Dawna D. Armstrong

The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission†

Purpose:  Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities.

International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: A Task Force report from the ILAE Commission on Diagnostic Methods

Hippocampal sclerosis (HS) is the most frequent histopathology encountered in patients with drug‐resistant temporal lobe epilepsy (TLE). Over the past decades, various attempts have been made to classify specific patterns of hippocampal neuronal cell loss and correlate subtypes with postsurgical outcome. However, no international consensus about definitions and terminology has been achieved. A task force reviewed previous classification schemes and proposes a system based on semiquantitative hippocampal cell loss patterns that can be applied in any histopathology laboratory. Interobserver and intraobserver agreement studies reached consensus to classify three types in anatomically well‐preserved hippocampal specimens: HS International League Against Epilepsy (ILAE) type 1 refers always to severe neuronal cell loss and gliosis predominantly in CA1 and CA4 regions, compared to CA1 predominant neuronal cell loss and gliosis (HS ILAE type 2), or CA4 predominant neuronal cell loss and gliosis (HS ILAE type 3). Surgical hippocampus specimens obtained from patients with TLE may also show normal content of neurons with reactive gliosis only (no‐HS). HS ILAE type 1 is more often associated with a history of initial precipitating injuries before age 5 years, with early seizure onset, and favorable postsurgical seizure control. CA1 predominant HS ILAE type 2 and CA4 predominant HS ILAE type 3 have been studied less systematically so far, but some reports point to less favorable outcome, and to differences regarding epilepsy history, including age of seizure onset. The proposed international consensus classification will aid in the characterization of specific clinicopathologic syndromes, and explore variability in imaging and electrophysiology findings, and in postsurgical seizure control.

Interaction of reelin signaling and Lis1 in brain development

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1+/− mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.

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. (J Child Neurol 2005;20:747–753). Received May 25, 2005. Accepted for publication June 10, 2005. From The Blue Bird Circle Rett Center, Baylor College of Medicine, Houston, TX. This work was supported by grants from the National Institutes of Health (P01 DA12661), the International Rett Syndrome Association, the Rett Syndrome Research Foundation, and the Harvard Brain Tissue Resource. Presented as part of the Rett Syndrome, Neurobiology of Disease in Children, National Institutes of Health Conference in Ottawa, ON, Canada, October 13–16, 2004, in conjunction with the 33rd annual meeting of the Child Neurology Society. Address correspondence to Dr Dawna Duncan Armstrong, Department of Pathology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Tel: 823-825-1873; fax: 823-825-1032; e-mail: dawnaa@bcm.tmc.edu.The neuropathology of the Rett syndrome is summarized utilizing a format of clinical pathological correlations, describing the pathology at specific anatomic sites which could correlate with the well defined clinical signs and symptoms in the Rett syndrome; decreased head and body size, autism, gait dysfunction, spasticity, movement and breathing disorder. Published reports of altered morphology in the cerebral cortex, basal ganglia, substantia nigra, cerebellum, spinal cord, muscle, nerve, pituitary gland and somatic organs are supplemented by the authors observations. These include studies of dendritic morphology employing Scholl analysis of Golgi preparation, and quantitation of cerebellar Purkinje cells. The possible pathoetiology of the Rett syndrome is considered, particularly, in relation to the ultrastructural demonstration of altered mitochondria and accumulations of lipidic bodies in several tissues.

