Congenital malformation of cns
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The document discusses various congenital malformations of the central nervous system (CNS), including neural tube defects and cortical migrational anomalies. It describes specific conditions like anencephaly, encephalocele, spina bifida, lissencephaly, polymicrogyria, heterotopia, and focal cortical dysplasia. It provides ICD-10 codes for different CNS malformations and includes images to illustrate various normal and abnormal brain structures.
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Congenital malformation of cns
- 1. Congenital Malformation of CNS - 1 Neural tube defects Cortical Migraional anomely
- 7. Anencephaly
- 8. Anencephaly Figure 4 F igure 3 F igure 2 F igure 1
- 16. Agyria (Lissencephaly type I)
- 17. Lissencephaly
- 20. Agyria-pachygyria-band spectrum, grade 2 Sagittal T1-weighted image ( A ) shows hypoplastic corpus callosum ( arrows ). The splenium is not bulbous; the genu and rostrum are not well seen. The telencephalic brain appears smooth and poorly sulcated, although this can be difficult to discern on midline sagittal images. Axial T1-weighted image ( B ) confirms the smooth lissencephalic brain; note the very primitive sulcation limited to the frontal region ( arrows ). A more cephalad axial T2-weighted image ( C ) shows primitive, enlarged ventricles, figure-8 shaped lissencephalic brain, and hyperintense cell-sparse layer A B C
- 21. Agyria-pachygyria-band spectrum, grade 3 Sagittal T1-weighted MPRage image ( D ) shows smooth, broad gyri typical of pachygyria. Axial T1-weighted image ( E ) also shows pachygyria which is more severe over the posterior than anterior regions. Also note the mildly enlarged ventricles with rounded margins. The abnormal hypointense foci along the periatrial margins are atypical, and their significance is not clear. Axial T2-weighted image ( F ) shows similar changes. D E F
- 22. Agyria-pachygyria-band spectrum, grade 5 Coronal T1-weighted MPRage image ( G ) shows bilateral undulating bands of abnormal gray matter ( arrows ) in the subcortical region. Note the normal olfactory sulci. Coronal proton density-weighted image at the same location ( H ) also shows bands of heterotopic gray matter ( arrows ). Further posteriorly, coronal MPRage image ( I ) again shows bands. However, the bands terminate superiorly in frank pachygyria (short arrows). Also note the subtle additional heterotopia (long arrows) deep to the band along the ventricles which are occasionally seen in subcortical band heterotopia. G H I
- 23. Agyria-pachygyria-band spectrum, grade 6 Axial T2-weighted image ( J ) shows typical subcortical band heterotopia deep to the overlying cortex. The signal intensity parallels gray matter. The ventricles are slightly enlarged and rounded. Slightly more cephalad, axial proton density-weighted ( K ) and T2-weighted ( L ) images show similar changes. The bands have the signal intensity of gray matter ( K, arrows ). The inner margin of the bands are usually smooth, as in this case. The outer margins may be smooth or may undulate with fingers of subcortical white matter, as in this case. The overlying cortex may be radiographically normal or pachygyric J L K
- 24. Polymicrogyria the surface of the cerebral hemispheres shows multiple small bumps, suggesting an excessive number of gyri. The cortex is thick and consists of the molecular and one other broad neuronal layer (in some cases there are three poorly defined neuronal layers). These layers are irregularly overfolded and fused, eliminating the sulci. Patients with polymicrogyria have severe psychomotor retardation and seizures.
- 28. Band heterotopia (double cortex) Band heterotopia, a. MR IR TSE coronal image, a continuous, bilateral band of grey matter interposed between the ventricles and the cortex. The laminar-shaped heterotopic grey matter parallels the signal of the normal cortex in all imaging sequences and seems a "double cortex".
- 29. Band heterotopia (double cortex) a, b. MR, T1- and T2-weighted images. A very thick cortex, with two layers separated by a very thin strand of white matter (double cortex) is seen bilaterally. c, d. Coronal images show the same pattern, and absence of digitations of the white matter leading towards the cortical convolutions. A B C D
Editor's Notes
- GENERAL PRINCIPLES Congenital abnormalities are among the leading causes of infant morbidity and mortality and fetal loss. The leading sites of congenital abnormalities are the skeleton, skin and brain. Congenital abnormalities of the CNS can be divided into developmental malformations and disruptions. Developmental malformations result from flawed development of the brain. This may be caused by chromosomal abnormalities and single gene defects that alter the blueprint of the brain or by imbalances of certain factors that control gene expression during development. Gene defects may be in the germline or develop after conception by spontaneous mutation or from the action of harmful physical or chemical agents. Some malformations are caused by multiple genetic and environmental factors acting in concert (multifactorial etiology). Disruptions result from destruction of the normally developed (or developing) brain caused by environmental or intrinsic factors such as fetal infection, exposure of the fetus to harmful chemicals, irradiation, and fetal hypoxia. For instance, holoprosencephaly, a condition in which the forebrain is not divided into two hemispheres, is a malformation. Hydranencephaly, in which massive destruction reduces the hemispheres into fluid-filled sacs, is a disruption. The line between malformation and disruption is sometimes blurred because an extrinsic factor (e.g. irradiation) may not only cause physical injury but may also damage genes that are important for development. In general, the pathological lesions of developmental malformations of the CNS are either midline or bilateral and symmetric and do not show gliosis. On the other hand, most disruptions are focal and asymmetric and are associated with gliosis and other reactive changes such as inflammation, phagocytosis and calcification. However, in disruptions occurring in the first trimester, these reactions are limited because the brain is immature. For these reasons, it is hard, sometimes, to distinguish malformation from disruption. This distinction carries important implications. Malformations carry a recurrence risk that can be calculated. Disruptions do not recur, unless the exposure recurs or continues. Exposure to teratogens, viral infections, etc., can occur throughout pregnancy. The timing of exposure is critical for both, malformations and disruptions. The earlier the exposure, the more severe the defect. For instance, fetal cytomegalovirus (CMV) infection before midgestation causes microcephaly and polymicrogyria. The most critical period for malformations and disruptions is the third to eighth week of gestation, during which most organs, including the brain, take form.
