NEUROPATHOLOGY II MALFORMATIONS OF THE CNS. DEFINITIONS. *Malformations -primary disturbance of embryonic or fetal development *Field defect *Disruption -secondary compromise of development due to vascular events, infections, etc.

NEUROPATHOLOGY II DEFINITIONS.... *Deformation -external mechanical influences affect ing development *Dysplasia -abnormal neuronal clustering/localiza tion secondary to neuronal migrational defects

NEUROPATHOLOGY Gestation Embryogenesis Effects 1st/2nd wk zygote3germ lay. Death Cranioschisis 3rd-4th wk neural tube form.: Anencephaly Anterior pore clos. Rachischisis Posterior pore clos. Encephalocele Meningom. Spina bifida Arnold-Chiari Dandy-Walker

NEUROPATHOLOGY II Gestation Embryogenesis Effects 5th-6th wk -develop.face/forebr. -differentiat.prosence Faciotelence- phalyolfact.tract, phalic malfor optic vesicles,telence mation phalon/diencephalon -cleavage of telencep. Holoprosen- into cerebral hemisp. cephaly

NEUROPATHOLOGY II Gestation Embryogenesis Effects 6th wk-4th -neuronal/glial Microceph mo. prolif./migration Megalenc. (develop of brain Lissencep. cortex,meninges, Pachygyria ventricles,foram., Polymicro- circul. of CSF) gyria Heterotop.

NEUROPATHOLOGY II Gestation Embryogenesis Effects 5th month -glial different. Porenceph. (astrocytesnu- Hydranen- trition,oligodend. cephaly myelination) -primary sulci appear

NEUROPATHOLOGY II Gestation Embryogenesis Effects 6th month -neuronal organiz. Down´s and architectonic syndrome (dendritic/axonal Hypothyr. connections,syna Phenilket. psis formation,apo- ptosis, myelination) 7h-9th mos. -second.sulci appear

NEUROPATHOLOGY II CAUSES OF MALFORMATIONS. *Chromosomal abnormalities -Trisomy 9, 13, 18, 21 - Deletions 4p, 17p -Gene mutations *Radiation *Viral infections -Herpes simplex/Varicella zoster -Cytomegalovirus -Rubella *Toxoplasmosis

NEUROPATHOLOGY II CAUSES OF MALFORMATIONS... *Metabolic -Maternal Diabetes mellitus: Holoprosencephaly Sacral agenesis -Maternal phenylketonuria Microcephaly -Anticonvulsivants(phenytoin) Microcephaly 2x risk of mental retardation 1-2% risk of spina bifida(valproic acid) -Dietary deficiency(folic acidneural tube defects)

NEUROPATHOLOGY II CAUSES OF MALFORMATIONS... -Retinoic acid/Isotretinoin(retinoid) Hydrocephalus, holoprosencephaly, microcephaly,abnormal cerebral/cere bellar cortical migration, cerebellar hypoplasia, agenesis of vermis,cerebellar microgenesis,heterotopia, focal agyria, calcification - -Warfarinmicrocephaly, meningocele, Dandy-Walker malf.,agenesis of corpus callosum and diffuse cerebral atrophy

NEUROPATHOLOGY II CAUSES OF MALFORMATIONS... *Alcohol -Fetal-alcohol syndrome 0.4-3.5/live births 190/1000 in some North American Indian pop.(genetic? poverty?) Neonatal mortality-5.8-17% Microcephaly,microphtalmia,mental re tardation,hyperactivity,motor problems Growth deficiency(often below 10th percentile)

NEUROPATHOLOGY II CAUSES OF MALFORMATIONS... *Cocaine -Myelomeningocele, encephalocele, agenesis of corpus callosum,hetero topias, schizencephaly, etc.

