the child’s vocabulary for the three months required to meet ADI-R criteria. In most studies, these children would not be included in a language regression group.

A later ADI-R item asks parents about losses in other domains (question 20, “Has there ever been a period when [your child] seemed to get markedly worse or dropped further behind in his/her development?”). If the parent indicates yes, then possible losses in motor, self-help, play, and social abilities are probed, in that order. If the parent does not endorse other losses, no querying is done nor examples given. This may lead to underendorsement of losses, particularly in the social domain. In our experience, parents do not as readily regard social behaviors as acquired skills or specific developmental achievements that can be lost. However, when examples are provided, such as asking whether the child got markedly worse in their eye contact or lost interest in interacting with them, parents occasionally recognize this pattern and change their report.

The vast majority of children losing language also lose behaviors indicative of social interest and engagement, such as direct gaze and response to name (Goldberg et al., 2003; Lord, Shulman, & DiLavore, 2004; Ozonoff et al., 2005), but the converse is not always true. Some children show marked changes only in social development and do not lose spoken language. While it is very uncommon for children to retain acquired speech when experiencing a clear loss of social interest and engagement, many children have not acquired language at the time of the regression and therefore have no language to lose (Goldberg et al., 2003; Kurita, 1985; Ozonoff et al., 2005). Hansen et al. (2008) found that only 18% of a large (n = 138) sample of children with regression lost language skills alone, while 46% exhibited social losses alone, and 36% had losses in both language and social behaviors. Goldberg et al. (2003) found similar rates in a smaller sample, with language losses reported to occur about 2 months after losses of direct gaze, orientation to name, and social exchanges.

There is debate about whether definitions of regression should require loss of language and how children who only lose social milestones should be classified. Early studies tended to characterize regression as speech loss (Brown & Prelock, 1995; Kurita, 1985; Rogers & DiLalla, 1990) without including loss of social milestones as part of the criteria. Requiring the loss of language excludes from the regression group children who only experience social losses without substantial language loss. In many studies, such children were placed into the no-regression or early onset group (Kurita, 1985; Lainhart et al., 2002). However, recent studies suggest that there are very few differences between children who lose both words and social skills and those who experience losses in social milestones alone (Lord et al., 2004; Luyster et al., 2005). In a multisite study of children with ASD, Luyster et al. (2005) compared 125 children with word loss to 38 children with nonword loss (regression in areas other than language). They found no differences between the two regression groups. Children with word loss and nonword loss regression lost the same skills, including prespeech behaviors, games, and routines, and phrase comprehension, with almost exactly the same frequency (Luyster et al., 2005). Therefore, more recent studies have expanded definitions of regression to include losses in domains other than language (Davidovitch et al., 2000; Fombonne & Chakrabarti, 2001; Kobayashi & Murata, 1998).

Not surprisingly, the prevalence of regression is dependent on the definitions used. When a narrower definition that required language loss was used, only 15% of a large epidemiological sample of children with ASD met criteria for regression, whereas when losses in either language or social behaviors was used to classify onset patterns, 41% were found to have experienced losses (Hansen et al., 2008). Thus, requiring loss of language appears to significantly underestimate the frequency of developmental regression.

There is one published study that reports the test-retest reliability of parent report of regression. Richler et al. (2006) reported data from the multisite Collaborative Programs of Excellence in Autism (CPEA) sample (n = 351). The ADI-R was used initially to determine study eligibility and then later a detailed interview about regression was conducted by telephone. The time lag between administration of these two instruments was not specified in the study, but ranged from several months to several years. Conflicting information about word loss on the ADI-R and regression interview was apparent for 18.9% of the sample, with 12.3% reporting no loss on the ADI-R, but loss on the phone interview and 6.6% demonstrating the opposite pattern.

In unpublished data from our lab, we administered the same instrument (ADI-R) on two occasions, an average of 2 years apart. Four of 34 parents (11.8%) reported conflicting information on the ADI-R at times 1 and 2, with two feeling that their child had not regressed when asked at a mean age of 34.4 months but reporting a definite regression when asked again at a mean age of 57.4 months, and two displaying the opposite pattern (regression reported at time 1 but denied at time 2). This study also examined concurrent reliability of report of regression using two different parent report instruments. We used both the ADI-R and the Early Development Questionnaire (EDQ), a measure that asks 45 questions about social and communication development in the first 18 months of life, as well as 25 detailed questions about regression. We found that 7 of 40 parents of children with autism (17.5%) gave inconsistent information about regression across the two measures. In all cases, report on the ADI-R indicated no losses (either definite reports of no regression, 7.5%, or losses that fell short of the criteria, 10%), while report on the EDQ suggested some regression. Similarly, another investigation conducted at the M.I.N.D. Institute, the Childhood Autism Risk from Genetics and Environment (CHARGE) study (Hansen et al., 2008), found that 23 of 245 parents (9.4%) from a largely independent sample gave inconsistent information about regression on these two measures.

When reports of onset are inconsistent, it is quite difficult to determine which is accurate. Two home movie studies (Goldberg, Thorsen, Osann, & Spence, 2008; Werner & Dawson, 2005) have compared parent report with videotape footage and shown that parent report is generally valid, but poorer for reports of social than word loss and for reports of regression than no regression. Specifically, the Goldberg et al. study found 85% concordance between parental reports and independent video coders’ ratings of loss or no loss of spoken language, but only 49% concordance between parent and home video coders’ reports of social losses. Parents were more consistent when reporting no loss than when reporting loss across both language and social domains (Goldberg et al., 2008). Thus, neither parent report nor home video analysis can be considered a gold standard method of documenting whether a child displayed early signs of autism or experienced a regression in skills and the respective limitations of each method need to be recognized by researchers.

