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Developmental Neuropathology

Developmental Neuropathology. Pathology, Radiology, and Clinical Correlations Bob Hevner, MD, PhD University of Washington Harborview Medical Center. Salvador Dali. Classification & Overview. Malformations

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Developmental Neuropathology

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  1. Developmental Neuropathology Pathology, Radiology, andClinical Correlations Bob Hevner, MD, PhD University of Washington Harborview Medical Center Salvador Dali

  2. Classification & Overview • Malformations • Neural tube defects: anencephaly, craniorachischisis totalis, encephalocele, spina bifida (myelomeningocele) • Patterning defects (holoprosencephaly) • Cell migration disorders: lissencephaly, polymicrogyria, heterotopia • Gyral abnormalities: Down syndrome, thanatophoric dysplasia • Cerebellar anomalies: Chiari malformations, syrinx • Spinal cord lesions: diastematomyelia, hydromyelia, spinal lipoma • Hypoxic/ischemic lesions • White matter: periventricular leukomalacia (PVL) • Gray matter: ulegyria, status marmoratus • White and gray: schizencephaly, multicystic encephalopathy • Hemorrhages • Mid-gestational: germinal matrix hemorrhage • Perinatal: cerebellar, choroid plexus, venous thrombosis • Metabolic disorders • Leigh’s disease • Autism

  3. Normal fetal brain development 17 wk 22 wk 28 wk • Morphogenesis (gyration) • Growth • Cell migrations • Axon connections • Myelination 30 wk

  4. Quantitative Measurements • Brain weight (overall growth) • Cerebral mantle thickness (ventriculomegaly)

  5. Neural tube defects • Failure of cranial or spinal patterning, closure, or differentiation • Neural tube closure starts at three different points • Potential for a great variety of defects due to failure of this process • Teratogens (valproic acid) • Genetic factors • Prevention: folic acid (19-70% reduction)

  6. Anencephaly • “Frog-like” appearance • Begins as exencephaly, with cranial defect; neural tissue destroyed by exposure to amniotic fluid. • Remaining tissue: “area cerebrovasculosa”

  7. Craniorachischisis totalis Complete failure of cranial and spinal neural tube or mesodermal (bony) closure. Early embryonic defect.

  8. Encephalocele Herniation of brain tissue through cranial defect. Occipital is most common in Western countries. Frontal is more common in Southeast Asia.

  9. Spinal Dysraphism A: Open myelomeningocele B: Closed myelomeningocele C: Dermal sinus D: Sacral agenesis (often hydromyelia, skin dimple)

  10. Myelomeningocele Open or barely closed neural tube defect. Most often occur in lumbosacral region. “Areamedullovasculosa” Associated withChiari type II

  11. Holoprosencephaly • Defect of dorsovental patterning in the embryonic forebrain. • Frequently associated with facial anomalies (cyclopia, proboscis) • Associated with mutations of Shh, Zic2, other genes • Lobar • Semilobar • Alobar • Lobar • Semilobar • Alobar

  12. Holoprosencephaly • Often diagnosed prenatally (23 wk GA) • Lobar • Semilobar • Alobar Anterior Posterior

  13. Neuronal Migration Disorders • Lissencephaly • “Smooth brain” with reduced number/absence of gyri and sulci • Synonyms: agyria (absence of gyri), pachygyria (thick gyri) • Polymicrogyria • Increased number of tiny gyri with microscopic fusion of layer 1 • Must be distinguished from increased gyral complexity, e.g., in hydrocephalus • Heterotopia • Laminar • Periventricular

  14. Migration Disorders:Polymicrogyria Diverse etiologies (genetic, hypoxic/ischemic, metabolic) Frequently associated with epilepsy

  15. Migration Disorders: Lissencephaly aka agyria/pachygyria Type I: smooth surface -Miller-Dieker (17p-), LIS1 Type II: irregular surface with glioneuronal heterotopias (subarachnoid)

  16. Migration Disorders: Lissencephaly

  17. Migration Disorders: Polymicrogyria

  18. Gyral Abnormalities: Down syndrome

  19. Gyral Anomalies: Thanatophoric Dysplasia Lateral view • Affected individuals also have severe dwarfism. • Excessive temporal lobe growth. “Bear claw”. • Caused by mutation of FGFR3, which regulates growth of bones and brain. Inferior view

  20. Chiari malformations • Type I • Cerebellar tonsils extend through foramen magnum into cervical spinal canal (chronic tonsillar herniation) • 40-75% associated with cervical cord syringomyelia • Usually becomes symptomatic in teen to early adult years • Type II • Arnold-Chiari malformation • Cerebellar vermis and hemispheres extend through foramen magnum into cervical spinal canal • Associated anomalies of brainstem (100%) • Associated myelomeningocele (95%) • Type III • Cerebellar encephalocele • Very rare • Type IV • Cerebellar aplasia/absence • May be secondary destructive lesion

  21. Chiari type I

  22. Chiari type II (Arnold-Chiari) • Pathogenesis unknown. • Cerebellar vermis herniation associated with lumbar myelomeningocele. • “Beaking” of the tectum • Flattened skull base • Kinking of the medulla • Hydrocephalus 22 wk fetus

  23. Spinal anomalies: Diastematomyelia Partial duplicationof the spinal cord. Defect of spinal cord patterning.

  24. Hydromyelia Dilatation of thecentral canal. Often associated with sacral agenesis. Asymptomatic. Distinguished from syrinx by presenceof ependyma

  25. Spinal Lipoma Sometimes associated with dysraphism. Reflects multipotentiality of “tail bud” embryonic tissue (cf. sacrococcygeal teratoma)

  26. Acquired developmental lesions: susceptibility Susceptibility to hypoxia-ischemia,hemorrhage, etc. depends on age

  27. Hypoxic-ischemic lesions • White matter • Periventricular leukomalacia (PVL): essentially, white matter infarcts • Gray matter • Ulegyria: mushroom gyri, atrophic at depths of sulci • Status marmoratus: “marbled state” of thalamus and basal ganglia, due to hypoxic injury with aberrant myelination • Gray and white matter: large destructive lesions • Schizencephaly and porencephaly • Multicystic encephalopathy

  28. Periventricular leukomalacia

  29. Periventricular leukomalacia: histology • Peak incidence 24-32 weeks gestation • Intrauterine hypoxia/ischemia • Basically a white matter “watershed” infarct • Fetal white matter is particularly susceptible

  30. Ulegyria • “Mushroom” gyri • Actually a response to perinatal hypoxia/ischemia • In swollen brain, cortex at depths of sulci loses blood flow

  31. Germinal matrix hemorrhage • Peak incidence 28-33 gestational weeks • Associated with premature birth • Can cause death when severe • May resolve with no sequelae

  32. Germinal matrix hemorrhage: Grading • Grade 1 • Isolated subependymal hemorrhage (SEH) • Grade 2 • SEH with intraventricular hemorrhage (IVH) but no ventricular enlargement • Grade 3 • SHE + IVH + enlarged ventricles • Grade 4 • SHE + IVH + extension of hemorrhage into brain tissue

  33. Pontosubicular necrosis • Peak incidence around term • Perinatal hypoxia/ischemia • Neuronal death • Morphologically identical to programmed cell death (i.e. ) apoptosis

  34. Ferrugination Neuronal • Neuronal cell death • Typical response of single neurons in infants

  35. The most common malformation? Microcephaly

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