NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY Gestation Embryogenesis Effects Gestation Embryogenesis Effects

1st/2nd wk zygote 1st/2nd wk zygote3germ lay. Death 3germ lay. Death Cranioschisis Cranioschisis 3rd-4th wk neural tube form.: Anencephaly 3rd-4th wk neural tube form.: Anencephaly Anterior pore clos. Anterior pore clos. Rachischisis Rachischisis Posterior pore clos. Encephalocele Posterior pore clos. Encephalocele

Meningom. Meningom. Spina bifida Spina bifida

Arnold- Arnold-Chiari Chiari Dandy-Walker Dandy-Walker

NEUROPATHOLOGY II

Gestation Embryogenesis Effects Gestation Embryogenesis Effects 5th-6th wk -develop.face/forebr. 5th-6th wk -develop.face/forebr.

-differentiat.prosence Faciotelence- -differentiat.prosence Faciotelence- phaly phalyolfact.tract, phalic olfact.tract, phalic malfor malfor optic vesicles,telence mation optic vesicles,telence mation phalon/diencephalon phalon/diencephalon -cleavage of telencep. Holoprosen- -cleavage of telencep. Holoprosen- into into cerebral hemisp. cephaly cerebral hemisp. cephaly

NEUROPATHOLOGY II

Gestation Embryogenesis Effects Gestation Embryogenesis Effects 6th wk-4th -neuronal/glial 6th wk-4th -neuronal/glial Microceph mo. Microceph mo. prolif./migration Megalenc. prolif./migration Megalenc.

(develop of brain Lissencep. (develop of brain Lissencep. cortex,meninges, cortex,meninges, Pachygyria Pachygyria ventricles,foram., Polymicro- ventricles,foram., Polymicro-

circul. of CSF) gyria circul. of CSF) gyria Heterotop. Heterotop.

NEUROPATHOLOGY II

Gestation Embryogenesis Effects Gestation Embryogenesis Effects 5th month -glial different. 5th month -glial different. Porenceph. Porenceph. (astrocytes(astrocytesnu- Hydranen- nu- Hydranen- trition,oligodend. cephaly trition,oligodend. cephaly myelination) myelination)

-primary sulci appear -primary sulci appear

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

CAUSES OF MALFORMATIONS... CAUSES OF MALFORMATIONS... *Metabolic *Metabolic --Maternal Diabetes mellitus: Maternal Diabetes mellitus: Holoprosencephaly Holoprosencephaly Sacral Sacral agenesis agenesis -Maternal -Maternal phenylketonuria phenylketonuria Microcephaly Microcephaly --Anticonvulsivants(phenytoin) Anticonvulsivants(phenytoin) Microcephaly Microcephaly 2x risk of mental retardation 2x risk of mental retardation

1-2% risk of spina bifida(valproic acid) 1-2% risk of spina bifida(valproic acid) -Dietary deficiency(folic acid-Dietary deficiency(folic acidneural tube neural tube

defects) defects)

NEUROPATHOLOGY II

CAUSES OF MALFORMATIONS... CAUSES OF MALFORMATIONS... -Retinoic acid/Isotretinoin(retinoid)-Retinoic acid/Isotretinoin(retinoid)

Hydrocephalus, holoprosencephaly, Hydrocephalus, holoprosencephaly, microcephaly,abnormal microcephaly,abnormal cerebral/cere cerebral/cere bellar cortical bellar cortical migration, cerebellar migration, cerebellar hypoplasia, hypoplasia, agenesis of vermis,cerebellar agenesis of vermis,cerebellar microgenesis,heterotopia, focal agyria, microgenesis,heterotopia, focal agyria, calcification calcification --

-Warfarin-Warfarinmicrocephaly, meningocele, microcephaly, meningocele, Dandy-Walker malf.,agenesis of corpus Dandy-Walker malf.,agenesis of corpus

callosum and diffuse cerebral atrophy callosum and diffuse cerebral atrophy

NEUROPATHOLOGY II

CAUSES OF MALFORMATIONS... CAUSES OF MALFORMATIONS... *Alcohol *Alcohol -Fetal-alcohol syndrome -Fetal-alcohol syndrome 0.4-3.5/live births 0.4-3.5/live births 190/1000 in some North American 190/1000 in some North American

Indian pop.(genetic? poverty?) Indian pop.(genetic? poverty?) Neonatal mortality-5.8-17% Neonatal mortality-5.8-17% Microcephaly,microphtalmia,mental re Microcephaly,microphtalmia,mental re tardation,hyperactivity,motor problems tardation,hyperactivity,motor problems Growth deficiency(often Growth deficiency(often below 10th below 10th percentile) percentile)

NEUROPATHOLOGY II

CAUSES OF MALFORMATIONS... CAUSES OF MALFORMATIONS...