As we end this section, we provide a few recommendations that may improve the quality of future data acquisition using parent report, the more feasible of the retrospective methods currently in use. First, interviewers need to be well trained to ask questions fully (with appropriate probes) without being too leading. They should realize that parents not only may have difficulty recalling specific behaviors and their exact timing, but also may not define or conceptualize behaviors in the same way as interviewers. Examples and queries are permitted on the ADI-R, a semistructured interview that encourages examiners to ask additional questions until they are certain that the parents have understood the behavior being measured and have given a valid response. Parents often do not ask for clarification of questions and it is the interviewer’s job to anticipate when this is necessary. Parents may misinterpret failures to progress as regression and this is an additional difficulty that examiners need to be aware of during their queries. It is not uncommon for an initial positive response to questions about regression to change to a negative report of losses after further probing, when it becomes clear that although the child failed to gain anticipated new skills, he did not experience any actual losses of acquired skills. This kind of querying needs to be balanced by the recognition that subtle losses of skills are indeed possible.

Evidence for Other Patterns of Loss

A second problem with current definitions of onset is that dichotomous categorical conceptualizations do not capture all the different ways that autism can emerge. The traditional view of regression has been that development is typical prior to the loss of skills. For example, Rogers and DiLalla (1990) reported that parents of children with later onset autism “were emphatic about the normalcy of their children’s behavior in the first year of life. The onset of their children’s symptoms began with a change in or a loss of the child’s previous apparently normal social behavior” (p. 866). Data from recent studies, however, have raised doubt regarding the universality of typical development prior to regression. Ozonoff et al. (2005) identified a subset of children who presented abnormalities prior to regression. Of 31 children with regression, 45% were reported by parents to have displayed social and communication delays prior to the onset of the losses. This subset of children were reported by their parents to have never displayed several typical early-developing social behaviors, such as joint attention, showing, and social games (Ozonoff et al., 2005). Kurita (1985) also described a subset of children who showed signs of abnormalities prior to regression. Of the 97 autistic children with speech loss in his study, 78.3% showed some developmental abnormalities before the onset of the speech loss, including lack of stranger anxiety and limited social responsiveness (Kurita, 1985). Goldberg et al. (2003) reported that over two thirds of their sample with regression were already delayed in their language acquisition prior to the loss of skills. Similarly, Heung (2008) found that two thirds of subjects with regression had some indication of delayed language or social development prior to the onset of their regression. These studies and others (Meilleur & Fombonne, 2009; Richler et al., 2006; Wiggins et al., 2009) suggest that mixed onset features, with evidence of both early delays and later losses, are quite common.

Further evidence that traditional onset classifications are insufficient comes from the CHARGE study, a large epidemiological investigation of genetic and environmental risks for autism. Using an independent measure of regression, the EDQ (described above), Hansen and colleagues (2008) demonstrated that even children whose parents reported no evidence of regression on the ADI-R occasionally reported subtle losses of specific skills on the EDQ. Figure 4-2 displays the distribution of scores on the EDQ as a function of onset subtype. This finding is consistent with another report that some children whose parents reported no losses indicative of regression on the ADI-R nevertheless demonstrated subtle loss of skills on home video (Werner & Dawson, 2005).

Figure 4–2. Number of skills lost in children with and without regression. Data from Hansen, R. L., Ozonoff, S., Krakowiak, P., Angkustsiri, K., Jones, C., Deprey, L. J., et al. (2008). Regression in autism: Prevalence and associated factors in the CHARGE study. Ambulatory Pediatrics, 8(1), 25–31.

Figure 4–2.
Number of skills lost in children with and without regression. Data from Hansen, R. L., Ozonoff, S., Krakowiak, P., Angkustsiri, K., Jones, C., Deprey, L. J., et al. (2008). Regression in autism: Prevalence and associated factors in the CHARGE study. Ambulatory Pediatrics, 8(1), 25–31.

Some parents report neither early signs of autism nor later regression. For example, in one sample, less than a third of parents of children who did not experience a regression reported concerns before the first birthday and, in fewer than half, were these concerns specifically social or autistic-like in nature (De Giacomo & Fombonne, 1998). In another sample, approximately one third of parents identified only nonspecific temperament or physiological patterns (e.g., irritability, passivity, eating or sleeping problems) before the first birthday “which evolved into typical autistic features like stereotypical behavior, aloneness, and a lack of eye contact in the second year of life” (Rogers & DiLalla, 1990, p. 866). In our own data, we have found that many parents who do not report a regression also report several intact early social behaviors. For example, 35% stated that their child often looked at others during social interactions in the first 18 months of life, 50% smiled back when others smiled at them, and 28% enjoyed interactive games such as peek-a-boo (Ozonoff et al., 2005).

Collectively, these findings suggest that there is an additional pattern of symptom emergence that is characterized by intact early social development and/or nonspecific abnormalities that are followed by a failure to progress and gain new skills as expected. It has been hypothesized that this pattern may be due to failures to use intact early dyadic social reciprocity skills to support the typical maturational processes of speech acquisition, intentional communication, and triadic social interactions (Chawarska et al., 2007). In such cases, the intact early behaviors fade away because they are not reinforced by the natural predisposition to seek and communicate with others. What might seem like a loss of skills is simply a failure to progress and transform the basic skills into their more developmentally advanced versions. Klin et al. (2004) used the term “pseudo-regression” to describe this pattern and it has also been referred to as “developmental stagnation” (Siperstein & Volkmar, 2004) and “developmental plateau” (Hansen et al., 2008; Kalb, Law, Landa, & Law, 2010). Little empirical research has been conducted on this pattern, and little is known about whether it differs from other onset patterns in phenotypic features unrelated to symptom emergence. A recent study suggests that the plateau onset pattern may be associated with better adaptive outcomes (Jones & Campbell, 2010).