NEUROPATHOLOGY II MAJOR GROUPS OF MALFORM.... *Neural tube closure defects *Disorders of forebrain induction *Neuronal migration defects *Encephaloclstic defects

NEUROPATHOLOGY II NEURAL TUBE DEFECTS(Dysraphic disorders) *Primary defects in closure of neuropore -Anencephaly -Craniorachischisis -Myelomeningocele *Primary bone defects(abnormality in axial mesoderm development) -Spina bifida occulta -Encephalocele -Meningocele

NEUROPATHOLOGY II ANENCEPHALY *Is the MOST common congenital malfor mation of the brain *Known as far back as Egyptian antiquity *Compared to the toad(Morgagni,1761) *Geographic variation in incidence: -1-6 / 1000 in Ireland and Wales -0.5-2 / 1000 in US

NEUROPATHOLOGY II ANENCEPHALY... *Etiology – unknown *Possible risk factors: -Geographic location -Socioeconomic factors -Diet  folic acid deficiency -Genetic few familial cases observed *More common in females

NEUROPATHOLOGY II ANENCEPHALY.... -Hypoplasia or absence of cranium -Shallow orbits with protrusion of eyes -Hypoplastic lungs -Large thymus -Abnormal pituitary(lack of hypothalamus/ neurohypophysis) -Other abnormalities: adrenal hypoplasia

NEUROPATHOLOGY II ANENCEPHALY.... -Associated craniorachischisis -Area cerebrovasculosa -Prenatal Dx: increased maternal serum/am niotic A-fetoprotein -Recurrence risk of 3-5%

NEUROPATHOLOGY II MYELOMENINGOCELE. *Herniation of both meninges/spinal cord through a large vertebral defect *Most often lumbosacral *Frequent association w/hydrocephalus -Arnold-Chiari malformation type II *Area medullovasculosa *Meningocele: herniation of meninges only *Occult spina bifida:mildest form of neural tube defect

NEUROPATHOLOGY II SPINAL DYSRAPHISM(spina bifida). *It may be an asymptomatic bone defect (spina bifida occulta) *Also, it can be a severe malformation w/ flattened and disorganized segment of spinal cord associated to an outpouching of meninges

NEUROPATHOLOGY II ARNOLD-CHIARI MALFORMATION. There are 4 types: *Type I –cerebellar tonsillar herniation *Type II- malformation of craniobasal bone, shallow posterior fossa *Type III-occipito-cervical bony defect -occipital encephalocele -herniation of cerebellum into en cephalocele *Type IV-cerebellar hypoplasia

NEUROPATHOLOGY II ARNOLD-CHIARI MALFORMATION... *TYPE II -Herniation of inferior cerebellar vermis -Elongation and downward displacement of medulla and cervical cord -Malformation of craniobasal bone, shallow posterior fossa

NEUROPATHOLOGY II ARNOLD-CHIARI MALFORMATION... *Associated hydrocephalus, meningomyelo cele, aqueductal stenosis or atresia, ventri cular neuronal heterotopia, microgyria, “beaking” of tectum *Craniolacunae – single or multiple translu cent thinning of cranium – dissapears at age of 1-2 yrs.

NEUROPATHOLOGY II SYRINGOMYELIA. *About 90% of cases associated w/Arnold- Chiari type I malformation(tonsillar herniat.) *Wasting and weakness of hand and fore- arm muscles, dissociated anesthesia of upper limbs *Kyphoscoliosis or Charcot´s joints *Slowly progressive *Syringobulbia may be present

NEUROPATHOLOGY II SYRINGOMYELIA.... *Characterized by formation of a fluid-filled cleft-like cavity in the inner cord *Lesion associated w/destruction of gray and white matter in the vacinity, surrounded by a dense reactive gliosis *The formed cavity may be extended from the cervical spinal cord upward into the brainstem

NEUROPATHOLOGY II NEURONAL MIGRATION DEFECTS. *Cerebral cortical dysplasia. (A) Status verrucosus (B) Four layered cortex (C) Irregular cord-like cortical dysplasia

