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  1. 1. NEUROPATHOLOGY II <ul><li>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. </li></ul>
  2. 2. NEUROPATHOLOGY II <ul><li>DEFINITIONS.... *Deformation -external mechanical influences affect ing development *Dysplasia -abnormal neuronal clustering/localiza tion secondary to neuronal migrational defects </li></ul>
  3. 3. NEUROPATHOLOGY <ul><li>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 </li></ul>
  4. 4. NEUROPATHOLOGY II <ul><li>Gestation Embryogenesis Effects 5th-6th wk -develop.face/forebr. </li></ul><ul><li> -differentiat.prosence Faciotelence- phaly  olfact.tract, phalic malfor optic vesicles,telence mation phalon/diencephalon -cleavage of telencep. Holoprosen- into cerebral hemisp. cephaly </li></ul>
  5. 5. NEUROPATHOLOGY II <ul><li>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. </li></ul>
  6. 6. NEUROPATHOLOGY II <ul><li>Gestation Embryogenesis Effects 5th month -glial different. Porenceph. (astrocytes  nu- Hydranen- trition,oligodend. cephaly  myelination) -primary sulci appear </li></ul>
  7. 7. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  8. 8. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  9. 9. NEUROPATHOLOGY II <ul><li>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) </li></ul>
  10. 10. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  11. 11. NEUROPATHOLOGY II <ul><li>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) </li></ul>
  12. 12. NEUROPATHOLOGY II <ul><li>CAUSES OF MALFORMATIONS... </li></ul><ul><li>*Cocaine -Myelomeningocele, encephalocele, agenesis of corpus callosum,hetero topias, schizencephaly, etc. </li></ul>
  13. 13. NEUROPATHOLOGY II <ul><li>MAJOR GROUPS OF MALFORM.... </li></ul><ul><li>*Neural tube closure defects </li></ul><ul><li>*Disorders of forebrain induction </li></ul><ul><li> *Neuronal migration defects </li></ul><ul><li> *Encephaloclstic defects </li></ul>
  14. 14. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  15. 15. NEUROPATHOLOGY II <ul><li>ANENCEPHALY </li></ul><ul><li>*Is the MOST common congenital malfor mation of the brain </li></ul><ul><li>*Known as far back as Egyptian antiquity </li></ul><ul><li>*Compared to the toad(Morgagni,1761) </li></ul><ul><li>*Geographic variation in incidence: -1-6 / 1000 in Ireland and Wales -0.5-2 / 1000 in US </li></ul>
  16. 16. NEUROPATHOLOGY II <ul><li>ANENCEPHALY... *Etiology – unknown *Possible risk factors: -Geographic location -Socioeconomic factors -Diet  folic acid deficiency -Genetic  few familial cases observed *More common in females </li></ul>
  17. 17. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  18. 21. NEUROPATHOLOGY II <ul><li>ANENCEPHALY.... -Associated craniorachischisis -Area cerebrovasculosa -Prenatal Dx: increased maternal serum/am niotic A-fetoprotein -Recurrence risk of 3-5% </li></ul>
  19. 23. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  20. 24. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  21. 28. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  22. 29. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  23. 32. NEUROPATHOLOGY II <ul><li>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. </li></ul>
  24. 33. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  25. 34. NEUROPATHOLOGY II <ul><li>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 </li></ul>
  26. 37. NEUROPATHOLOGY II <ul><li>NEURONAL MIGRATION DEFECTS. </li></ul><ul><li>*Cerebral cortical dysplasia. </li></ul><ul><li>(A) Status verrucosus </li></ul><ul><li>(B) Four layered cortex </li></ul><ul><li>(C) Irregular cord-like cortical dysplasia </li></ul>
  27. 38. NEUROPATHOLOGY II <ul><li>NEURONAL MIGRATION... </li></ul><ul><li>*Cerebral cortical dyplasia... </li></ul><ul><li>-Lissencephaly(agyria) </li></ul><ul><li>-Pachygyria </li></ul><ul><li>smooth brain + 4 layered cortex </li></ul>
  28. 43. NEUROPATHOLOGY II <ul><li>NEURONAL MIGRATION.... *Cerebral cortical dysplasia... </li></ul><ul><li>-Miller-Dieker syndrome: Microencephaly </li></ul><ul><li>Seizures </li></ul><ul><li>Mental retardation </li></ul><ul><li>Furrowed forehead </li></ul><ul><li>Neonatal jaundice </li></ul><ul><li>Purpura </li></ul><ul><li>Deletion of L1S1 gene,chromosome 17p13.3(90% of patients) </li></ul>