Cytogenetic analysis of 120 primary pediatric brain tumors and literature review

We report chromosome results from 108 pediatric central nervous system (CNS) tumors. From our data and those in the literature we found that (1) cerebellar and low-grade astrocytic tumors, including gangliogliomas, are most often karyotypically normal; (2) supratentorial tumors were more frequently high-grade tumors that demonstrated a complex karyotype. Chromosome abnormalities were similar to those described in adult astrocytic tumors, namely, +7, 9p abnormalities, and -10; (3) primitive neuroectodermal tumors (PNETs) were virtually always karyotypically abnormal with a high frequency of +7, -8, i(17q), and -22. PNETs with -22 may represent a subset of tumors; (4) typical choroid plexus papillomas showed a normal karyotype, atypical papillomas showed a hyperdiploid karyotype (with +7, +12, and +20), choroid plexus carcinomas showed a hyperhaploid karyotype; (5) a few ependymomas showed hyperdiploidy or hypertetraploidy; (6) germ cell tumors showed complicated karyotypes; (7) monosomy 22 or 22q abnormalities appear to be a recurring finding in the malignant rhabdoid tumors; and (8) meningiomas showed -22 or 22q abnormalities associated with a complex karyotype. In general, in pediatric CNS tumors the least differentiated neoplasms have the greatest number of cytogenetic abnormalities. However, our present morphologic criteria for tumor diagnosis do not always correlate with a consistent karyotype, and further study of pediatric brain tumor morphology, site, behavior, and karyotype is required.

Rett syndrome neuropathology review 2000

This paper will review the study of the neuropathology of Rett syndrome as it has evolved through several phases. In the 1986 the first descriptions of the Rett brain, by Seitelberger and Jellinger, identified that the brains were small, and that there was quantitatively less melanin in the pars compacta of the substantia nigra than in non-Rett brains. There were reports of non- specific gliosis and cell loss in the spinal cords and in the cerebellum, but with traditional neuropathology techniques there were no pathognomonic features that defined a specific neuropathology for Rett syndrome. This apparent absence of pathology was enigmatic in view of the profound clinical phenotype which involved dysfunction of cortex, basal ganglia, the limbic. autonomic and peripheral nervous systems. In the 1990s evaluation of the accumulating and careful reports of the clinical, functional, anatomic and chemical features of Rett syndrome suggested that the basis of Rett syndrome could be an interruption of brain development. MRI and autopsy examinations revealed that the brain in Rett syndrome was small, and that, unlike the brain in a degenerative disease, it did not become progressively smaller over time. Moreover, only the brain, and no other organ was small, emphasizing the susceptibility of the nervous system in the Rett disorder. Using Golgi studies a selective alteration in the size of dendrites of pyramidal neurons in the frontal, motor and temporal lobes was defined. Regional decreases of dendritic spines were also observed and immunocytochemical studies defined alterations in synaptic sites, early response gene activity and interneurons. MAP-2 immunoreactivity was found to be altered in selected neuronal populations. Studies of neurotransmitters using various techniques in various brain regions and CSF defined alterations (increases or decreases) in most systems, with only, according to Wenk, the studies of the cholinergic system being consistently decreased. The hypothesis that there are decreased neurotransmitters in Rett syndrome remains attractive, for it explains many of the functional deficits in Rett syndrome, and suggests a mechanism for defective brain maturation. However, the measurement of neurotransmitters and the interpretation of the results is problematic; the studies have included girls and women at various stages of the Rett disorder, using numerous techniques and various Rett tissues. In 2000 Rett families and researchers rejoiced at the long awaited identification of a mutated gene in Rett syndrome. Now MeCP2 is the focus of research into the neuropathology of Rett syndrome. An understanding of how this DNA methylating protein contributes to normal brain development should allow us to understand the deficits in Rett syndrome. Most importantly, it may allow us to devise strategies for therapy.

Periventricular leukomalacia : Relation to gestational age and axonal injury

Eighty-five infants ranging from 22 to 41 weeks gestation were diagnosed as having periventricular leukomalacia (PVL) using traditional neuropathologic methods. The lesions were also studied by immunocytochemistry for beta-amyloid precursor protein (beta-APP), a glycoprotein that has been observed in PVL. Using this technique, the distribution of white matter tissue necrosis was defined as focal, widespread, and diffuse. The type of PVL correlated with the gestational age at birth. The youngest infants tended to demonstrate widespread necrosis, and the oldest infants exhibited more focal necrosis. beta-APP immunopositivity was present in the axons around the foci of white matter necrosis in 76% of the patients and in the neurons of the adjacent cortex in 66% of the patients. In age-matched control patients, there was no beta-APP reactivity in the cerebral white matter or the cortex. In most patients the distribution of beta-APP-positive axons proved to be a useful marker for demonstrating the type of PVL; however, the relationship of beta-APP to the pathogenesis of PVL requires further study.