Data from two large population-based studies at the M.I.N.D. Institute reinforce the notion of additional onset patterns beyond the traditionally defined categories. Byrd et al. (2002) recruited a random sample of children with autism from California’s Regional Centers, which provide services for persons with developmental disabilities. Two cohorts were studied, one born in 1983–1985 and the other in 1993–1995. The CHARGE study, described above, is a large epidemiological sample also recruited from the Regional Center system, with the birth cohort extending from 1998 to 2004. The ADI-R was employed in both studies. Not only does it ask about regression, as described above, but also it asks about “onset as perceived with hindsight” (Question 4). Examining the intersection of these questions is informative to onset typology. Traditional definitions of onset suggest that most or all children without regression displayed symptoms early in life, while most or all with regression had typical early development. Thus, there should be very few, if any, subjects in the shaded diagonals of Tables 4-1 and 4-2. As is evident, however, almost half of both samples fell in these cells.

Table 4–1. Data from Byrd et al., 2002

Loss of Skills

(ADI-R Q 11 or 25)

No

Yes

Symptoms before 1st birthday

(ADI-R Q 4)

Early Onset

N = 82

28.7%

Mixed

N = 34

11.9%

Symptoms after

1st birthday

(ADI-R Q 4)

Plateau

N = 96

33.6%

Regression

N = 74

25.9%

Notes : n = 286. Byrd, R., et al. (2002). Report to the legislature on the principal findings from the epidemiology of autism in California: A comprehensive pilot study. Davis: M.I.N.D. Institute, University of California, Davis.

Table 4–2. Data from Hansen et al., 2008

Loss of Skills

(ADI-R Q 11 or 25)

No

Yes

Symptoms before 1st birthday

(ADI-R Q 4)

Early Onset

N = 123

35%

Mixed

N = 58

17%

Symptoms after

1st birthday

(ADI-R Q 4)

Plateau

N = 94

27%

Regression

N = 76

22%

Notes: n = 351. Hansen, R. L., Ozonoff, S., Krakowiak, P., Angkustsiri, K., Jones, C., Deprey, L. J., et al. (2008). Regression in autism: Prevalence and associated factors in the CHARGE study. Ambulatory Pediatrics, 8(1), 25–31.

In summary, recent research suggests that there may be several different patterns of symptom emergence. Whether these are best characterized as additional onset types or conceptualized in some other way is not yet clear. We will return to this topic after finishing this section with insights from recent prospective studies of autism onset.

Onset as Measured in Prospective Investigations

Prospective investigations are a very helpful method of studying onset, because they reduce errors due to parental recall and biases introduced by selective home videotaping, as well as provide the opportunity to test specific hypotheses through experimental methods. In the past decade, several research groups have instigated prospective investigations that study children at higher risk for autism because they have one or more siblings with the condition. Several infant sibling studies have now been published and thus far all have failed to find differences before the first birthday (at 4, 6, and 9 month visits of the respective studies) between children who are later diagnosed with autism and those who develop typically (Landa & Garrett-Mayer, 2006; Nadig et al., 2007; Zwaigenbaum et al., 2005; see also Yirmiya & Ozonoff, 2007 for a summary of this work). Bryson and colleagues (2007), in a consecutive case series of infant siblings followed prospectively from 6 months of age, describe several children whose symptoms are not present at their 6 and 12 month visits, but emerge slowly during the second year of life. Not a single child who developed autism (n = 9) displayed marked limitations in social reciprocity at 6 months. All nine infants were described as interested in social interactions, responsive to others, demonstrating sustained eye contact and social smiles. Most of the children did not experience an explicit loss of previously acquired skills that would meet established definitions of regression either. Two prospective case studies (Dawson et al., 2000; Klin et al., 2004) report on children who were noted to be symptomatic by the first birthday, but who presented with mostly intact social behavior at 6 months and did not experience a clear regression as symptoms began to emerge.

Data from the UC Davis Infant Sibling study (Ozonoff et al., 2010) are consistent with this published research. We followed 90 infants with older siblings with autism from birth through age 3. At each visit, they were administered the Mullen Scales of Early Learning, among other measures, and parents completed detailed questionnaires eliciting concerns about development and presence of autism symptoms. After each visit, the examiner made summary ratings of the infant’s eye contact, social reciprocity, spontaneous engagement, initiatives, shared affect, and vocalizations. Interactions between the examiner and infant were also recorded and coded later by research staff unaware of the infant’s group membership or outcome. The first 13 infants to be diagnosed with autism are included in Table 4-3, which depicts a reconstruction of the onset of developmental concerns and autism symptoms in these children.

Table 4–3. Onset of concerns and age of diagnosis in infants with autism/ASD outcomes

Child

6

Months

12

Months

18

Months

24

Months

36

Months

1

No concerns

No concerns

Concerns

Diagnosed

Diagnosed

2

No concerns

No concerns

Concerns

Diagnosed

Diagnosed

3

No concerns

Concerns

Concerns

Diagnosed

Diagnosed

4

No concerns

Concerns

Diagnosed

Diagnosed

Diagnosed

5

Concerns

Concerns

Diagnosed

Diagnosed

Diagnosed

6

Concerns

Concerns

Concerns

Diagnosed

7

Concerns

Diagnosed

Diagnosed

Diagnosed

8

No concerns

Concerns

Concerns

Diagnosed

9

No concerns

Concerns

Concerns

Diagnosed

10

No concerns

Concerns

Diagnosed

Diagnosed

11

No concerns

Concerns

Concerns

Diagnosed

12

Concerns

Diagnosed

Diagnosed

13

Concerns

Concerns

Diagnosed

Notes: Data from the UC Davis Infant Sibling Study (Ozonoff et al., 2010). Blank entries indicate the child was not seen at that visit.

