INTRODUCTION

1. A Study of Macrocephaly and Microcephaly in Young Children with AutismMichelle Mendelsohn, Dr. Sarah Spence PhD., Dr. Susan Swedo MD NIMH, Pediatric Developmental and Neuropsychiatry branch INTRODUCTION Autism 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). ABSTRACT Studying 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. RESULTS • Increased 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 CONCLUSION • There 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 1: Studies of Macrocephaly in Autism • 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). METHOD • A 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 • Terminology • Head 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. Table 2: Accelerated head growth References • Courchesne and Pierce: Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity Int J devel neuroscience 23 (2005) 153-170. • Courchesne E, Ruth C, Akshoomoff N: Evidence of brain overgrowth in the first year of life in autism. JAMA 2003 June; 290 (3): 337-44 • Davidovitch M, Patterson B, Gartside P: Head Circumference Measurements in Children with Autism J. Child Neurol. 11 (1996) pp. 389-393 • Dementieva Y, Vance D, Donnelly S, Elston L, Wolfpert C, Ravan S, et al.: Accelerated head growth in early development of individuals with autism 2004 Pediatr Neurol. 2005 Feb;32(2):102-8 • Fidler DJ, Bailey JN, Smalley SL: Macrocephaly in autism and other pervasive developmental disorders.  Developmental Med and Child Neuro 2000, 42: 737-740. • Frombonne E, Rouge B, Claverie J, Courty S, Fremolle J: Microcephaly and Macrocephaly in Autsim. Journal of Autism and Developmental disorders, 1999; 29 (2): 113-119 • Gillberg C and de Souza L: Head circumference in autism, Asperger syndrome and ADHD: a comparative study. Developmental Medicine and Child Neurology 2002, 44: 296-300. • Hazlett H, Poe M, Gerig G, Smith R, Provenzale J et al.: Magnetic resonance imaging and head circumference study of brain size in autism. Arch Gen Psychiatry, 2005; 62: 1366-1376. • Lainhart J: Increased Rate of Head Growth During Infancy in Autism.  Jama, 2003; 290: 393-394. • Lainhart J, Piven J, Wzorek M, Landa R, Santangelo S, Coon H, Folstein S: Macrocephaly in Children and Adults with Autism. JAM Acad Child Adolesc Psychiatry 1997 Feb; 32 (2): 282-90. • Miles JH, Hadden LL, Takashi TN, Hillman RE: Head circumference is an independent clinical finding associated with autism. Am J Med Genet. 2000 Dec 11; 95(4): 339-50. • Redcay E and Courchesne E: When is the brain enlarged in autism? A Meta-analysis of all brain size reports. Biol Psychiatry. 2005 Jul 1; 58 (1): 1-9. • Spence S J, Miyamoto, J Black, D O Geshwind, D H: The occurance of macrocephaly in autistic and nonautistic individuals from a large famililal idiopathic autism sample (AGRE). 2005. Paper Presented at 4th annual International Meeting for Autism Research. • Torrey E, Dhavale D, Lawlor J, Yolken R: Autism and head circumference in the first year of life. Biol Psychiatry. 2004 Dec 1; 56 (11): 892-4.