- Q00-Q07Congenital malformations of the nervous system Q01EncephaloceleQ01.xx0 Encephalomyelocele, Q01.xx1 Hydroencephalocele, Q01.xx2 Hydromeningocele, cranial, Q01.xx3 Meningocele , cerebral, Q01.xx4 MeningoencephaloceleQ01.0Frontal encephalocele Q01.1Nasofrontal encephalocele Q01.2Occipital encephalocele Q01.8Encephalocele of other sites Q01.80Parietal encephalocele Q01.81Nasopharyngeal encephalocele Q01.82Temporal encephalocele Q01.83Orbital encephalocele Q01.9Encephalocele, unspecified Q02Microcephaly Q02.-0Hydromicrocephaly Q02.-1Micrencephalon Q03Congenital hydrocephalusIncludes:hydrocephalus in newbornQ03.0Malformations of aqueduct of Sylvius Q03.1Atresia of foramina of Magendie and Luschka (Dandy Walker Syndrome) Q03.8Other congenital hydrocephalus Q03.80Congenital hydrocephalus in malformations classified elsewhere Q03.9Congenital hydrocephalus, unspecified Q04Other congenital malformations of brain Q04.0Congenital malformations of corpus callosum Q04.00Total agenesis of corpus callosum Q04.01Partial agenesis of corpus callosum Q04.02Agenesis with lipoma of corpus callosum Q04.08Other congenital malformation of corpus callosum Q04.1Arhinencephaly Q04.2Holoprosencephaly Q04.3Other reduction deformities of brain Q04.30Agyria Q04.31Lissencephaly Q04.32Microgyria Q04.33Pachygyria Q04.34Agenesis of part of brain , unspecified Q04.3x0Frontal Q04.3x1Temporal Q04.3x2Parietal Q04.3x3Occipital Q04.3x4Brain stem Q04.3x5Cerebellum hemispheres Q04.3x6Cerebellar vermis Q04.3x7Optic nerves Q04.3x8Thalamus or basal ganglia Q04.3x9Hypothalamus Q04.4Septo-optic dysplasia Q04.5Megalencephaly Q04.6Congenital cerebral cysts Q04.8Other specified congenital malformations of brain Q04.9Congenital malformation of brain, unspecified Q05Spina bifidaExcludes:Arnold-Chiari syndrome(Q07.0);spina bifidQ05.0Cervical spina bifida with hydrocephalus Q05.1Thoracic spina bifida with hydrocephalusSpina bifida:dorsal,thoracolumbar-with hydrocephalQ05.2Lumbar spina bifida with hydrocephalusLumbosacral spina bifida with hydrocephalusQ05.3Sacral spina bifida with hydrocephalus Q05.4Unspecified spina bifida with hydrocephalus Q05.5Cervical spina bifida without hydrocephalus Q05.6Thoracic spina bifida without hydrocephalus Q05.7Lumbar spina bifida without hydrocephalus Q05.8Sacral spina bifida without hydrocephalus Q05.9Spina bifida, unspecified Q06Other congenital malformations of spinal cord Q06.0Amyelia Q06.1Hypoplasia and dysplasia of spinal cord Q06.2Diastematomyelia Q06.3Other congenital cauda equina malformations Q06.4Hydromyelia Q06.8Other specified congenital malformations of spinal cord Q06.9Congenital malformation of spinal cord, unspecified Q07Other congenital malformations of nervous system Q07.0Arnold-Chiari syndrome Q07.8Other specified congenital malformations of nervous system Q07.9Congenital malformation of nervous system, unspecified
- Pathophysiology: Anencephaly is due to failure of primary neurulation (neurulation is the process which progenitors of the central nervous system are shaped, separated from and brought beneath the epidermis). In the normal human embryo, the neural plate arises approximately 18 days after fertilization (fig 2 and 3). During the fourth week of development, the neural plate invaginates along the embryonic midline to form the neural groove. The neural tube is formed as closure of the neural groove proceeds from the middle of the groove and progresses toward the ends in both directions, with completion between day 24 for the cranial end and day 26 for the caudal end (fig. 4). Disruptions of the normal closure process give rise to NTDs. Anencephaly results from failure of neural tube closure at the cranial end of the developing embryo. Absence of the brain and calvaria may be partial or complete.
- The neural plate appears on the 17th day of gestation as a thickening of the embryonic ectoderm over the notochord. This neuroectoderm gives rise to the central nervous system. On day 18, the neural plate invaginates along the midline, forming the neural groove with the neural folds on either side. The neural tube is formed by approximation and fusion of the neural folds by the end of the third week. The cranial end of the neural tube closes by 24 days and the caudal by 25-26 days. The neural tube then is covered dorsally by mesenchyme that forms the vertebrae and skull. Closure of the vertebral arches is completed at 11 weeks of gestation. Defective closure of the neural tube results in neural tube defects (NTDs) which are classified as anterior (anencephaly, encephalocele) and posterior (spina bifida).
- Q00Anencephaly and similar malformations Q00.0Anencephaly Q00.00Acrania Q00.01Acephaly Q00.02Atelencephaly clausa Q00.03Atelencephaly aparta Q00.04Hemicephaly Q00.05Hemianencephaly Q00.06Amyelencephaly Q00.07Hydrencephaly Q00.08Other anencephaly Q00.1Craniorachischisis Q00.2Iniencephaly Q00.20Iniencephaly clausa Q00.21Iniencephaly aperta
- What is anencephaly? Anencephaly is a neural tube defect (NTD) in which the brain and cranial vault are grossly malformed. A major portion of the brain is reduced or absent, but the hindbrain is present. Facial structures are generally present and appear relatively normal (fig. 1). The cranial lesion is occasionally covered by skin, but, usually, it is not. This defect results when the neural tube fails to close during the third to fourth weeks of development, leading to fetal loss, stillbirth, or neonatal death. Anencephaly, like other forms of NTDs, generally follows a multifactorial pattern of transmission, with interaction of multiple genes as well as environmental factors. Anencephaly can be detected prenatally through maternal serum alpha-fetoprotein screening or ultrasound imaging. Folic acid has been shown to be an efficacious preventive agent that reduces the potential risk of anencephaly and other NTDs by approximately two thirds.