Data used to rate onset of concerns included, at all ages, Mullen scores, parent concerns elicited at the end of each session, and examiner summary ratings of social engagement. At 18 months and up, scores on the Autism Diagnostic Observation Schedule (Lord et al., 2000), Social Communication Questionnaire (Rutter et al., 2003), and Modified-Checklist for Autism in Toddlers (Robins et al., 2001) were used as well. Table 4-3 demonstrates the rarity of children with developmental concerns at 6 months and the gradual emergence of concerns over time. Four of the five infants seen at 6 months were in the average range on all developmental tests, had no concerns raised by parents, and were rated as typical in social engagement by experienced examiners unaware of group status. The fifth infant (Child 5 in Table 4-3) scored low on motor testing, and both parents and examiners expressed concern about motor development, but social, communicative, and cognitive development were all in the average range. At 12 months, concerns had been raised about 5 of 11 children seen at this age, but over half the group continued to present relatively normally to both examiners and parents and to score in the average range on standardized testing. By 18 months, however, concerns had been raised about all children with eventual autism/ASD outcomes and 3 were formally diagnosed.

On the ADI-R, none of these 13 children was rated as having significant regression in development by their parents. Two parents noted loss of individual skills: loss of eye contact between 12 and 18 months in Child 6 and loss of gestures and language comprehension between 18 and 24 months in Child 11. Concerns had already been raised about the development of both children prior to these losses (see Table 4-3). No parents reported that their child had acquired and then lost language.

The scarcity of children with symptoms before 12 months, combined with the lack of parent-reported regression, was initially unexpected but is consistent with the results of retrospective studies reported in the previous section. To further examine the validity of this phenomenon, we used growth curve analyses to examine developmental trajectories of examiner summary ratings of social engagement. Analyses revealed a significant group by time effect (F 3, 49.38) = 9.71, p < .001). As seen in Figure 4-3, the interaction effect was due to a significant decline in social engagement over time in the autism/ASD group. Post hoc tests revealed no group differences at 6 months. At 12 months, the autism/ASD group scored significantly lower than a group with no family history of autism (Low-Risk Typical group; Beta = .604, t = 2.44, p < .05). By 24 months and later, the autism/ASD group had significantly lower scores than a Speech Delay group, a group with a positive family history of autism but who was developing typically (High Risk Typical group), and the Low Risk Typical group (Beta = .814, t = 3.22, p < .01). Coded data of the frequency of eye contact, vocalizations, and shared affect during the lab visit were highly consistent with the picture revealed by the examiner summary ratings, indicating again intact skills during the first year of life, followed by diminishing rates of social and communicative behaviors over time. See Figure 4-4. Similar declining trajectories in the onset of autism in infant siblings have also been reported by other research teams (Dawson, Munson, Webb, Nalty, Abbott, & Toth, 2007; Landa, Holman, & Garrett-Mayer, 2007).

Figure 4–3. Developmental trajectories of social engagement ratings.

Figure 4–3.
Developmental trajectories of social engagement ratings.

Figure 4–4. Frequency of eye contact with the examiner coded during the session.

Figure 4–4.
Frequency of eye contact with the examiner coded during the session.

Thus, infant sibling studies are consistent with retrospective studies in finding that for many, perhaps most, children with autism symptoms emerge gradually over the first 18 months or so of life.

Summary

The research literature reviewed in this chapter suggests that onset of autism is a gradual process that involves both diminishment of certain key social behaviors and failure to progress in other more advanced social-communicative processes over time. Autism appears to emerge over the first year and a half of life and is not present in most cases from shortly after birth, as once suggested by Kanner (1943).

Data from both retrospective and prospective studies are consistent in finding that two-category onset classification systems do not fit the empirical data well. There is evidence that the traditionally defined categories of early onset and regressive autism are overly narrow prototypes that may not in fact be very common. There is ample evidence of other ways in which symptoms emerge that are not captured by these prototypes. One possibility is that we need to expand the number of categories used to describe onset. For example, perhaps there are four rather than two categories of onset, adding a plateau and a mixed group. We suggest another possibility, however. We hypothesize that symptom emergence may better be considered as a continuum. The two extremes of this continuum are anchored by the traditionally defined, prototypical early onset and regressive cases, such as those of Isaac and Kyle described above, but many intermediate phenotypes containing mixed features and varying degrees of early deficits, subtle diminishments, failures to progress, and frank losses are also possible. We propose that variable combinations and timings of these processes across children lead to symptoms exceeding the threshold for diagnosis at different points in the first 24 months for different children, as also suggested by Landa et al. (2007).

A second insight from the body of research summarized in this chapter is that regression may be much more common than initially thought. If defined narrowly, in the traditional manner (requiring loss of language, as in the ADI-R criteria), regression is relatively rare. If defined more broadly, to include diminishment in social engagement, regression may be the rule rather than the exception. However, losses are subtle, are usually preceded by some early concerns, and are followed by failures to progress in other areas, rather than characterized by typical development followed by catastrophic losses, as traditionally defined. Others have suggested that many, even most, children with autism undergo some regression during the course of symptom onset (Dawson et al., 2007). Along these lines, we propose that symptom emergence may better be conceptualized as a continuum characterized by the amount and timing of regression. In this conceptualization, at one end of the continuum lie children who display loss of social interest so early that the regression is difficult to see and symptoms appear to have always been present. At the other end of the continuum lie children who experience losses of social interest and communication skills so late that the regression appears quite dramatic.