Serotonin Transporter Abnormality in the Dorsal Motor Nucleus of the Vagus in Rett Syndrome: Potential Implications for Clinical Autonomic Dysfunction

Autonomic dysfunction is prevalent in girls with Rett syndrome, an X-chromosome-linked disorder of mental retardation resulting from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). This gene plays a role in regulating neuronal activity-dependent gene expression, including brain-derived neurotrophic factor (BDNF), which is a potent serotonergic (5-HT) neuronal growth factor. We analyzed selected parameters of the 5-HT system of the medulla in autopsied patients with Rett syndrome because of the role of BDNF in 5-HT cell development and because 5-HT plays a key role in modulating autonomic control. 5-HT neurons were identified by immunostaining for tryptophan hydroxylase, the biosynthetic enzyme for 5-HT. We quantitated the number of 5-HT cells in the medulla at 2 standardized levels in 11 Rett and 7 control cases. There was no significant difference in 5-HT cell number between the groups. We analyzed binding to the serotonin transporter (SERT) using the radioligand [125I]-RTI-55 with tissue autoradiography in 7 Rett and 5 controls in 9 cardiorespiratory-related nuclei. In the dorsal motor nucleus of the vagus (DMX) (preganglionic parasympathetic outflow), SERT binding for the control cases decreased significantly over time (p = 0.049) but did not change in the Rett cases (p = 0.513). Adjusting for age, binding between the Rett and control cases differed significantly in this nucleus (p = 0.022). There was a marginally significant age versus diagnosis interaction (p = 0.06). Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome. These data suggest hypotheses concerning 5-HT modulation of vagal function for testing in MeCP2 knockout mice to understand mechanisms underlying autonomic dysfunction in patients with Rett syndrome.

Organ growth in Rett syndrome: a postmortem examination analysis.

Rett syndrome is a disorder of unknown etiology in females that manifests as severe mental and motor retardation during the first years of life. A postnatal pattern of altered growth is its earliest clinical expression. Head growth decelerates during the first year of age and is followed by a decline in somatic (height/weight) growth. The decreased occipitofrontal circumference (OFC) is reflected in decreased brain size, and measurements of the dendrites of cortical neurons suggest that a developmental and growth arrest have occurred. To further document growth in Rett syndrome, measurements of organ weights, as recorded in 39 postmortem examination studies were compared with normal organ weights for females of comparable age and height. These organ weights suggest that the pattern of growth failure in Rett syndrome, as compared with other forms of mental handicap, such as Down syndrome and Turners syndrome, may be unique. In Rett syndrome the rate of brain growth, as derived from OFC, decelerates after birth. The increment in normal brain weight after 4 years of age, the age of the first postmortem examinations, is not observed in the Rett brain. The heart, kidneys, liver, and spleen grow at the normally defined rate until 8-12 years of age, when their growth rate decelerates, but their growth continues achieving organ weights that are appropriate for the height of the female. Adrenal weights are normal. These observations suggest that despite a generalized decreased growth in Rett syndrome the brain may be preferentially affected in this syndrome.

Seizure Control and Cognitive Outcome after Temporal Lobectomy: A Comparison of Classic Ammon's Horn Sclerosis, Atypical Mesial Temporal Sclerosis, and Tumoral Pathologies

Summary:  Purpose: Neuropathologic examination of resected tissue after anterior temporal lobectomy (ATL) for treatment of complex partial seizures revealed several distinct histologic substrates. Our study examined the relation between neuropathology, seizure control, and cognition in ATL patients and described preliminary profiles to aid in the prediction of outcome.