*Cocaine *Cocaine -Myelomeningocele, -Myelomeningocele, encephalocele, encephalocele, agenesis of corpus agenesis of corpus callosum,hetero callosum,hetero

topias, schizencephaly, etc. topias, schizencephaly, etc.

NEUROPATHOLOGY II

MAJOR GROUPS OF MALFORM.... MAJOR GROUPS OF MALFORM....

*Neural tube closure defects*Neural tube closure defects

*Disorders of forebrain induction*Disorders of forebrain induction

*Neuronal migration defects*Neuronal migration defects

*Encephaloclstic defects*Encephaloclstic defects

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

ANENCEPHALYANENCEPHALY*Is the MOST common congenital malfor *Is the MOST common congenital malfor mation of the brain mation of the brain*Known as far back as Egyptian antiquity*Known as far back as Egyptian antiquity*Compared to the toad(Morgagni,1761)*Compared to the toad(Morgagni,1761)*Geographic variation in incidence: *Geographic variation in incidence: -1-6 / 1000 in Ireland -1-6 / 1000 in Ireland and Wales and Wales -0.5--0.5-2 / 1000 in US2 / 1000 in US

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

ARNOLD-CHIARI MALFORMATION. ARNOLD-CHIARI MALFORMATION. There are 4 types: There are 4 types: *Type I –cerebellar tonsillar herniation *Type I –cerebellar tonsillar herniation *Type II- malformation of craniobasal *Type II- malformation of craniobasal bone, bone, shallow posterior shallow posterior fossa *Type III-fossa *Type III-occipito-cervical bony defect occipito-cervical bony defect

-occipital encephalocele -occipital encephalocele -herniation of cerebellum into en -herniation of cerebellum into en

cephalocele cephalocele *Type IV-cerebellar hypoplasia *Type IV-cerebellar hypoplasia

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

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

NEUROPATHOLOGY II

NEURONAL MIGRATION DEFECTS.NEURONAL MIGRATION DEFECTS.

*Cerebral cortical dysplasia.*Cerebral cortical dysplasia.

(A) Status verrucosus(A) Status verrucosus

(B) Four layered cortex(B) Four layered cortex

(C) Irregular cord-like cortical dysplasia(C) Irregular cord-like cortical dysplasia

NEUROPATHOLOGY II

NEURONAL MIGRATION...NEURONAL MIGRATION...

*Cerebral cortical dyplasia...*Cerebral cortical dyplasia...

-Lissencephaly(agyria)-Lissencephaly(agyria)

-Pachygyria-Pachygyria

smooth brain + 4 layered cortexsmooth brain + 4 layered cortex

NEUROPATHOLOGY II

NEURONAL MIGRATION.... NEURONAL MIGRATION.... *Cerebral cortical dysplasia...*Cerebral cortical dysplasia...

-Miller-Dieker syndrome: -Miller-Dieker syndrome: MicroencephalyMicroencephalySeizuresSeizuresMental retardationMental retardationFurrowed foreheadFurrowed foreheadNeonatal jaundiceNeonatal jaundicePurpuraPurpuraDeletion of L1S1 gene,chromosome Deletion of L1S1 gene,chromosome

17p13.3(90% of patients)17p13.3(90% of patients)

NEUROPATHOLOGY II

NEURONAL MIGRATION....NEURONAL MIGRATION....

*Cerebral cortical dysplasia...*Cerebral cortical dysplasia...

-Polymicrogyria-Polymicrogyria

Increased number of gyri w/ Increased number of gyri w/ abnormal abnormal cytoarchitecture cytoarchitecture

(4 layers of cortex) (4 layers of cortex)

NEUROPATHOLOGY II

NEURONAL MIGRATION...NEURONAL MIGRATION... *Cerebral cortical dysplasia...*Cerebral cortical dysplasia...

-Polymicrogyria...-Polymicrogyria... Etiology:Etiology:

Ischemia,infections(CMV, Ischemia,infections(CMV, toxoplasma,varicella zoster,toxoplasma,varicella zoster,

syphilis)syphilis)Familial syndromesFamilial syndromesMetabolic diseases(peroxisomal,Metabolic diseases(peroxisomal,mitochondria encephalopathy,etc)mitochondria encephalopathy,etc)

NEUROPATHOLOGY II

DISORDERS OF FOREBRAIN INDUCT. DISORDERS OF FOREBRAIN INDUCT. *Holoprosencephaly. *Holoprosencephaly.

-Anomalies of prosencephalic outgrowth -Anomalies of prosencephalic outgrowth and cleavage and cleavage

-Types – classified by degree of gyral de -Types – classified by degree of gyral de velopment:velopment:

AlobarAlobarSemilobarSemilobarLobarLobar

NEUROPATHOLOGY II

DISORDERS OF FOREBRAIN INDUCT... DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly.... *Holoprosencephaly....