Conclusions

Thus, it is clear that existing definitions of onset patterns will need to undergo further development as new data emerges from future studies. Investigations using prospective samples may be especially fruitful because they will be less affected by potential videotaping, reporting, and recall biases inherent in retrospective studies. Further research clarifying whether onset is better conceptualized categorically (dichotomously) or dimensionally is urgently needed for etiologic studies, which have been hindered already by the tremendous heterogeneity of the autism phenotype. Finally, future research should strive to find early processing or biological markers that may predict who will develop autism prior to the onset of behavioral symptoms. It is possible that infants who are behaviorally asymptomatic at 6 and 12 months may show differences in lower-level underlying processes that can impact later development. For example, differences in visual attention, such as prolonged visual fixations (Landry & Bryson, 2004), might lead to joint attention deficits or behavioral rigidity a few months later. Deficits in the dorsal stream visual pathway, which is specialized for quick processing of global, low spatial-frequency information, could create a cascade of functional differences in brain regions downstream. Recently, McCleery et al. (2007) found high luminance contrast sensitivity in a subgroup of younger siblings of children with autism on a task measuring the integrity of the magnocellular visual pathway (part of the dorsal stream). Two of the infants developed autism, leading the authors to speculate that early abnormalities in the magnocellular pathway might be a risk marker for autism. Thus, research on lower level processes that may signal an affected child prior to the onset of behavioral signs could permit interventions to be applied that might significantly lessen disability or perhaps even prevent the disorder from developing.

Finally, this body of work has clinical implications for screening, diagnosis, and intervention. Universal screening has been recommended by the American Academy of Pediatrics at 18 and 24 months (Johnson et al., 2007), but many have hoped that identification even earlier than this might be possible. The research reviewed here suggests that identification of autism prior to the first birthday will be a major challenge and may not possible in many children. In fact, for the large group of infants whose autism emerges through diminishment in skills, they may be showing few or no behavioral signs of the disorder at the first birthday. Therefore, screening twice, at both 18 and 24 months, is essential, as many children will be missed at the earlier time point. Given the gradual and protracted course of symptom emergence, we urge professionals to consider referring children for intervention at the point that there is a suspicion of autism and not wait for a definitive diagnosis. Finally, development of treatments appropriate for infants and young toddlers is an urgent priority.

Challenges and Future Directions

  • Studies of larger, community-ascertained samples at high risk for autism must be conducted, ideally with enrollment during pregnancy or shortly after birth, prior to the emergence of developmental concerns that may bias subject inclusion and study results

  • Identification of risk markers prior to the onset of behavioral signs of autism

  • Development of diagnostic criteria appropriate for infants and toddlers

  • Development of screening guidelines that incorporate results of recent research on infants at risk for autism

  • Development of treatments appropriate for infants and toddlers

Suggested Readings

Goldberg, W. A., Thorsen, K. L., Osann, K., & Spence, A. M. (2008). Use of home videotapes to confirm parental reports of regression in autism. Journal of Autism and Developmental Disorders, 38, 1136–1146.

Werner, E., Dawson, G., Munson, J., & Osterling, J. (2005). Variation in early developmental course in autism and its relation with behavioral outcome at 3–4 years of age. Journal of Autism and Developmental Disorders, 35, 337–350.

Zwaigenbaum, L., Bryson, S., Lord, C., Rogers, S., Carter, A., et al. (2009). Clinical assessment and management of toddlers with suspected ASD: Insights from studies of high-risk infants. Pediatrics, 123, 1383–1391.

References

Andrews, N., Miller, E., Grant, A., Stowe, J., Osborne, V., & Taylor, B. (2004). Thimerosal exposure in infants and developmental disorders: A retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics, 114(3), 584–591.Find this resource:

Baird, G., Charman, T., Pickles, A., Chandler, S., Loucas, T., Meldrum, D., et al. (2008). Regression, developmental trajectory, and associated problems in disorders in the autism spectrum: The SNAP study. Journal of Autism and Developmental Disorders, 38(10), 1827–1836.Find this resource:

Baranek, G. T. (1999). Autism during infancy: A retrospective video analysis of sensory-motor and social behaviors at 9–12 months of age. Journal of Autism and Developmental Disorders, 29(3), 213–224.Find this resource:

Bernard, S., Enayati, A., Redwood, L., Roger, H., & Binstock, T. (2001). Autism: A novel form of mercury poisoning? Medical Hypotheses, 56, 462–471.Find this resource:

Blaxill, M. F., Redwood, L., & Bernard, S. (2004). Thimerosal and autism? A plausible hypothesis that should not be dismissed. Medical Hypotheses, 62(5), 788–794.Find this resource:

Brown, J., & Prelock, P. A. (1995). The impact of regression on language development in autism. Journal of Autism and Developmental Disorders, 25(3), 305–309.Find this resource:

Byrd, R., et al. (2002). Report to the legislature on the principal findings from the epidemiology of autism in California: A comprehensive pilot study. Davis: M.I.N.D. Institute, University of California, Davis.Find this resource:

    Bryson, S. E., Zwaigenbaum, L., Brian, J., Roberts, W., Szatmari, P., Rombough, V., et al. (2007). A prospective case series of high-risk infants who developed autism. Journal of Autism and Developmental Disorders, 37(1), 12–24.Find this resource:

    Chawarska, K., Klin, A., Paul, R., & Volkmar, F. (2007). Autism spectrum disorder in the second year: Stability and change in syndrome expression. Journal of Child Psychology and Psychiatry, 48(2), 128–138.Find this resource:

    Dales, L., Hammer, S. J., & Smith, N. J. (2001). Time trends in autism and in MMR immunization coverage in California. Journal of the American Medical Association, 285(9), 1183–1185.Find this resource:

    Davidovitch, M., Glick, L., Holtzman, G., Tirosh, E., & Safir, M. P. (2000). Developmental regression in autism: Maternal perception. Journal of Autism and Developmental Disorders, 30(2), 113–119.Find this resource:

    Dawson, G., Munson, J., Webb, S. J., Nalty, T., Abbott, R., & Toth, K. (2007). Rate of head growth decelerates and symptoms worsen in the second year of life in autism. Biological Psychiatry, 61, 458–464.Find this resource:

