A Study of Macrocephaly and Microcephaly in Young Children with AutismA Study of Macrocephaly and Microcephaly in Young Children with AutismMichelle Mendelsohn, Dr. Sarah Spence PhD., Dr. Susan Swedo MDMichelle Mendelsohn, Dr. Sarah Spence PhD., Dr. Susan Swedo MD

NIMH, Pediatric Developmental and Neuropsychiatry branch NIMH, Pediatric Developmental and Neuropsychiatry branch

INTRODUCTIONINTRODUCTIONAutism is a complex developmental disability characterized by

social and communication deficits, as well as repetitive and stereotyped behaviors.The disorder is thought to be related to abnormalities of

neurodevelopment, which typically manifest themselves during the first two years of life. Measurements of head size (head circumference (HC)) are

useful for noninvasive studies of brain growth in autism. HC provides a close approximation of brain size in children under 7 years of age (Redcay and Courchesne, 2004)Macrocephaly (HC > 97%tile) may reflect increased brain size (normal or abnormal) or space-occupying brain abnormalities, such as hydrocephalus. Microcephaly (HC <3%tile) often represents stunting of brain growth and development – either congenital or acquired.HC measurements are typically taken at birth and at regular intervals during the first three years of life, providing an easily accessible source of information about brain growth.

Macrocephaly is one of the only physical features associated with autism. Large head size was noted even in Leo Kanner’s original description of the disorder (1943).

# children with autism

Age range control group Percentile definition of macrocephaly

percent with Macrocephaly

Percent with microcephaly

Mean percentile

Davidovitch 1996 148 46-51 months Population norms

98th percentile 18.2% 2.7% 82.4%

Dementieva2004

251 0-3636-216 months

Population norms

98th percentile 19% 3%

Fidler2000

41 Tuberous sclerosisn=21

98th percentile 12.2%vs. 9.5%/8.3% control

Frombonne1999

126 Population norms

98th percentile 16.7% 15.1% (med disorders) 58th percentile

Gillberg2002

50 1-13 years Asperger syndrome n=50 ADHD n=50 Swedish Norms

2 SD 9.5% 2%

Lainhart1996

91 0-12 yrssubjects:3-30 yrs

Fels Longitudinal study n=888

98th percentile 14.3% 67th percentile

Miles2000

137 Avg age 8 years

2 SD 23.4% 7.3%

Torrey2004

15 0-1 year NCPP database n=40,000

98th percentile 13.3% birth6.7% 1 year

Woodhouse1996

19 autism16 atypical autism 3 PDD-NOS

<16 yrs Control n=52 Axis I diagnosis and Lang disorders

>97th percentile 29.3%

Table 1: Studies of Macrocephaly in Autism

RESULTSRESULTSIncreased Prevalence

All of the papers reviewed reported an increased prevalence in macrocephaly in autistic individuals.

The reported rate ranged from 9.5% (Gillberg and de Souza, 2002) to 29% (Woodhouse et al., 1996). (see Table 1)

Variability could be secondary to:

Definitions of macrocephaly: some papers use ≥98th (≥2 SD above the mean) and others use >97th (>1.88 SD above the mean)

Sample characteristics:

Definition of autism has changed over time: older papers used the DSM-III (Davidovitch et al., 1996; Lainhart et al., 1996) or ICD-9 (Fombonne et al., 1999), later papers used DSM-IV (Dementieva et al., 2004; Hazlett et al., 2005; Torrey et al., 2004)

Differential inclusion of autism subtypes/variants of autism, such as Asperger syndrome and PDD-NOS, might have different rates of macrocephaly (Gillberg and de Souza, 2002).

Inclusion of subjects with comorbid medical disorders known to be associated with macrocephaly in some studies, but not others.

Different HC norms were utilized in the studies, including norms developed by the Centers for Disease Control, Fels Longitudinal Study, and Swedish government standards.

Different techniques were utilized to measure HC, and to define the occipitofrontal circumference

Timing of Increased Growth Controversial (See Table 2)Knowing when the accelerated growth of the HC occurs is important because, if the macrocephaly is related to brain volume, then it can be determined when the brain begins to overgrow and hopefully be able to shed light on the etiology and developmental timing of autism.However researchers don’t agree on whether HC is abnormal at birth

Courschesne reports smaller than norm(2003)Dementieva reports normal HC (2004)

But, several studies suggest that the growth happens within the first year of life. Courchesne states that the abnormal growth increase occurs between 1 to 2 months and 6 to 14 months (Courchesne et al., 2003)Dementieva also reports that HC has a rapid acceleration around the period of 1 to 2 months (Dementieva et al., 2004). Hazlett states the accelerated growth occurs in close proximity to the end of the first year of life (2005).