- FEATURED ARTICLE OF THE MONTH Exencephaly – Anencephaly Sequence and its Sonographic Features by Martin Necas RDMS, RVT , Terry DuBose , MS, RDMS and Vicki Taylor , LM, CPM June 2000 Citation: NecasM, DuBoseT, TaylorV: "Exencephaly -Anencephaly Sequence and its Sonographic Features". June 2000; http://www.obgyn.net/us/cotm/0006/exencephaly-anencephaly.htm Introduction Anencephaly represents the most common neural tube defect. It’s incidence is approximately 1:1000 with female predominance (4:1) and geographical variability.1,2 The etiology of anencephaly closely mirrors that of spina bifida. The condition results from the failure of the rostral (cephalic) neuropore to close. Sonographic as well as pathologic evidence points to a close link between exencephaly (also frequently referred to as "acrania") and anencephaly. It has been proposed that the brain tissue of exencephalics may gradually degenerate due to the exposure to amniotic fluid in combination with mechanical trauma. This wearing down of the brain stroma produces the classic anencephalic features with flattened brain remnants behind the prominent orbits. This hypothesis is supported by animal studies, pathologic analysis of exencephalic brain stroma when compared with cerebrovasculosa2, as well as observations on ultrasonography combined with amniotic fluid cytology. 3 Ultrasound Findings Reliable sonographic diagnosis of anencephaly is usually possible in early second trimester (10-14wks GA) 4. Conventional 2D ultrasound is accurate in diagnosing anencephaly5 and the sensitivity is virtually 100% after 14wks GA6. 3D sonography has been shown to be equally effective in detecting anencephaly. 7 On ultrasound, the cranial vault (bony calvarium) is symmetrically absent. Rudimentary brain tissue (area cerebrovasculosa) is covered by a membrane, but not bone (Figure 1,2). This be seen protruding from the base of the skull in the early second trimester, and gradually degenerates until the appearance of the head is completely flattened behind the facial structures. Facial views reveal frog-like appearance with prominent bulging eyeballs (Figure 3,4). Associated polyhydramnios usually develops in the second trimester and is likely due to absent or ineffective fetal swallowing (Figure 3). High degree of fetal activity is often observed. 1,2,6 Figure 1 Figure 2 Figure 3 Figure 4 Sonographic pitfalls in the diagnosis of anencephaly usually revolve around difficulties in imaging such as vertex presentation with deep head location. 1,2 Differentiation of anencephaly from severe microcephaly or large encephaloceles can also be difficult, but in these conditions the cranial vault is always present.6,8 Amniotic band syndrome associated with cranial disruption(s) may also mimic anencephaly. 2,6 Finally, inexperienced operator may confuse the angiomatous stroma with normal fetal calvarium in the early second trimester. Therefore, identification of the fetal head does not rule out anencephaly.8 Conclusion The prognosis of anencephaly is dismal with live newborns invariably dying shortly post delivery. Termination of pregnancy is usually offered regardless of the gestational age. Anencephalic fetuses have been considered as potential organ-donors, however the ethical considerations in these cases are still under debate. 9
- Q01Encephalocele Q01.xx0 Encephalomyelocele, Q01.xx1 Hydroencephalocele, Q01.xx2 Hydromeningocele, cranial, Q01.xx3 Meningocele , cerebral, Q01.xx4 Meningoencephalocele Q01.0Frontal encephalocele Q01.1Nasofrontal encephalocele Q01.2Occipital encephalocele Q01.8Encephalocele of other sites Q01.80Parietal encephalocele Q01.81Nasopharyngeal encephalocele Q01.82Temporal encephalocele Q01.83Orbital encephalocele Q01.9Encephalocele, unspecified
- viwG_MasE01_ICD10NA_Q00-99_CongenitalChromosomal ICD 10DiseaseRemark Q05Spina bifida Excludes:Arnold-Chiari syndrome(Q07.0);spina bifid
- viwG_MasE01_ICD10NA_Q00-99_CongenitalChromosomal ICD 10DiseaseRemark Q06Other congenital malformations of spinal cord Q06.0Amyelia Q06.1Hypoplasia and dysplasia of spinal cord Q06.2Diastematomyelia Q06.3Other congenital cauda equina malformations Q06.4Hydromyelia Q06.8Other specified congenital malformations of spinal cord Q06.80Diplomyelia Q06.81Tethered spinal cord Q06.9Congenital malformation of spinal cord, unspecified
- MALFORMATIONS DUE TO ABNORMAL NEURONAL MIGRATION The neurons and glial cells that form the cerebral cortex are generated around the ventricles of the brain and migrate to the cortex. Proliferating multi-potential precursor cells form a thick layer around the ventricles, the proliferative neuroepithelium . The first wave of migration results in formation of a provisional cortex, the preplate . This is replaced by the permanent cortical plate. Neurons migrate to the cortex along the radial glia , a scaffold of astrocytic processes that strech from the ventricular wall to the pial surface. They are guided by adhesion molecules present on their membranes and on radial glial fibers and by chemical signals some of which are produced by the preplate. Neurons that form the permanent cortical plate migrate in an inside-out , outside last pattern. The precursor cells of the proliferative zone are organized into genetically related groups, the proliferative units . The offspring of each proliferative unit migrate into