    Dawson, G., Osterling, J., Meltzoff, A. N., & Kuhl, P. (2000). Case study of the development of an infant with autism from birth to 2 years of age. Journal of Applied Developmental Psychology, 21, 299–313.Find this resource:

    De Giacomo, A., & Fombonne, E. (1998). Parental recognition of developmental abnormalities in autism. European Child and Adolescent Psychiatry, 7(3), 131–136.Find this resource:

    Deonna, T., Ziegler, A.-L., Maeder, M.-I., Ansermet, F., & Roulet, E. (1995). Reversible behavioral autistic-like regression: A manifestation of a special (new?) epileptic syndrome in a 28-month-old child: A 2-year longitudinal study. Neurocase, 1(2), 91–99.Find this resource:

      Farrington, C. P., Miller, E., & Taylor, B. (2001). MMR and autism: Further evidence against a causal association. Vaccine, 19(27), 3632–3635.Find this resource:

      Finney, H. C. (1981). Improving the reliability of retrospective survey measures. Evaluation Review, 5, 207–229.Find this resource:

      Fombonne, E., & Chakrabarti, S. (2001). No evidence for a new variant of measles-mumps-rubella-induced autism. Pediatrics, 108(4), E58.Find this resource:

      Goldberg, W. A., Osann, K., Filipek, P. A., Laulhere, T., Jarvis, K., Modahl, C., et al. (2003). Language and other regression: Assessment and timing. Journal of Autism and Developmental Disorders, 33(6), 607–616.Find this resource:

      Goldberg, W. A., Thorsen, K. L., Osann, K., & Spence, A. M. (2008). Use of home videotapes to confirm parental reports of regression in autism. Journal of Autism and Developmental Disorders, 38, 1136–1146.Find this resource:

      Hansen, R. L., & Ozonoff, S. (2003). Alternative theories: Assessment and therapy options. In S. Ozonoff & S. J. Rogers (Eds.), Autism spectrum disorders: A research review for practitioners (pp. 187–207). Washington, DC: American Psychiatric Publishing.Find this resource:

        Hansen, R. L., Ozonoff, S., Krakowiak, P., Angkustsiri, K., Jones, C., Deprey, L. J., et al. (2008). Regression in autism: Prevalence and associated factors in the CHARGE study. Ambulatory Pediatrics, 8(1), 25–31.Find this resource:

        Harper, J., & Williams, S. (1975). Age and type of onset as critical variables in early infantile autism. Journal of Autism and Childhood Schizophrenia, 5(1), 25–36.Find this resource:

        Henry, B., Moffitt, T. E., Caspi, A., Langley, J., & Silva, P. A. (1994). On the “remembrance of things past”: A longitudinal evaluation of the retrospective method. Psychological Assessment, 34, 49–68.Find this resource:

          Heung, K. (2008). Is autistic regression too narrowly defined? Doctoral dissertation, University of California, Davis. University Microfilms International.Find this resource:

            Hoshino, Y., Kaneko, M., Yashima, Y., Kumashiro, H., Volkmar, F. R., & Cohen, D. J. (1987). Clinical features of autistic children with setback course in their infancy. Japanese Journal of Psychiatry and Neurology, 41(2), 237–245.Find this resource:

            James, S. J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D. W., et al. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. American Journal of Clinical Nutrition, 80(6), 1611–1617.Find this resource:

            Johnson, C. P., & Myers, S. M. (2007). Identification and evaluation of children with autism spectrum disorders. Pediatrics, 120(5): 1183–1215.Find this resource:

            Jones, L. A., & Campbell, J. M. (2010). Clinical characteristics associated with language regression for children with autism spectrum disorders. Journal of Autism and Developmental Disorders, 40(1), 54–62.Find this resource:

            Kalb, L. G., Law, J. K., Landa, R., & Law, P. A. (2010). Onset patterns prior to 36 months in autism spectrum disorders. Journal of Autism and Developmental Disorders, 40(11), 1389–1402.Find this resource:

            Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217–250.Find this resource:

              Kaye, J. A., del Mar Melero-Montes, M., & Jick, H. (2001). Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. British Medical Journal, 322(7284), 460–463.Find this resource:

              Klin, A., Chawarska, K., Paul, R., Rubin, E., Morgan, T., Wiesner, L., et al. (2004). Autism in a 15-month-old child. American Journal of Psychiatry, 161(11), 1981–1198.Find this resource:

              Kobayashi, R., & Murata, T. (1998). Setback phenomenon in autism and long-term prognosis. Acta Psychiatrica Scandinavica, 98(4), 296–303.Find this resource:

              Kurita, H. (1985). Infantile autism with speech loss before the age of thirty months. Journal of the American Academy of Child Psychiatry, 24(2), 191–196.Find this resource:

              Lainhart, J. E., Ozonoff, S., Coon, H., Krasny, L., Dinh, E., Nice, J., et al. (2002). Autism, regression, and the broader autism phenotype. American Journal of Medical Genetics, 113(3), 231–237.Find this resource:

              Landa, R., & Garrett-Mayer, E. (2006). Development in infants with autism spectrum disorders: A prospective study. Journal of Child Psychology and Psychiatry, 47(6), 629–638.Find this resource:

              Landa, R., Holman, K. C., & Garrett-Mayer, E. (2007). Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Archives of General Psychiatry, 64(7), 853–864.Find this resource:

              Landry, R., & Bryson, S. E. (2004). Impaired disengagement of attention in young children with autism. Journal of Child Psychology and Psychiatry, 45(6), 1115–1122.Find this resource:

              Loftus, E. F., & Marburger, W. (1983). Since the eruption of Mt. St. Helens, has anyone beaten you up? Improving the accuracy of retrospective reports with landmark events. Memory and Cognition, 11, 114–120.Find this resource:

              Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., DiLavore, P. C., et al. (2000). The Autism Diagnostic Observation Schedule—Generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30(3), 205–223.Find this resource:

              Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24(5), 659–685.Find this resource:

              Lord, C., Shulman, C., & DiLavore, P. (2004). Regression and word loss in autistic spectrum disorders. Journal of Child Psychology and Psychiatry and Allied Disciplines, 45, 1–21.Find this resource:

              Luyster, R., Richler, J., Risi, S., Hsu, W. L., Dawson, G., Bernier, R., et al. (2005). Early regression in social communication in autism spectrum disorders: A CPEA Study. Developmental Neuropsychology, 27(3), 311–336.Find this resource:

              Madsen, K. M., Lauritsen, M. B., Pedersen, C. B., Thorsen, P., Plesner, A. M., Andersen, P. H., et al. (2003). Thimerosal and the occurrence of autism: Negative ecological evidence from Danish population-based data. Pediatrics, 112(3 Pt 1), 604–606.Find this resource:

              Mantovani, J. F. (2000). Autistic regression and Landau-Kleffner syndrome: Progress or confusion? Developmental Medicine and Child Neurology, 42(5), 349–353.Find this resource:

              McCleery, J., Allman, E., Carver, L., & Dobkins, K. (2007). Abnormal magnocellular pathway visual processing in infants at risk for autism. Biological Psychiatry, 62(9), 1007–1014.Find this resource:

              Meilleur, A. S., & Fombonne, E. (2009). Regression of language and non-language skills in pervasive developmental disorders. Journal of Intellectual Disability Research, 53, 115–124.Find this resource:

              Molloy, C. A., Keddache, M., & Martin, L. J. (2005). Evidence for linkage on 21q and 7q in a subtest of autism characterized by developmental regression. Molecular Psychiatry, 10, 741–746.Find this resource:

              Murch, S. H., Anthony, A., Casson, D. H., Malik, M., Berelowitz, M., Dhillon, A. P., et al. (2004). Retraction of an interpretation. Lancet, 363(9411), 750.Find this resource:

              Nadig, A. S., Ozonoff, S., Young, G. S., Rozga, A., Sigman, M., & Rogers, S. J. (2007). Failure to respond to name is indicator of possible autism spectrum disorder. Archives of Pediatrics and Adolescent Medicine, 161, 378–383.Find this resource:

              Nass, R., Gross, A., Wisoff, J., & Devinsky, O. (1999). Outcome of multiple subpial transections for autistic epileptiform regression. Pediatric Neurology, 21(1), 464–470.Find this resource:

              Nelson, K. B., & Bauman, M. L. (2003). Thimerosal and autism? Pediatrics, 111(3), 674–679.Find this resource:

              Neville, B. G., Harkness, W. F., Cross, J. H., Cass, H. C., Burch, V. C., Lees, J. A., et al. (1997). Surgical treatment of severe autistic regression in childhood epilepsy. Pediatric Neurology, 16(2), 137–140.Find this resource:

              Osterling, J., & Dawson, G. (1994). Early recognition of children with autism: A study of first birthday home videotapes. Journal of Autism and Developmental Disorders, 24(3), 247–257.Find this resource:

              Ozonoff, S., Iosif, A. M., Baguio, F., Cook, I. C., Hill, M. M., Hutman, T., Rogers, S. J., Sangha, S., Sigman, M., Steinfeld, M.B., & Young, G. S. (2010). A prospective study of the emergence of early behavioral signs of autism. Journal of the American Academy of Child and Adolescent Psychiatry, 49(3), 256–266.Find this resource:

              Ozonoff, S., Young, G. S., Goldring, S., Greiss-Hess, L., Herrera, A. M., Steele, J., et al. (2008). Gross motor development, movement abnormalities, and early identification of autism. Journal of Autism and Developmental Disorders, 38, 644–656.Find this resource:

              Ozonoff, S., Williams, B. J., & Landa, R. (2005). Parental report of the early development of children with regressive autism: The delays-plus-regression phenotype. Autism, 9(5), 461–486.Find this resource:

              Palomo, R., Belinchon, M., & Ozonoff, S. (2006). Autism and family home movies: A comprehensive review. Journal of Developmental and Behavioral Pediatrics, 27(2), S59–S68.Find this resource:

              Parr, J. R., Lamb, J. A., Bailey, A. J., & Monaco, A. P. (2006). Response to paper by Molloy et al.: Linkage on 21q and 7q in autism subset with regression. Molecular Psychiatry, 10(8), 741–746.Find this resource:

              Piven, J. (2001). The broad autism phenotype: A complementary strategy for molecular genetic studies of autism. American Journal of Medical Genetics, 105(1), 34–35.Find this resource:

              Poling, J. S. (2006). Developmental regression and mitochondrial dysfunction in a child with autism. Journal of Child Neurology, 21, 170–172.Find this resource:

              Richler, J., Luyster, R., Risi, S., Hsu, W. L., Dawson, G., Bernier, R., et al. (2006). Is there a “regressive phenotype” of Autism Spectrum Disorder associated with the measles-mumps-rubella vaccine? A CPEA study. Journal of Autism and Developmental Disorders, 36(3), 299–316.Find this resource:

              Robins, D. L., Fein, D., Barton, M. L., & Green, J. A. (2001). The Modified Checklist for Autism in Toddlers: An initial study investigating the early detection of autism and pervasive developmental disorders. Journal of Autism and Developmental Disorders, 31, 131–144.Find this resource:

              Robins, L. C. (1963). The accuracy of parental recall of aspects of child development and child rearing practices. Journal of Abnormal Social Psychology, 66, 261–270.Find this resource:

              Rogers, S. J., & DiLalla, D. L. (1990). Age of symptom onset in young children with pervasive developmental disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 29(6), 863–872.Find this resource:

