Unusual brain growth patterns in early life in patients with autistic disorder An MRI study E. Courchesne, PhD; C.M. Karns, BS; H.R. Davis, BS; R. Ziccardi, BS; R.A. Carper, PhD; Z.D. Tigue, BS; H.J. Chisum, BA; P. Moses, PhD; K. Pierce, PhD; C. Lord, PhD; A.J. Lincoln, PhD; S. Pizzo, PhD; L. Schreibman, PhD; R.H. Haas, MD; N.A. Akshoomoff, PhD; and R.Y. Courchesne, BA Article abstract—Objective: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. Methods: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. Results: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1  1.3 cm versus clinical norms: 34.6  1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI–VII than normal controls. Conclusions: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism. NEUROLOGY 2001;57:245–254 Little is known about the neuroanatomic abnormali- ties present in autistic disorder at 2 to 3 years of age or the pathologic growth trajectories of these abnor- malities during subsequent years. It is difficult to identify young autistic children and to recruit nor- mal youngsters, leading to insufficient direct infor- mation on abnormal neuroanatomy at early ages and across a wide age range in autism. Although post- mortem data have provided rich information on brain structure in autism, the small number of post- mortem cases limits information regarding brain de- velopment. Only seven postmortem cases of autism under 19 years of age have been reported, 1-4 and only one of these was younger than 6 years of age (one 4-year-old case 1 ). At that young age, the diagnosis of autism remains uncertain, 5 and obviously no longitu- dinal observations may be performed to confirm or alter an initial diagnosis of suspected autism. Con- versely, MRI affords the ability to image large num- bers of patients and chart brain growth more directly. To date, only a handful of quantitative MRI studies have reported specifically on autistic infants or young children, 6,7 and only one 6 investigated age- related changes during development. To our knowl- edge, studies of autism have not employed an experimental design that confirms the diagnoses of very young autistic children after they grow older. We investigated the development of the autistic cerebrum (white and cortical gray matter) and cere- bellum from 2 to 3 years through adolescence. A cross-sectional MRI design was used; boys who were under 5 years of age at the time of the MRI scan were diagnostically re-evaluated after age 5 to con- firm the diagnosis of autism. Methods. The study was approved by the Institutional Review Board of San Diego Children’s Hospital Research Center, and procedures were explained to each subject. Informed consent was obtained from each subject’s parent and all patients and control subjects were paid for their participation. Autistic patients. Sixty boys with autism (age 2 to 16 years) participated (89.2% Caucasian, 2.5% Hispanic, 5.9% From the Department of Neuroscience (Drs. E. Courchesne, Carper, Pierce, and Haas), School of Medicine, and Department of Psychology (Dr. Schreibman), University of California, San Diego, La Jolla; Laboratory for Research on the Neuroscience of Autism (Drs. E. Courchesne, Carper, Moses, Pierce, Pizzo, and Akshoomoff, and C.M. Karns, H.R. Davis, R. Ziccardi, Z.D. Tigue, H.J. Chisum, and R.Y. Courchesne), Children’s Hospital Research Center, San Diego, CA; Department of Psychiatry (Dr. Lord), The University of Chicago, IL; and California School for Professional Psychology (Dr. Lincoln), San Diego. Supported by funds from National Institute of Neurological Disorders and Stroke (2-R01-NS-19855) awarded to E.C. Received September 11, 2000. Accepted in final form April 18, 2001. Address correspondence and reprint requests to Dr. Eric Courchesne, Laboratory for Research on the Neuroscience of Autism, 8110 La Jolla Shores Drive, La Jolla, CA 92037; e-mail: ecourchesne@ucsd.edu Copyright © 2001 by AAN Enterprises, Inc. 245