adjacent positions at the cortex and are organized into a functional module, the ontogenetic column . Thus, the cortex has a horizontal organization into five neuronal layers and a vertical arrangement into ontogenetic columns. Neurogenesis in fish, amphibians, birds and rodents continues after birth. Until recently, it was thought that neurogenesis and migration in primates is completed by mid-gestation except for the hippocampus and granular layer of the cerebellum where it continues during early postnatal life. Recent research shows that neurogenesis also occurs in the adult primate cortex. New neurons are generated in the periventricular area and migrate to the the neocortex. The significance of this observation in terms of neuronal plasticity is not known. The proliferative neuroepithelium produces more neurons than are necessary to populate the cerebral cortex. Neurons that do not make working synapses die. Other neurons are eliminated by genetically programmed apoptosis. The extent of programmed neuronal death in humans is not known. The surface of the hemispheres during the first trimester is smooth. Cortical folding begins during neuronal migration. The Sylvian fissure, central sulcus, calcarine fissure, and parieto-occipital fissure are formed by 26 weeks. The entire surface of the hemispheres is folded by 32 weeks. Defective neuronal migration results in the formation of a disorganized cerebral cortex in which neurons are not normally related or connected with one another. The gyral pattern is also abnormal and is the basis for the morphologic classification of neuronal migration defects into lissencephaly, pachygyria and polymicrogyria. The most severe migration defect is lissencephaly (smooth brain) or agyria , in which cortical sulci are absent except, usually, for the Sylvian fissure. ETIOLOGY-PATHOGENESIS OF NMDs Lissencephaly, SBH and PH have a genetic basis. PMG is thought to be a disruption. Lissencephaly occurs in two distinct genetic disorders, X-linked lissencephaly-subcortical band heterotopia (XLIS-SBH) and the Miller-Dieker syndrome (MDS) . XLIS-SBH is caused by mutations of a gene on Xq22.3-q23 that codes for Doublecortin (DCX), a microtubule associated protein. This suggests that XLIS-SBH is caused by an abnormality of the cytoskeleton of migrating neurons. XLIS-SBH is an X-linked dominant defect. Affected males have type 1 lissencephaly. Due to random X-inactivation, affected females have a mosaic cellular phenotype, i.e. half of their cells are affected and the other half are not. This results in a less severe malformation, SBH. The MDS is caused by a microdeletion of 17q13.3 involving the LIS1 gene. The LIS1 protein forms complexes with other cellular proteins that are crucial for cell division, migration, and intracellular transport. Complete loss of LIS1 is fatal. Deletion of one copy of the gene is causes lissencephaly. The MDS is characterized by type 1 lissencephaly, dysmorphic face, visceral abnormalities and polydactyly. Periventricular Heterotopia is an X-linked dominant defect which is lethal in males and causes PH in females. The mutation involves the gene of Filamin I on Xq28. Filamin I, an actin-binding protein that crosslinks actin filaments, is important for the cytoskeleton and cellular locomotion. Many cases of polymicrogyria are thought to be disruptions caused, most frequently, by HIE and fetal infections. In fetal HIE, layer 5 is damaged and layers superficial to it overfold and fuse together. The damage occurs either after neuronal migration is completed or after migration of layer 6 neurons. In the latter case, layer 4, 3 and 2 neurons pass through the damaged layer 5 and are arranged in an abnormal fashion superficial to it. The disruptive pathogenesis of polymicrogyria is supported by animal experiments. Polymicrogyria is seen frequently in vascular territories or watershed areas and in the borders of porencephalic cysts and schizencephaly defects. However, there are also genetic polymicrogyria syndromes that involve symmetrically the frontal lobes or the perisylvian areas. Patients with bilateral frontal polymicrogyria present with psychomotor retardation, spasticity and impaired language fuction. Patients with perisylvian polymicrogyria present with cognitive deficits, seizures, paralysis of tongue movements, drooling, and dysarthric speach. NMDs WITH CONGENITAL MUSCULAR DYSTROPHY : Three rare syndromes, the Walker-Warburg Syndrome, Fukuyama Congenital Muscular Dystrophy, Muscle-Eye-Brain Disease are characterized by type 2 (unorganized) lissencephaly, subarachnoid glioneuronal heterotopias, hydrocephalus and retinal detachment. NMDs ASSOCIATED WITH METABOLIC DISORDERS : The main entities in this group are the Zellweger Syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and glutaric aciduria IIA. Two key features of the ZS and NALD, deficiency of plasmalogens and elevated very long chain fatty acids, may cause membrane abnormalities that could impair guidance of migrating neurons. ANIMAL MODELS OF NMDs : The mouse mutant Reeler shows an inverted arrangement of the cortical layers, crowding of the cortex in the subpial zone and cerebellar dysplasia. This phenotype is caused by a mutation of reelin, a protein secreted by preplate cells that probably is an important chemical signal for migrating neurons.
- THREE GENES AND THEIR EFFECTS ON RADIAL NEURAL CELL MIGRATION IN THE CEREBRAL CORTEX I. NEUREGULIN AND ITS ISOFORMS Neuregulin goes by many names: Neuregulin, heregulin, neu differentiation factor, glial growth factor (GGF), acetylcholine receptor-inducing activity (ARIA), and sensory-and-motor-derived factor (SMDF). Neuregulin was independently shown to be the factor critically involved in each of these these different functions, and it is thus an extremely important molecule in neural development. However, recent evidence shows that some of these functions are actually done by different splicing isoforms of the neuregulin gene. In other words, the neuregulin gene generates a family of proteins, and some of these related proteins have different functions. For instance, if one deletes the entire neuregulin gene from mouse embryos, the neural crest cells fail to develop properly, and the embryo lacks cranial neurons and most of its Schwann cells. However, deletion of specific introns shows that the type I isoforms (which would generate the ARIA/NDF/heregulin proteins) are responsible for forming the cranial neurons, while type III isoforms (originally isolated as SMDF proteins) are responsible for forming the Schwann cells (Meyer et al., 1997). The type II isoform of the neuregulin gene produces GGF . This soluble form of neuregulin appears to be expressed in migrating cortical neurons and appears to be essential for their migration along the radial glial fibers. GGF appears to stimulate the glial cells to produce brain lipid binding protein (BLBP), and this protein is critical in maintaining and elongating the glial fibers (Anton et al., 1997). The neuregulins are made by several types of neuronal and muscle cell types, and the type II message is seen in the notochord. They elicit their effects by working through the erb2, erb3, and erb4 tyrosine kinases in the membranes of the responding cell types such as neural crest cells (Carraway and Burden, 1995). We see here, then, that a single gene can produce a family of proteins, and that different members of that family can (a) be expressed in different cell types at different times and (b) have different properties that enable different aspects of neural development. II. Doublecortin and LIS-1: Genes responsible for human lissencephaly Lissencephaly ("smooth brain") is an extremely severe malformation of the human cerebral cortex. Patients suffering from lissencephaly show an absence or reduced number of convulted gyres (giving the brain a smooth appearance). This results from the migrational arrest of all cortical neurons before they reach their normal expected destinations. It produces profound mental retardation and epileptic seizures (Dobyns and Truwit, 1995). One of the genes, LIS1 , whose mutant forms cause lissencephaly has been mapped to chromosome 17p13. It appears to encode a regulatory subunit of a hydrolase whose activity in the nervous system had not been previously known (Dobyns et al., 1993; Hattori, et al., 1994). The cerebral cortex of these people, instead of having six well defined layers, has four layers overlying a thin rim of white matter. The second of the genes whose mutant forms produce lissencephaly has been mapped to the long arm of the X chromosome (Ross et al., 1997; Gleeson et al., 1998; Portes et al., 1998). Males suffering from this condition show a severely mentally retarded phenotype, similar to those who have mutations in the LIS1 genes. Females who have X-linked lissencephaly typically have a milder condition, presumably resulting from a mosaic of random inactivation of either the wild-type or mutant C-chromosome. The brains of these affected girls shows two populations of cortical neurons--one which has migrated nomally to the periphery of the cortex, and another population that has migrated only halfway and stops within the subcortical white matter of the brain. This second population produces a "band" of neuronal cells within the white matter and causes this phenomenon to sometimes be called "double cortex lissencephaly " (Figure 1). This region of the genome became interesting when a woman was found whose lissencephaly was correlated with a translocation of part of her X chromosme to chromosome 2. The breakpoint mapped within an open reading frame, and nine families with X-linked lissencephaly were found to have mutations in the same genetic region. This open reading frame would encode a 40 kDa protein that has now been called " Doublecortin ." In situ hybridization shows the expression of the doublecortin gene in the ventricular zone, intermediate zone, and cortical plate neurons. It is not known whether doublecortin and the product of the LIS1 gene lie on the same developmental pathway, but the similarities of the phenotypes suggest that they do. This brings to five the number of proteins associated with cortical layering: The mouse reelin gene (which encodes for an extracellular matrix protein), the mouse disabled gene (which may be part of the response pathway in those cells recognizing reelin), glial growth factor, LIS1, and doublecortin.
- The cortex, in type 1lissencephaly, is thick and consists of the molecular and three neuronal layers. The depest of these layers is also the thickest and most cellular, presumably comprised of neurons that migrated a certain distance from the germinal matrix but failed to reach their normal destinations. There is a small amount of white mater between the abnormal cortex and the ventricles. In type 2 lissencephaly, no layers are present and there are glioneuronal heterotopias in the subarachnois space. Pachygyria (thick gyri) is a milder variant of lissencephaly with a reduced number of broad gyri. Lissencephaly arises between 12 and 16 weeks of gestation. Patients with lissencephaly-pachygyria have severe psychomotor retardation and intractable seizures.
- Clinical Profile: There was a H/O seizures and mental retardation. Findings: There is thickening of the cortex in both cerebral hemispheres. The sulci are shallow and sparse and the gyri are flat and broad based. There is slight ventricular dilatation and the brainstem appears a little smaller in size. The cerebellum also appears to be dysplastic. Discussion: Lissencephaly means smooth brain and refers to a paucity of gyral and sulcal development on the surface of the brain. Smooth brain results from many causes like congenital infections (CMV), impaired stem cell formation and abnormal neuronal migration. Children with lissencephaly are severely disabled physically and intellectually. Agyria is defined as absence of gyri on the surface of the brain, synonymous with complete lissencephaly, while pachygyria is defined as few broad flat gyri, synonymous with incomplete lissencephaly. Two major pathological subtypes of lissencephaly exist :- Classical Lissencephaly: This results from arrest of migration of neurons. Children with classical lissencephaly always have global developmental delay and seizures, although the age of onset and severity of symptoms may vary. Some patients have chromosome 17 defects or X chromosome defect. Children with classical complete lissencephaly are hypotonic at birth gradually developing spasticity and those with incomplete lissencephaly have less severe motor abnormalities with hypertonia. Medically refractory epilepsy with increasing complex seizure disorder over time is characteristic. Most patients have areas of agyria and pachygyria. Systemic abnormalities of the eyes, ears, heart and kidney are also present. Microscopically, the cerebral cortex is composed of a thin outer layer of neuron, a cell sparse zone and a thick inner layer of neurons. This inner layer represents young neurons that were stopped prematurely from their migration to the cortex or some abnormality of fetal ependymia. The MR imaging appearance of classical lissencephaly reveals a smooth brain surface with diminished white matter and shallow vertically oriented Sylvian fissure. The cerebrum has a "figure of eight" appearance with corpus callosal hypogeneis with large ventricular trigones and occipital horns. The small brain stem results from maldevelopment of corticospinal and corticobulbar tracts. Cobblestone Lissencephaly: This results from overmigration of neurons. These patients suffer from associated muscular dystrophy and hypotonia, myelination delay, hydrocephalus and ocular abnormalities. The MR appearance shows a thickened cortex with few shallow sulci, an irregular gray-white matter junction, pontine hypogenesis, vermian hypogenesis with cerebellar polymicrogyria, hydrocephalus, micro-opthalmia and callosal hypogenesis and an occasional occipital cephalocele. When the abnormality is seen in the frontal cortex, frontal polymicrogyria is seen as an irregularity of the cortical surface and cortical white matter junction. The temporo-occipital abnormality is seen as a thickened cortex with a smooth outer surface but an irregular inner surface. Dysplasia of the cerebellar cortex manifests as dysplastic folia with subcortical cysts located predominantly in the dorsal portion of the cerebellar hemisphere. Myelination is often delayed. References: Lee BC, Engel M.: MR of lissencephaly: AJNR Am J Neuroradiol. 1988 Jul-Aug;9(4):804. Byrd SE, Bohan TP, Osborn RE, Naidich TP: The CT and MR evaluation of lissencephaly: AJNR Am J Neuroradiol. 1988 Sep;9(5):923-7. Barkovich AJ, Chuang SH, Norman D: MR of neuronal migration anomalies: AJR Am J Roentgenol. 1988 Jan;150(1):179-87.