              Rutter, M. (1985). The treatment of autistic children. Journal of Child Psychology and Psychiatry and Allied Disciplines, 26(2), 193–214.Find this resource:

              Rutter, M., Bailey, A., Lord, C., & Berument, S. K. (2003). Social Communication Questionnaire. Los Angeles, CA: Western Psychological Services.Find this resource:

                Rutter, M., Le Couteur, A., & Lord, C. (2003). Autism Diagnostic Interview-Revised (ADI-R). Los Angeles, CA: Western Psychological Services.Find this resource:

                  Schechter, R., & Grether, J. K. (2008). Continuing increases in autism reported to California’s developmental services system. Archives of General Psychiatry, 65, 19–24.Find this resource:

                  Schellenberg, G. D., Dawson, G., Sung, Y. J., Estes, A., Munson, J., et al. (2006). Evidence for multiple loci from a genome scan of autism kindreds. Molecular Psychiatry, 11, 1049–1060.Find this resource:

                  Shinnar, S., Rapin, I., Arnold, S., Tuchman, R. F., Shulman, L., Ballaban-Gil, K., et al. (2001). Language regression in childhood. Pediatric Neurology, 24(3), 183–189.Find this resource:

                  Short, A. B., & Schopler, E. (1988). Factors relating to age of onset in autism. Journal of Autism and Developmental Disorders, 18(2), 207–216.Find this resource:

                  Siperstein, R., & Volkmar, F. (2004). Parental reporting of regression in children with pervasive developmental disorders. Journal of Autism and Developmental Disorders, 34(6), 731–734.Find this resource:

                  Stone, W. L., Hoffman, E. L., Lewis, S. E., & Ousley, O. Y. (1994). Early recognition of autism. Parental reports vs. clinical observation. Archives of Pediatric and Adolescent Medicine. 148(2), 174–179.Find this resource:

                  Stone, W. L., Lee, E. B., Ashford, L., Brissie, J., Hepburn, S. L., et al. (1999). Can autism be diagnosed accurately in children under 3 years? Journal of Child Psychology and Psychiatry, 40(2), 219–226.Find this resource:

                  Taylor, B., Miller, E., Lingam, R., Andrews, N., Simmons, A., & Stowe, J. (2002). Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: Population study. British Medical Journal, 324(7334), 393–396.Find this resource:

                  Taylor, B., Miller, E., Farrington, C. P., Petropoulos, M. C., Fayot-Mayaud, I., Li, J., et al. (1999). Autism and measles, mumps and rubella vaccine: No epidemiological evidence for a causal association. Lancet, 353, 2026–2029.Find this resource:

                  Tuchman, R. F., & Rapin, I. (1997). Regression in pervasive developmental disorders: Seizures and epileptiform electroencephalogram correlates. Pediatrics, 99(4), 560–566.Find this resource:

                  Uchiyama, T., Kurosawa, M., & Inaba, Y. (2007). MMR-vaccine and regression in autism spectrum disorders: Negative results presented from Japan. Journal of Autism and Developmental Disorders, 37, 210–217.Find this resource:

                  Volkmar, F. R., & Cohen, D. J. (1989). Disintegrative disorder or “late onset” autism. Journal of Child Psychology and Psychiatry, 30(5), 717–724.Find this resource:

                  Wakefield, A. J., Murch, S. H., Anthony, A., Linnell, J., Casson, D. M., Malik, M., et al. (1998). Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet, 351(9103), 637–641.Find this resource:

                  Webb, J., Nalty, T., Munson, J., Brock, C., Abbott, R., & Dawson, G. (2007). Rate of head circumference growth as a function of autism diagnosis and history of autistic regression. Journal of Child Neurology, 22(10), 1192–1190.Find this resource:

                  Weissman, J. R., Kelley, R. I., Bauman, M. L., Cohen, B. H., Murray, K. F., et al. (2008). Mitochondrial disease in autism spectrum disorder patients: A cohort analysis. PLoS ONE, 3, 1–6.Find this resource:

                  Werner, E., & Dawson, G. (2005). Validation of the phenomenon of autistic regression using home videotapes. Archives of General Psychiatry, 62, 889–895.Find this resource:

                  Werner, E., Dawson, G., Munson, J., & Osterling, J. (2005). Variation in early developmental course in autism and its relation with behavioral outcome at 3–4 years of age. Journal of Autism and Developmental Disorders, 35(3), 337–350.Find this resource:

                  Werner, E., Dawson, G., Osterling, J., & Dinno, N. (2000). Recognition of autism spectrum disorder before one year of age: A retrospective study based on home videotapes. Journal of Autism and Developmental Disorders, 30(2), 157–162.Find this resource:

                  Wetherby, A. M., Woods, J., Allen, L., Cleary, J., Dickinson, H., & Lord, C. (2004). Early indicators of autism spectrum disorders in the second year of life. Journal of Autism and Developmental Disorders, 35(5), 473–493.Find this resource:

                  Wiggins, L. D., Rice, C. E., & Baio, J. (2009). Developmental regression in children with an autism spectrum disorder identified by a population-based surveillance system. Autism, 13, 357–374.Find this resource:

                  Xi, C. Y., Ma, H. W., Lu, Y., Zhao, Y. J., Hua, T. Y., et al. (2007). MeCP2 gene mutation analysis in autistic boys with developmental regression. Psychiatric Genetics, 17(2), 113–116.Find this resource:

                  Yirmiya, N., & Ozonoff, S. (2007). The very early phenotype of autism. Journal of Autism and Developmental Disorders, 37, 1–11.Find this resource:

                  Zwaigenbaum, L., Bryson, S., Rogers, T., Roberts, W., Brian, J., & Szatmari, P. (2005). Behavioral manifestations of autism in the first year of life. International Journal of Developmental Neuroscience, 23, 143–152.Find this resource: