1. 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.

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

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

4. NEUROPATHOLOGY II
Gestation Embryogenesis Effects th-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

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

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

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

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

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

10. 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

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

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

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

14. 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

15. 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: / 1000 in Ireland and Wales / 1000 in US

16. 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

17. 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

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

23. 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

24. 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

28. 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

29. 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

32. 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.

33. 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

34. 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

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

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

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

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

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

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

51. 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

53. 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

54. 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

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

58. 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.

59. 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

63. 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)

67. 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

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