- MRI appearance of human lissencephaly and double cortex syndrome. MRI images of cerebral cortex in a normal human being (Normal), a patient with LIS1 mutation (LIS1), a female patient with DCX mutation (DCX-Female) and a male patient with DCX mutation (DCX-Male). Notice that patients with mutations in LIS1 and male DCX patients show strikingly similar lissencephalies, whereas female patients with DCX mutations present with 'double cortex' syndrome, in which a band of grey matter is embedded within the white matter beneath the normal cortex.
- Figure 1: A-C , agyria-pachygyria-band spectrum, grade 2. Sagittal T1-weighted image ( A ) shows hypoplastic corpus callosum ( arrows ). The splenium is not bulbous; the genu and rostrum are not well seen. The telencephalic brain appears smooth and poorly sulcated, although this can be difficult to discern on midline sagittal images. Axial T1-weighted image ( B ) confirms the smooth lissencephalic brain; note the very primitive sulcation limited to the frontal region ( arrows ). A more cephalad axial T2-weighted image ( C ) shows primitive, enlarged ventricles, figure-8 shaped lissencephalic brain, and hyperintense cell-sparse layer
- Figure 1: D-F , agyria-pachygyria-band spectrum, grade 3. Sagittal T1-weighted MPRage image ( D ) shows smooth, broad gyri typical of pachygyria. Axial T1-weighted image ( E ) also shows pachygyria which is more severe over the posterior than anterior regions. Also note the mildly enlarged ventricles with rounded margins. The abnormal hypointense foci along the periatrial margins are atypical, and their significance is not clear. Axial T2-weighted image ( F ) shows similar changes.
- Figure 1: G-I , agyria-pachygyria-band spectrum, grade 5. Coronal T1-weighted MPRage image ( G ) shows bilateral undulating bands of abnormal gray matter ( arrows ) in the subcortical region. Note the normal olfactory sulci. Coronal proton density-weighted image at the same location ( H ) also shows bands of heterotopic gray matter ( arrows ). Further posteriorly, coronal MPRage image ( I ) again shows bands. However, the bands terminate superiorly in frank pachygyria (short arrows). Also note the subtle additional heterotopia (long arrows) deep to the band along the ventricles which are occasionally seen in subcortical band heterotopia.
- Figure 1: J-L , agyria-pachygyria-band spectrum, grade 6. Axial T2-weighted image ( J ) shows typical subcortical band heterotopia deep to the overlying cortex. The signal intensity parallels gray matter. The ventricles are slightly enlarged and rounded. Slightly more cephalad, axial proton density-weighted ( K ) and T2-weighted ( L ) images show similar changes. The bands have the signal intensity of gray matter ( K, arrows ). The inner margin of the bands are usually smooth, as in this case. The outer margins may be smooth or may undulate with fingers of subcortical white matter, as in this case. The overlying cortex may be radiographically normal or pachygyric.
- In polymicrogyria (many small gyri), the surface of the cerebral hemispheres shows multiple small bumps, suggesting an excessive number of gyri. The cortex is thick and consists of the molecular and one other broad neuronal layer (in some cases there are three poorly defined neuronal layers). These layers are irregularly overfolded and fused, eliminating the sulci. Patients with polymicrogyria have severe psychomotor retardation and seizures.
- Etiology: • Polymicrogyria is increased numbers of small gyri with two, four or more lamination. • It can be sporadic due to intrauterine anoxia or ischemia or intrauterine infection. • It can also be familial. Pathogenesis: • Polymicrogyria is due to abnormal migration of neurons to the cortex or post migrational damage. Epidemiology: • Polymicrogyria is relatively rare, but can be the cause of mental retardation or seizures. General Gross Description: • Polymicrogyria may involve the whole brain but more often it involves parts of the brain symmetrically or asymmetrically. • It consists of small wormlike gyri in the area involved. • The brain may be either large or small. General Microscopic Description: • The four layered cortex has a marginal area, a cellular layer, and acellular layer followed by another cellular layer. • The two layered cortex has a marginal layer and a poorly organized cellular layer. • The brain has decreased white matter and enlarged ventricles often with microscopic gliosis. Clinical Correlations: • Patients with varying degrees of polymicrogyria may have mental retardation, spasticity, and/or seizures References: • Cotran RS, Kumar V, Robbins SL: Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, W.B. • Greenfield's Neuropathology, 6th ed. Graham DI, Lantos PL (ed), New York: Arnold, 1997, pp. 442-446. Synopsis by: Dr ML Grunnet
- Focal cortical dysplasia ö microdysgenesis is characterized by a focally thickened cortex with a disordered cytoarchitecture, large abnormally oriented neurons and hypertrophic astrocytes. Such lesions are often seen in specimens resected for epilepsy. The lesion is thought to represent a focal abnormality of neuronal migration and differentiation. It resembles the cortical lesions of tuberous sclerosis.
- viwG_MasE01_ICD10NA_Q00-99_CongenitalChromosomal ICD 10DiseaseRemark Q04.8Other specified congenital malformations of brain Q04.80Macrogyria Q04.81Ulegyria Q04.82Agenesis of septum pellucidum Q04.83Copocephaly Q04.84Diorders of neuronal migration Q04.840Cortical lamination abnormality Q04.841Neuronal hetrotopia
- Band heterotopia, (also called laminar heterotopia and double cortex), a diffuse grey matter heterotopia. The mode of inheritance is X-linked and the anomaly has been reported only in females. Patients present with mild to severe mental retardation, behavioural problems and epilepsy usually refractory to medical therapy. MR reveals a bilateral band of heterotopic grey matter between the lateral ventricles and cortex, separated by normal-appearing white matter (Fig.1). The band is isointense with the cortex in all MR pulse sequences and does not show contrast enhancement
- The overlying cortex can be normal or pachygyric proportionally to the thickness of the heterotopic band. Electrical seizure activity seems to originate from the band. Band heterotopia is considered the mildest expression of disorders that include type I lissencephaly.
- return to Shufflebrain main menu web contact: [email_address] RETURN TO FIRST SET CORTICAL HETEROTOPIA 1998. A search of the recent literature at Indiana University, Bloomington, Indiana The following MEDLINE items were compiled by SilverPlatter and are presented with their generous permission. ( See SilverPlatter's Worldwide Library for bibliographic search information .) Record 1 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: [The value of images in diagnosis of neuron migration disorders] AUTHOR(S): Pascual-Castroviejo-I; Viano-J; Roche-C; Martinez-Bermejo-A; Martinez-Fernandez-V; Arcas-J; Pascual-Pascual-SI; Lopez-Martin-V; Tendero-A; Fernandez-Jaen-A; Quijano-S SOURCE (BIBLIOGRAPHIC CITATION): Rev-Neurol. 1998 Aug; 27(156): 246-58 INTERNATIONAL STANDARD SERIAL NUMBER: 0210-0010 LANGUAGE OF ARTICLE: SPANISH; NON-ENGLISH ABSTRACT: OBJECTIVE: To present the fitest classification and the imaging peculiarities of the malformations of cortical development, most of which have been related with the epilepsy origin. METHODS: The study is based on an anatomical-histological classification scheme that shows three great groups of malformations of cortical development: 1. Malformations due to abnormal neuronal and glial proliferation. 2. Malformations due to abnormal neuronal migration. 3. Malformations due to abnormal cortical organization. RESULTS: The result of these abnormalities of the cortical development is the presence of several anatomical histological entities, actually perfectly identified by the magnetic resonance (MR), especially with the new high resolution methods. The most frequent entities, such as polymicrogyria, lissencephaly, pachygyria, schizencephaly, cerebral heterotopia (cortical, subcortical or subependymal), and other rarer types are reviewed according with the numerous references of the literature and the findings observed in the cases of our series of about one hundred patients which includes cases of every type of malformation. CONCLUSION: MR is a conclusive study in order to identify and classify the malformations of cortical development, most of which are associated with neurological disturbances: epilepsy, mental retardation, language and/or behavioral problems or motor dysfunction. MEDLINE ACCESSION NUMBER: 98408162 Record 2 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: Intermittent rhythmic delta activity (IRDA) in a patient with band heterotopia. AUTHOR(S): Nakano-M; Abe-K; Ono-J; Yanagihara-T SOURCE (BIBLIOGRAPHIC CITATION): Clin-Electroencephalogr. 1998 Jul; 29(3): 138-41 INTERNATIONAL STANDARD SERIAL NUMBER: 0009-9155 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: We report a patient with band heterotopia whose electroencephalogram (EEG) showed typical morphological features of intermittent rhythmic delta activity (IRDA). This 18-year-old woman had complex partial seizures. Neuropsychometry revealed mental dysfunction. Magnetic resonance imaging (MRI) showed bilaterally symmetrical layer of heterotopic gray matter in deep white matter over the frontal, parietal and occipital regions. This case is the first report of IRDA detected in band heterotopia. MEDLINE ACCESSION NUMBER: 98324236 Record 3 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: Neuronal migration disorders: heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex. AUTHOR(S): Chevassus-Au-Louis-N; Congar-P; Represa-A; Ben-Ari-Y; Gaiarsa-JL SOURCE (BIBLIOGRAPHIC CITATION): Proc-Natl-Acad-Sci-U-S-A. 1998 Aug 18; 95(17): 10263-8 INTERNATIONAL STANDARD SERIAL NUMBER: 0027-8424 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: Neuronal migration disorders have been involved in various pathologies, including epilepsy, but the properties of the neural networks underlying disorders have not been determined. In the present study, patch clamp recordings were made from intrahippocampal heterotopic as well as from neocortical and hippocampal neurons from brain slices of rats with prenatally methylazoxymethanol-induced cortical malformation. We report that heterotopic neurons have morphometrical parameters and cellular properties of neocortical supragranular neurons and are integrated in both neocortical and hippocampal networks. Thus, stimulation of the white matter induces both antidromic and orthodromic response in heterotopic and neocortical neurons. Stimulation of hippocampal afferents evokes a monosynaptic response in the majority of heterotopic neurons and a polysynaptic all-or-none epileptiform burst in the presence of bicuculline to block gamma-aminobutyric acid type A inhibition. Furthermore, hippocampal paroxysmal activity generated by bath application of bicuculline can spread directly to the neocortex via the heterotopia in methylazoxymethanol-treated but not in naive rats. We conclude that heterotopias form a functional bridge between the limbic system and the neocortex, providing a substrate for pathological conditions. MEDLINE ACCESSION NUMBER: 98374340 Record 4 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: A case of depressive disorder with neuronal heterotopia. AUTHOR(S): Maruyama-Y; Onishi-H; Miura-T; Kosaka-K SOURCE (BIBLIOGRAPHIC CITATION): Psychiatry-Clin-Neurosci. 