  29. 44. NEUROPATHOLOGY II <ul><li>NEURONAL MIGRATION.... </li></ul><ul><li>*Cerebral cortical dysplasia... </li></ul><ul><li>-Polymicrogyria </li></ul><ul><li>Increased number of gyri w/ abnormal cytoarchitecture (4 layers of cortex) </li></ul>
  30. 47. NEUROPATHOLOGY II <ul><li>NEURONAL MIGRATION... </li></ul><ul><li>*Cerebral cortical dysplasia... </li></ul><ul><li>-Polymicrogyria... </li></ul><ul><li> Etiology: </li></ul><ul><li>Ischemia,infections(CMV, toxoplasma,varicella zoster, </li></ul><ul><li>syphilis) </li></ul><ul><li>Familial syndromes </li></ul><ul><li>Metabolic diseases(peroxisomal, </li></ul><ul><li>mitochondria encephalopathy,etc) </li></ul>
  31. 48. NEUROPATHOLOGY II <ul><li>DISORDERS OF FOREBRAIN INDUCT. *Holoprosencephaly. </li></ul><ul><li>-Anomalies of prosencephalic outgrowth and cleavage </li></ul><ul><li>-Types – classified by degree of gyral de velopment: </li></ul><ul><li>Alobar </li></ul><ul><li>Semilobar </li></ul><ul><li>Lobar </li></ul>
  32. 51. NEUROPATHOLOGY II <ul><li>DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly.... </li></ul><ul><li>-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 </li></ul>
  33. 53. NEUROPATHOLOGY II <ul><li>DISORDERS OF FOREBRAIN INDUCT... *Holoprosencephaly.... </li></ul><ul><li> -Incidence: 1/16,000-1/31,000 </li></ul><ul><li> -M:F = 1:3 </li></ul><ul><li> -Chromosomal abnormalities </li></ul><ul><li>Trisomy 13(most common), 18, etc </li></ul><ul><li>Familial: AR or AD or X-linked R </li></ul><ul><li>Maternal diabetes </li></ul><ul><li>Maternal infections:toxoplasma,rubella </li></ul><ul><li>Fetal-alcohol syndrome </li></ul>
  34. 54. NEUROPATHOLOGY II <ul><li>ENCEPHALOCLASTIC DEFECTS. </li></ul><ul><li>*Porencephaly </li></ul><ul><li>-Defects in the wall of the cerebral he misphere with communication between ventricle and the surface </li></ul><ul><li>-”Basket brain”(Schizencephaly) w/seve re bilateral hemispheric porencephalic </li></ul><ul><li>defects  smooth walled and surrounded by gyral pattern </li></ul>
  35. 57. NEUROPATHOLOGY II <ul><li>ENCEPHALOCLASTIC DEFECTS..... </li></ul><ul><li>*Porencephaly... </li></ul><ul><li>Clinical: </li></ul><ul><li>-Spasticity </li></ul><ul><li>-Seizures </li></ul><ul><li>-Severe mental retardation </li></ul><ul><li>-Blindness </li></ul><ul><li>-Survival into adult life in some patients </li></ul><ul><li>*Other associated anomalies </li></ul>
  36. 58. NEUROPATHOLOGY II <ul><li>“ Basket brain”(Schizencephaly) *Etiology – unknown -Presumably destructive events occurring early during fetal life </li></ul><ul><li>-Events antedate the acquisition of mature astroglial response or completion of convo- lutional development </li></ul><ul><li>-Vascular insults, infections, trauma, etc. </li></ul>
  37. 59. NEUROPATHOLOGY II <ul><li>ENCEPHALOCLASTIC DEFECTS... *Hydranencephaly. -Etiology: </li></ul><ul><li>Vascular events </li></ul><ul><li> Maternal infections-CMV,toxoplasm Trauma </li></ul><ul><li>-Clinical feature: </li></ul><ul><li> Seizures,spascity,poor psychomotor development </li></ul><ul><li> Survival is short but can be up to 1 yr or longer </li></ul>
  38. 63. NEUROPATHOLOGY II <ul><li>ENCEP-HALOCLASTIC DEFECTS... </li></ul><ul><li>*Agenesis of corpus callosum. </li></ul><ul><li>-Relatively a common malformation(1 in 19,000 autopsies and 2.3% in chil dren w/mental retardation) </li></ul><ul><li>-Defect that can be partial or complete </li></ul><ul><li>-May present seizures, intellectual im- pairment, psychosis(due mostly to other </li></ul><ul><li> associated anomalies) </li></ul>
  39. 67. NEUROPATHOLOGY II <ul><li>ENCEPHALOCLASTIC DEFECTS.... </li></ul><ul><li>*Multicystic encephalomalacia. </li></ul><ul><li>Encephloclastic mechanism as in porencephaly and hydranencephaly </li></ul><ul><li>-Mainly related to vascular events ocurring in the third trimester or perinatal life </li></ul><ul><li>-Severe forms are due to global hemispheric necrosis -May also follow viral infections </li></ul>
  40. 68. NEUROPATHOLOGY II <ul><li>ENCEPHALOCLASTIC DEFECTS... </li></ul><ul><li>*Multicystic encephalomalacia... </li></ul><ul><li> -Are cavities ragged and irregular without cortical malformations </li></ul><ul><li>-Gliosis and lipid laden macrophages are his tological characteristics </li></ul>
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