-Varying grades of facial dysmorphim: -Varying grades of facial dysmorphim: “the face predicts the brain” “the face predicts the brain” -Other systemic malformations are -Other systemic malformations are freq. freq. -Mild form of these is -Mild form of these is known as arrhinen known as arrhinen

cephaly w/lack of development of the cephaly w/lack of development of the olfactory bulb and tract olfactory bulb and tract

NEUROPATHOLOGY II

DISORDERS OF FOREBRAIN INDUCT... DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly....*Holoprosencephaly....

-Incidence: 1/16,000-1/31,000 -Incidence: 1/16,000-1/31,000 -M:F = 1:3-M:F = 1:3 -Chromosomal abnormalities-Chromosomal abnormalities

Trisomy 13(most common), 18, etcTrisomy 13(most common), 18, etcFamilial: AR or AD or X-linked RFamilial: AR or AD or X-linked RMaternal diabetesMaternal diabetesMaternal infections:toxoplasma,rubellaMaternal infections:toxoplasma,rubellaFetal-alcohol syndromeFetal-alcohol syndrome

NEUROPATHOLOGY II

ENCEPHALOCLASTIC DEFECTS.ENCEPHALOCLASTIC DEFECTS. *Porencephaly*Porencephaly

-Defects in the wall of the cerebral he -Defects in the wall of the cerebral he misphere with communication misphere with communication between between ventricle and the surface ventricle and the surface

-”Basket brain”(Schizencephaly) w/seve -”Basket brain”(Schizencephaly) w/seve re bilateral hemispheric re bilateral hemispheric porencephalic porencephalic

defectsdefectssmooth walled and surrounded smooth walled and surrounded by gyral pattern by gyral pattern

NEUROPATHOLOGY II

ENCEPHALOCLASTIC DEFECTS.....ENCEPHALOCLASTIC DEFECTS..... *Porencephaly...*Porencephaly... Clinical:Clinical:

-Spasticity-Spasticity-Seizures-Seizures-Severe mental retardation-Severe mental retardation-Blindness-Blindness-Survival into adult life in some patients-Survival into adult life in some patients

*Other associated anomalies*Other associated anomalies

NEUROPATHOLOGY II ““Basket brain”(Schizencephaly) Basket brain”(Schizencephaly)

*Etiology – unknown *Etiology – unknown -Presumably destructive events -Presumably destructive events occurring early during fetal lifeoccurring early during fetal life

-Events antedate the acquisition of mature -Events antedate the acquisition of mature astroglial response or completion of astroglial response or completion of convo- lutional convo- lutional developmentdevelopment-Vascular insults, infections, trauma, etc.-Vascular insults, infections, trauma, etc.

NEUROPATHOLOGY II

ENCEPHALOCLASTIC DEFECTS... ENCEPHALOCLASTIC DEFECTS... *Hydranencephaly. *Hydranencephaly. -Etiology:-Etiology:

Vascular eventsVascular events Maternal infections-CMV,toxoplasm Maternal infections-CMV,toxoplasm

Trauma Trauma-Clinical feature:-Clinical feature:

Seizures,spascity,poor psychomotor Seizures,spascity,poor psychomotor development development

Survival is short but can be up to 1 yr or Survival is short but can be up to 1 yr or longer longer

NEUROPATHOLOGY II

ENCEP-HALOCLASTIC DEFECTS...ENCEP-HALOCLASTIC DEFECTS...*Agenesis of corpus callosum.*Agenesis of corpus callosum.

-Relatively a common malformation(1 -Relatively a common malformation(1 in 19,000 autopsies and 2.3% in chil in 19,000 autopsies and 2.3% in chil

dren w/mental retardation) dren w/mental retardation)-Defect that can be partial or complete-Defect that can be partial or complete-May present seizures, intellectual im- -May present seizures, intellectual im-

pairment, psychosis(due mostly to pairment, psychosis(due mostly to otherother

associated anomalies)associated anomalies)

NEUROPATHOLOGY II

ENCEPHALOCLASTIC DEFECTS....ENCEPHALOCLASTIC DEFECTS.... *Multicystic encephalomalacia.*Multicystic encephalomalacia.

Encephloclastic mechanism as in porencephaly Encephloclastic mechanism as in porencephaly and hydranencephaly and hydranencephaly

-Mainly related to vascular events ocurring -Mainly related to vascular events ocurring in in the third trimester or perinatal life the third trimester or perinatal life

-Severe forms are due to global hemispheric -Severe forms are due to global hemispheric necrosis necrosis -May -May also follow viral infectionsalso follow viral infections

NEUROPATHOLOGY II

ENCEPHALOCLASTIC DEFECTS... ENCEPHALOCLASTIC DEFECTS...

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