n autistic control Definition abnormal growth

Percent abnormal growth Measurements taken

Courchesne2003

15 CDC norms >2SD birth -6-14 months

59%control-6%

Birth, 1-2 month, 3-5month, 6-14 month

Dementieva2004

79 Population Norm + 25% 35% At least 2Not at birth necessarily

Dementieva2004

37 Population norm +25% 65% At least 21 at birth

Hazlett2005

51 25 control chldern 18-35 months

Growth above control group

Shows an increase in HC growth at 1 year

Birth to 4 years

Lainhart 1996

11 Reference sample +25% 9.1% increased head growth54.4% stable rate

2 or more between birth-3 yrs

Lainhart1996

35 Reference sample +25% 37.1% increased 54.3% stable

2-12 yrs

CONCLUSIONCONCLUSIONThere is an increased prevalence of macrocephaly in autism. Reported rates are variable, but based on a meta-analysis by Frombonne using over 500 subjects, macrocephaly was present in an average of 20% of autistic subjects.The HC literature is limited by inconsistent methodologies, small sample sizes (of autistic subjects) and lack of systematic, prospectively collected data. Further, measurements of HC will never provide direct measures of brain growth nor approximate the development of disorder-specific structures, such as the amygdale. However, based on the studies reviewed, it appears that a subgroup of autistic individuals may be characterized by a developmental pattern of normocephaly at birth and then accelerated growth leading to macrocephaly.Etiology of large HC unknown

There have been various explanations in the literature for the reported increase in macrocephaly in autism; some possible factors include:

The few studies that included data such as weight and height, in addition to HC, found that these factors at least somewhat accounted for the macrocephaly (Davidovitch et al.,1996; Lainhart et al., 1997; Torrey et al., 2004) suggesting that the larger HC could be an artifact of increased body size.Both macrocephaly and autism have been shown to be familial. Some studies have shown increased HC among unaffected family members as well as correlations of HC between parents and children and between sibs (affected and unaffected) (Fidler et al., 2000; Spence et al., 2005). Large HC may therefore be a familial trait unrelated to autism, or may be a marker of genetic vulnerability to autism.

Some hypothesize that macrocephaly is a direct result of overgrowth in the brain’s white and gray matter, and that this is part of the pathophysiology of autism. HC would then be an important marker of the abnormal growth in the autistic brain. (Courchesne and Pierce, 2005)FOR THE FUTURE

Determination of the exact rate will require more consistent methodologies

There needs to be a standardization of results and definitions, such as defining macrocephaly as >97% or +2 SD of the mean and determining the specific diagnosis of autism to be used for the studies and specifically excluding known genetic syndromes. Studies should also control for height and weight

Evaluate the role of genetics by taking family HC measurements. This might also provide a useful biomarker for autistic endophenotypes.Define the point at which the HC overgrowth occurs to determine when the change in brain growth patterns occurs and how this relates to the development of autism.

This could be achieved by collecting HC measurements from birth until age 2 years in a large population-based cohort of children. Alternatively, high-risk individuals could be followed prospectively to determine the point at which macrocephaly develops in autism. This study is currently underway in the CPEA/STAART network study of baby siblings of children with autism.

Because HC is only an external measurement, it is necessary to also look at the internal structure of the brain. Structural MRI scans can provide direct measurements of brain growth, and also allow examination of the specific structures that are contributing to the increased brain volume. A better understanding of these specific structural brain changes may help shed light on the etiology of autism.

Table 2: Accelerated head growth

METHODMETHODA comprehensive literature review was conducted on HC studies in autism.

A Using the PubMed search engine and the key words “autism and macrocephaly” and “autism and head circumference”, 61 citations were found. Review of the abstracts revealed 18 articles whose main topic was HC and autism, 4 of which were reviews.Relevant abstracts from the International Meeting for Autism Research from the last two years were also reviewed. Citations dated from 1993-2005

TerminologyHead circumference measurements (taken in cm) are routinely converted to %iles based on age and gender related norms. Normal range is +/- 2 SD of 50%tile.Macrocephaly has been defined >2 SD above the mean, or >97%tile. Thus, one expects fewer than 3% of measurements to fall within the macrocephalic range.

ABSTRACTABSTRACTStudying brain size may help in determining the etiology of autism, a neurodevelopmental disorder. Head circumference is noninvasive and readily available method of measurement. Large head size, macrocephaly (head circumference > 97th %ile) has been found to be associated with autism in many studies. However, the extent of increased prevalence is variable. Results have ranged from 9.5% (Gillberg 2002) to 30% (Woodhouse 1996). This could be the result of inconsistent methodologies including the varying definition of autism and varying head circumference norms. In addition, there has been controversy about the exact timing of accelerated growth and development of macrocephaly which could be the key to understanding the development autistic disorder. This poster reviews the prevalence of macrocephaly in autistic children, and further discusses ideas about causes of marocephaly and the timeframe in which it develops. There is a need to standardize the methodology by which the growth and development of macrocephaly in autistic children is studied; then, researchers can utilize the full potential of the data collected to extend our knowledge of the etiology of this neurodevelopmental disorder.

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