Neuropathology of Autism
Neuropathology of Autism
ABSTRACTS & COMMENTARY
Sources: Bailey A, et al. A clinicopathological study of autism. Brain 1998;121:889-905; Rapin I, Katzman RI. Neurobiology of autism. Ann Neurol 1998;43:7-14; Rapin I. Autism. N Engl J Med 1997;337:97-104.
Autism, arguably the most severely damaging developmental brain syndrome, is characterized by 1) severe qualitative impairment of social interaction, 2) impaired language development, 3) an absence of play, and 4) restricted stereotyped behavior. Delayed or absent behavioral developments arise before age 3, affecting social interaction, language, or imaginative play (Rapin, 1997). Males predominate with a ratio of 4:1 or more, as does male parentage. Prevalence in the United States ranges between 0.4 and 1.0 per thousand children.
Despite its somewhat varying phenotype, strong evidence indicts infantile autism as a genetic disorder transmitted mainly through males. (Also, about 15% of boys with fragile-X are autistic, and familial tracing incriminates paternal lines as causative.) Concordance of traits in monozygotic twins approximates 90%, with less than 10% concordance in dizygotic twins. The birth of an autistic child signifies a possible likelihood of autism-about 5%-in any succeeding children from the same parentage. The advent of epilepsy in about 25% is recorded as inducing a regression in language and/or behavior in affected cases. Known chemical abnormalities are few. Blood serotonin levels, however, are abnormally high in about 25% of autistics, and Cook and colleagues (Mol Psychiatry 1997;2:247-250) have identified a linkage of a deviant serotonin transporter gene in autistics.
The morphology of autism differs from subject to subject. MRI studies of brain inconsistently show varying abnormalities, including increased brain volume, cerebellar shrinkage, and smallness of the corpus callosum. Rapin and Katzman indicate that fewer than 35 brains have been examined at autopsy. Bailey and associates raise the total to about 46. Both Bailey's and Rapin's studies indicate that less than 10 such brains have received comprehensive, post-mortem examination. None except Bailey's have been analyzed by currently available cytochemical techniques to examine fundamental cell-molecular abnormalities.
Against the above background, Bailey et al use standard methods to carefully examine gross morphologic factors in the post-mortem brains of six autistic males aged 4-24 years. Using classic techniques of studying the entire brain plus selective employment of electron microscopy and immunohistochemistry, Bailey et al describe the following abnormalities that are already recognized, as well as additional, previously unobserved changes. Numbers in parentheses indicate individual brains.
Cerebrum. Cerebral cortical dysgenic abnormalities were found in (4) brains and included the following: irregular cortical laminar patterns including abnormal neurons, thickened cortex (megalencephaly) in two, and areas of abnormal neuronal density.
Cerebral white matter abnormalities (5) contained ectopic gray matter, increased number of single neurons, and subpial gliosis.
Miscellaneous changes (2) were cortical foci of gliosis and subpial corpora amylacea.
Brainstem. Olivary dysplasia (3) involved reduplication of medial olive and bilateral breaks in inferomedial and inferior olives.
Neuronal ectopic (3) foci were found lateral to olives and inferior cerebellar peduncle.
Miscellaneous (5 abnormalities in 4 brains) included large medulla, small pyramids (1); aberrant tracts (2); locus coeruleus dispersed (2); and other small anomalies.
Cerebellum. Identified abnormalities were cytoplasmic inclusions in vermis and hemisphere; decreased numbers of Purkinje cells (5), and areas of increased Bergmann glia cells (4). Also apparent were breaks in dentate ribbons (2).
The net result of the above findings (and in other series) consisted most frequently of grossly enlarged cerebral structures (4), as well as microscopic abnormalities in the cerebrum, brain stem, and Purkinje cells of the cerebellum. Individual abnormalities are cited above. Hippocampal density was unequivocally increased in only one patient. Compared to some previous studies, megalencephaly was more frequent, although other reports also have commented on enlarged autistic brains, all without satisfactory explanation. Both in the cerebrum and brainstem structures, Bailey and associates' study shows more clearly than previous reports that autistic brains exhibit evidence of developmental as well as prenatal brain stem abnormalities. Some of these changes may relate to seizures, but the megalencephaly can hardly be attributed to epileptic disorders.
COMMENTARY
Bailey et al's article reflects the product of a serious effort to identify pathological abnormalities in autistic brains. The article substantiates earlier observations of Purkinje cell loss but also indicates by the presence of Bergmann glia that some of these cells are degenerating well into an autistic child's growth cycle. The cerebral and brainstem dysgenic findings, however, must trace their origins to prenatal errors in architectural bioconstruction. Abnormalities of the olives and other medullary abnormalities imply abnormal projections to or from remote areas of brain, but at this time one can do no more than observe their presence. What this thorough analysis reflects is that, whatever its biochemical-pharmacological anomalies may turn out to be, the autistic brain contains abundant structural abnormalities that contribute importantly to its tragic psychologic deprivations and abnormal expressions. -fp
Addendum: Kates et al (Ann Neurol 1998;43:782-791) add additional neurological information about autism based on MRI scans and behaviors of 5-year-old male monozygotic twins. One showed classic features of the syndrome, whereas the less affected brother demonstrated little more than constriction of social interaction and play. MRI of the seriously involved boy identified a smaller caudate, amygdala, hippocampus, and cerebellar compared to his less symptomatic twin. Both demonstrated reduced size of the superior temporal gyrus and the frontal lobe. Kates et al speculate that the more severely involved brain consists of a damaged subcortical network bearing some resemblance to circuitry associated with Tourette's syndrome.
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