NEUROPATHOLOGY II NEURONAL MIGRATION... *Cerebral cortical dyplasia... -Lissencephaly(agyria) -Pachygyria smooth brain + 4 layered cortex

NEUROPATHOLOGY II NEURONAL MIGRATION.... *Cerebral cortical dysplasia... -Miller-Dieker syndrome: Microencephaly Seizures Mental retardation Furrowed forehead Neonatal jaundice Purpura Deletion of L1S1 gene,chromosome 17p13.3(90% of patients)

NEUROPATHOLOGY II NEURONAL MIGRATION.... *Cerebral cortical dysplasia... -Polymicrogyria Increased number of gyri w/ abnormal cytoarchitecture (4 layers of cortex)

NEUROPATHOLOGY II NEURONAL MIGRATION... *Cerebral cortical dysplasia... -Polymicrogyria... Etiology: Ischemia,infections(CMV, toxoplasma,varicella zoster, syphilis) Familial syndromes Metabolic diseases(peroxisomal, mitochondria encephalopathy,etc)

NEUROPATHOLOGY II DISORDERS OF FOREBRAIN INDUCT. *Holoprosencephaly. -Anomalies of prosencephalic outgrowth and cleavage -Types – classified by degree of gyral de velopment: Alobar Semilobar Lobar

NEUROPATHOLOGY II DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly.... -Varying grades of facial dysmorphim: “the face predicts the brain” -Other systemic malformations are freq. -Mild form of these is known as arrhinen cephaly w/lack of development of the olfactory bulb and tract

NEUROPATHOLOGY II DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly.... -Incidence: 1/16,000-1/31,000 -M:F = 1:3 -Chromosomal abnormalities Trisomy 13(most common), 18, etc Familial: AR or AD or X-linked R Maternal diabetes Maternal infections:toxoplasma,rubella Fetal-alcohol syndrome

NEUROPATHOLOGY II ENCEPHALOCLASTIC DEFECTS. *Porencephaly -Defects in the wall of the cerebral he misphere with communication between ventricle and the surface -”Basket brain”(Schizencephaly) w/seve re bilateral hemispheric porencephalic defectssmooth walled and surrounded by gyral pattern

NEUROPATHOLOGY II ENCEPHALOCLASTIC DEFECTS..... *Porencephaly... Clinical: -Spasticity -Seizures -Severe mental retardation -Blindness -Survival into adult life in some patients *Other associated anomalies

NEUROPATHOLOGY II “Basket brain”(Schizencephaly) *Etiology – unknown -Presumably destructive events occurring early during fetal life -Events antedate the acquisition of mature astroglial response or completion of convo- lutional development -Vascular insults, infections, trauma, etc.

NEUROPATHOLOGY II ENCEPHALOCLASTIC DEFECTS... *Hydranencephaly. -Etiology: Vascular events Maternal infections-CMV,toxoplasm Trauma -Clinical feature: Seizures,spascity,poor psychomotor development Survival is short but can be up to 1 yr or longer

NEUROPATHOLOGY II ENCEP-HALOCLASTIC DEFECTS... *Agenesis of corpus callosum. -Relatively a common malformation(1 in 19,000 autopsies and 2.3% in chil dren w/mental retardation) -Defect that can be partial or complete -May present seizures, intellectual im- pairment, psychosis(due mostly to other associated anomalies)

NEUROPATHOLOGY II ENCEPHALOCLASTIC DEFECTS.... *Multicystic encephalomalacia. Encephloclastic mechanism as in porencephaly and hydranencephaly -Mainly related to vascular events ocurring in the third trimester or perinatal life -Severe forms are due to global hemispheric necrosis -May also follow viral infections

NEUROPATHOLOGY II ENCEPHALOCLASTIC DEFECTS... *Multicystic encephalomalacia... -Are cavities ragged and irregular without cortical malformations -Gliosis and lipid laden macrophages are his tological characteristics