1998 Jun; 52(3): 361-2 INTERNATIONAL STANDARD SERIAL NUMBER: 1323-1316 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: We describe a case of depressive disorder with neuronal heterotopia. The patient, a 55-year-old woman, had a history of depressive episodes since the age of 53. Magnetic resonance imaging (MRI) disclosed bilateral periventricular heterotopia. The patient had not experienced any epileptic episodes, and an electroencephalogram did not reveal any epileptic discharge. Single photon emission computed tomography (SPECT) disclosed diffuse cerebral hypoperfusion. This is the first report on a case of depression with neural migration disorder. Patients with neural migration disorders can be detected more frequently with the increasing use of MRI. MEDLINE ACCESSION NUMBER: 98344916 Record 5 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: Bilateral periventricular nodular heterotopia with mental retardation and frontonasal malformation. AUTHOR(S): Guerrini-R; Dobyns-WB SOURCE (BIBLIOGRAPHIC CITATION): Neurology. 1998 Aug; 51(2): 499-503 INTERNATIONAL STANDARD SERIAL NUMBER: 0028-3878 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: BACKGROUND AND OBJECTIVE: Bilateral periventricular nodular heterotopia (BPNH) is a recently recognized malformation of neuronal migration in which nodular masses of gray matter line the walls of the lateral ventricles. Most affected individuals are females with epilepsy and normal intelligence, but no other congenital anomalies. Studies in families with multiple affected individuals, always all females, have mapped one BPNH gene to chromosome Xq28. Several other BPNH syndromes associated with mental retardation and epilepsy but without significant dysmorphic facial features have been observed in males only, which may also be X-linked. This report describes a new syndrome with BPNH. METHODS: Clinical and MRI study and cognitive testing of two unrelated boys, aged 8 and 5.5 years, and review of the enlarging spectrum of syndromes associated with BPNH. RESULTS: Similarities between the two boys are sufficient to delineate a new multiple congenital anomaly-mental retardation syndrome that consists of BPNH, regional cortical dysplasia, mild mental retardation, and frontonasal malformation. CONCLUSIONS: The cause of this unusual syndrome is unknown; based on linkage of other BPNH syndromes to chromosome Xq28 and the report of possible X-linked inheritance of frontonasal malformation, we suspect the cause is genetic, with possible X-linked inheritance. MEDLINE ACCESSION NUMBER: 98373799 Record 6 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects. AUTHOR(S): Sossey-Alaoui-K; Hartung-AJ; Guerrini-R; Manchester-DK; Posar-A; Puche-Mira-A; Andermann-E; Dobyns-WB; Srivastava-AK SOURCE (BIBLIOGRAPHIC CITATION): Hum-Mol-Genet. 1998 Aug; 7(8): 1327-32 INTERNATIONAL STANDARD SERIAL NUMBER: 0964-6906 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: Subcortical band heterotopia (SBH) and classical lissencephaly (LIS) result from deficient neuronal migration which causes mental retardation and epilepsy. A single LIS/SBH locus on Xq22.3-q24 was mapped by linkage analysis and physical mapping of the breakpoint in an X;2 translocation. A recently identified gene, doublecortin ( DCX ), is expressed in fetal brain and mutated in LIS/SBH patients. We have identified four novel missense mutations in the gene, one familial mutation with LIS in a male and SBH in the carrier females, one de novo mutation in an SBH female, and two mutations in sporadic SBH female patients. The DCX gene is found to be expressed exclusively at a very high level in the adult frontal lobe. We have also cloned the X-linked mouse doublecortin (Dcx) gene. It encodes isoforms of a highly hydrophilic 40 kDa protein, homologous to its human counterpart and containing several potential phosphorylation sites. Both human and mouse DCX proteins are homologous to a CNS protein containing a Ca2+/calmodulin kinase domain, suggesting that the DCX protein may belong to a novel class of intracellular proteins involved in neuronal migration through Ca2+-dependent signaling. MEDLINE ACCESSION NUMBER: 98334553 Record 7 of 7 in MEDLINE EXPRESS (R) 1998/11-1998/12 TITLE: Histologic types and surveillance of gastric polyps: a seven year clinico-pathological study. AUTHOR(S): Papa-A; Cammarota-G; Tursi-A; Montalto-M; Cuoco-L; Certo-M; Fedeli-G; Gasbarrini-G SOURCE (BIBLIOGRAPHIC CITATION): Hepatogastroenterology. 1998 Mar-Apr; 45(20): 579-82 INTERNATIONAL STANDARD SERIAL NUMBER: 0172-6390 LANGUAGE OF ARTICLE: ENGLISH ABSTRACT: BACKGROUND/AIMS: This is a seven-year prospective study based on all gastroscopic examinations of our patient population in order to study gastric polyps. METHODOLOGY: One hundred and twenty-one polyps, removed from 96 patients were analysed. All polyps, after endoscopic polypectomy, were classified according to their histotype. The follow-up was carried out in 49 patients for a mean time of 40 months. RESULTS: Polypoid lesions were more frequent in females (57.3%) and they were preferentially located in antrum (60.3%). Hyperplastic and inflammatory polyps were 55.4% and 28.9%, respectively, while adenomatous lesions were 9.9%. Four fundic gland polyps, 1 carcinoid, 1 type I early gastric cancer and 1 pancreatic heterotopia were also found. During the follow-up no malignant lesion was encountered. On the other hand 25 benign polyps were found in 19 patients. CONCLUSIONS: Our experience confirms that there is a close relationship between the size of the polyps and the neoplastic change. In fact, in our series all polyps were smaller than 2 cm and only one malignancy was found (an early gastric cancer). None of adenomatous polyps was associated with gastric adenocarcinoma. Our data also indicates that when a polypectomy is carried out for small polyps (smaller than 2 cm.) a strict follow-up is necessary for the neoplastic polyps only. MEDLINE ACCESSION NUMBER: 98302311 web contact: pietsch@indiana.edu return to Shufflebrain menu
- In subcortical band heterotopia (SBH), misplaced neurons are arranged in a separate layer between the cortex and the ventricles. Patients with SBH have psychomotor retardation, seizures and behaviour problems.
- Periventricular heterotopia (PH) is characterized by unorganized islands of neurons under the ependyma of the lateral ventricles and may coexist with other migration defects. These neurons presumably failed to migrate and differentiated in their original positions. Patients with PH have normal intelligence and seizures.