As mentioned, elements of autism, but not the whole syndrome with its positive and negative attributes, may appear in other diseases that interfere with brain development, specifically fragile X and Rett syndromes, and fragmentary similarities are found in a few children with phenylketonuria, tuberous sclerosis, Angelman syndrome, and, rarely, Down syndrome—but these patients are easily distinguished from those with the far more common type of autism. Bolton and Griffiths have made the intriguing observation that autistic traits in patients with tuberous sclerosis correspond to the finding of tubers in the temporal lobe, and DeLong and Heinz point out that patients with seizures from bilateral (but not unilateral) hippocampal sclerosis may fail to develop (or may lose) language ability as well as failing to acquire social skills after a period of normal development, in a manner similar to autism.
Etiology and Pathology of Autism
The basis of childhood autism is as much a mystery today as it was when Kanner and Asperger described it. Most of these children are physically normal except for a slightly larger head size, on average, but with no other somatic anomalies. Despite instances in which the onset of mental and behavioral regression seems to be quite sudden, no environmental factors, including the often-mentioned measles-mumps-rubella (MMR) vaccination, mercury exposure, and food allergies, have been credibly connected to autism. The genetic microdeletions and microduplications described earlier have given few hints as to the biologic cause. The EEG is normal. Biological explanations have replaced psychological ones, prevalent at one time, largely due to the efforts of Frith, many years ago.
Early investigations into the neuroanatomic abnormalities associated with autism were inconclusive. The significance of cerebellar vermal changes, reported originally by Courchesne and colleagues, remains uncertain (Filipek). In 5 brains studied in serial sections by Bauman and Kemper, smallness of neurons and increased packing density were observed in the medial temporal areas (hippocampus, subiculum, entorhinal cortex), amygdala and septal nuclei, and mammillary bodies. In a subsequent review of the neuropathology, Kemper and Bauman concluded that three changes stood out: a curtailment of the normal development of neurons in the limbic system; a decrease in the number of Purkinje cells that appears to be congenital; and age-related changes in the size and number of the neurons in the diagonal band of Broca (located in the basal frontal and septal region), as well as in the cerebellar nuclei and inferior olive. The latter changes were inferred from studying the brains of autistic children who died at different ages, and they gave the appearance of a progressive or ongoing pathology that continues into adult life. These findings are in keeping with the concept of autism as a neurodevelopmental disorder, but they allow only speculation regarding the derivation of the clinical features of the disease. An increased concentration of platelet serotonin and low serum serotonin is detected in many but not all patients; also, serum oxytocin is reduced. The biologic significance of these findings is unclear.
More recently, cerebral overgrowth and increased brain volume, particularly but not exclusively in the frontal lobes, has been a finding in young children with autism. High resolution imaging techniques with morphometric and volumetric analysis have confirmed this. The abnormalities may be difficult or impossible to detect on routine CT or MRI. A recent neuroanatomic investigation by Stoner and colleagues has identified focal regions of abnormal cortical laminar architecture and neuronal disorganization in prefrontal and temporal lobes in children with autism. The abnormalities were most consistently found in cortical layers 4 and 5. These findings again support the conceptualization of autism as a neurodevelopmental disorder.
Course, Treatment, and Prognosis