Epilepsy-induced microarchitectural changes in the brain.

Our understanding of the pathogenesis of the neuropathology of epilepsy has been challenged by a need to separate the "lesions" that cause epilepsy from the "lesions" that are produced by the epilepsy. Significant clinical, genetic, pathologic, and experimental studies of Ammon horn sclerosis (AHS) suggest that AHS is the result and cause of seizures. The data support the idea that seizures cause alterations in cell numbers, cell shape, and organization of neuronal circuitry, thus setting up an identifiable seizure-genic focus. As such, AHS represents a slowly progressive lesion and a search for the cause of the initiating seizure has led to the identification of ion channel mutations. In this report, the neuropathology of other conditions associated with intractable epilepsy is considered, suggesting that in them similar epilepsy-produced alterations in microarchitecture can be observed. The idea is important to define the optimum time for epilepsy surgery and the underlying etiology of these seizure-genic lesions.

Neuropathology of Rett syndrome.

Rett syndrome is a sporadic disorder (except for a few familial cases) occurring in 1 in 10,000 to 1 in 23,000 girls worldwide. It is associated with profound mental and motor handicap. About 90% of cases involve a mutation in the methyl-CpG binding protein 2 gene (MECP2). The role of this gene in the pathogenesis of this enigmatic disorder is being extensively investigated in animal models. Rett syndrome is associated with a complex phenotype that is unique in every aspect of its presentation, clinical physiology, chemistry, and pathology. Years of concentrated observations have defined the clinical presentation of classic Rett syndrome and its variants and related features (eg, neurophysiologic, radiologic, chemical, metabolic, and anatomic). This article reviews the neuropathology of Rett syndrome, which involves individual neurons, perhaps selected neurons, of decreased size, dendritic branching, and numbers of spines. This article also summarizes the studies in the human and mouse brain with Rett syndrome that are beginning to reveal the disorder's pathoetiology.

Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?

The mutated gene for Rett syndrome, MECP2, has now been identified in ninety percent of cases. Molecular biologists are immersed in the study of this gene's biology determining how its mutation could be responsible for such an enigmatic phenotype. In this paper the same question is considered, re-examining the structural phenotype of the Rett brain and asking; is MeCP2 present at the appropriate time and place in brain development to influence the structural and chemical abnormalities which characterize the Rett brain? Data from the literature and previous research suggest that MeCP2 is expressed during critical periods of brain development at several sites and in different neurons. It supports the idea that inadequate functioning of MeCP2 alters trophic factors and raises the possibility that replacement of these factors might improve brain function. The availability of mouse models now makes it possible to test such ideas.

Survey of MeCP2 in the Rett syndrome and the non-Rett syndrome brain.

The clinical and neuropathologic aspects of Rett syndrome suggest that an arrest of brain development produces the phenotype, but it is not understood how the gene implicated in Rett syndrome, methyl-CpG protein 2 (MeCP2), is regulated during brain development. In this study, the ontogeny of MeCP2 is examined in the developing human brain and in the female Rett syndrome brain to evaluate the relationship between MeCP2 expression and brain development in health and disease, respectively. Immunocytochemistry using an antibody to the C-terminal region of the protein was performed in paraffin sections of the developing brain to define the age and the sites of MeCP2 protein expression. In development, there is no MeCP2 expression in the germinal matrix or in the progenitor cells. At 10 to 14 weeks' gestation, the neurons of the brain stem and the Cajal-Retzius and subplate neurons of the cortex express MeCP2. By midgestation, some neurons of the basal ganglia express MeCP2, and at late gestation, the most mature cortical neurons in the lower cortical layers are positive. The postnatal cortex continues to increase its expression of neuronal MeCP2. In the Rett syndrome brain, fewer neurons express MeCP2 than in the normal brain. This reduction is most apparent in the brain stem and thalamus. The neurons of the cerebral cortex show the least reduction. We conclude that the regulation of MeCP2 abundance is related to human brain development, being expressed in neurons when they appear mature. In Rett syndrome, however, the expression pattern of MeCP2 does not completely resemble that of the normal immature brain, suggesting that the maintenance of MeCP2 might be determined in specific neurons by factors other than those controlling maturation. In the developing brain, synaptic activity and plasticity could be necessary to maintain MeCP2 in selected neuronal populations.

Neuropathology of Rett syndrome.

Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72-76.