Developmental Neuropathology Pathology, Radiology, and Clinical Correlations Reid Heffner MD Distinguished Teaching Professor Department of Pathology and Anatomy
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Contents A. MALFORMATIONS -Microcephaly -Hydrocephalus -Neural tube defects -Midline cerebral defects -Cell migration disorders -Cerebellar anomalies -Spinal cord lesions
Contents B. PERINATAL DISORDERS - Periventricular leukomalacia - Germinal matrix hemorrhage - Porencephaly
CNS malformations Incidence 1-2% of live births More common in setting of multiple birth defects Different parts of brain develop at different times, so different malformations depend on when injury occurs
Causes of CNS malformations Chromosome abnormalities Mutations Maternal factors Infections Medications (valproate), alcohol Diabetes Vitamin deficiencies-ex: folate X-ray exposure
Causes of CNS malformations Microcephaly: Viral infections Hydrocephaly: LiCAM gene Neural tube defects: Valproate, folic acid, MTHFR gene Midline defects Holoprosencepaaly: many genes incl. SHH, ZIC2 Agenesis of corpus callosum: Fetal alcohol Cell migration disorders Polymicrogyria: 22q.11 deletions Heteropias Cerebellar abnormalities Arnold-Chiari Dandy-Walker: FoxC1(transcription factor) Spinal cord lesions-hox genes
Ultrasound(20 weeks) Chromosome analysis Blood sample-folate Screening
Four week embryo SHH gene LiCAM gene FoxC1 gene HOX genes
Prevalence of CNS malformations Composite of several studies Neural tube disorders 35% Hydrocephalus 20-30% Microcephaly 8-15% Midline disorders 10% Cerebellar disorders 10% Syrinx 1-2% Polymicrogyria 1-2%
Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth Hengli Tang, Christy Hammack, Sarah C. Ogden, Zhexing Wen, Xuyu Qian, Yujing Li, Bing Yao, Jaehoon Shin, Feiran Zhang, Emily M. Lee, Kimberly M. Christian, Ruth A. Didier, Peng Jin, Hongjun Song, Guo-li Ming ZIKV Infects hipsc-derived Neural Progenitor Cells with High Efficiency (A and B) Sample confocal images of forebrain-specific hnpcs (A) and immature neurons (B) 56 hr after infection with ZIKV supernatant, immunostained for ZIKV envelop protein (ZIKVE; green) and DAPI (gray). (D) Production of infectious ZIKV particles by infected hnpcs. Supernatant from hnpc cultures 72 hr after ZIKV infection was collected and added to Vero cells for 2 hr. The Vero cells were further cultured for 48 hr. Shown are sample images of ZIKVE immunostaining (green) and DAPI (gray). Scale bars, 20 μm. Copyright 2016 Elsevier Inc. Terms and Conditions
Microcephaly 3-18% of CNS malformations Intrauterine infections Zika virus Toxoplasmosis CMV Rubella Medications during pregnancy Alcohol, toxin exposure in utero X-rays (in rats, maybe humans)
Brain is also small Destructive CNS lesions Gliosis Calcifications Neuronal loss
Macrocephaly
Hydrocephalus in newborn Causes Aqueduct stenosis X-linked, L1CAM gene Infections in utero Tumors usually later in life Cognitive and motor deficits Treated by shunting Ventriculoperitoneal catheter
HYDROCEPHALUS Acute or chronic High pressure Block in ventricular flow Block in meningeal circulation Block in reabsorption Normal pressure Hydrocephalus Ex vacuo About 500 ml CSF produced each day
CSF drainage system Arachnoid villi
Obstructive hydrocephalus Notice the loss of white matter and intact cortex
Aqueductal stenosis, atresia, forking
Aqueductal stenosis Gliosis of aqueduct, forking (branching into blind alleys)
Neural tube defects -Anencephaly -Encephalocele -Spinal dysraphism (Spina bifida or cut in two)
Neural tube defects- 8/1000 births Closure by 4 weeks
Neural tube defects (dysraphism) Failure of cranial or spinal neural tube closure Teratogens (valproic acid) Genetic factors-200 genes MTHFR gene Increased a-fetoprotein in maternal serum or amniotic fluid Prevention: folic acid (folate deficiency causes disease)
Anencephaly Failure of neural tube and anterior neuropore to close Baby has frog-like appearance Begins as exencephaly and neural tissue destroyed by amniotic fluid Remaining tissue is a disorganized mass of neural and vascular tissue This is called the cerebrovasculosa
Anencephaly incompatible with life Pituitary insufficiency
Anencephaly
Herniation of brain tissue through cranial defect. Occipital is most common 55% survival Encephalocele
Spinal Dysraphism
Meningomyelocele Occurs in lumbar sacral region Associated with Arnold-Chiari II malformation Sphincter control problems, paralysis, infection
Protrusion of meninges and subarachnoid space through bony defect Meningocele
Meningocele
Midline cerebral defects Holoprosencephaly Arhinencephaly Cyclopia Agenesis of corpus callosum Sonic hedgehog gene Patterning gene Specialization Developing midline structures
Holoprosencephaly Failure of formation of the forebrain vesicles Frequently associated with facial anomalies (cyclopia) Associated with mutations of SHH, Zic2, other genes One hemisphere instead of two Abnormal midline structures Single ventricle
Holoprosencephaly Posterior fossa structures are normal Anterior Posterior
Cyclopia One eye Often have holoprosencpaly Incompatible with life
Arhinencephaly can occur alone without HPE Cleft palate and hair lip Agenesis of olfactory nerve, gyrus rectus, olfactory cortex
Agenesis of the corpus callosum Causes 8/1000 live births May be recessive or X-linked Infection in utero-12-26th week Fetal alcohol syndrome Clinical features Seizures Feeding problems Psychomotor retardation Associated disorders Polymicrogyria Absence of cingulate sulcus and cingulate gyrus
Agenesis of the corpus callosum Normal corpus callosum
Agenesis of the corpus callosum Absence of cingulate gyrus
Migration disorders Polymicrogyria Heterotopias
Normal fetal brain development 17 wk 22 wk 30 wk 28 wk Period of cortical and deep gray matter development
Polymicrogyria is an abnormal migration of neuroblasts to the surface Migrate along radial glia Neuroblasts (stem cells) in germinal matrix
Polymicrogyria Usually occurs after fifth month of development Causes are genetic mutations, intrauterine infections and hypoxia May be diffuse or focal Cortical gyri are small; cortical structure abnormal
Migration Disorders: Polymicrogyria Diverse etiologies 22q.11 deletion Frequently associated with Epilepsy Other symptoms depend on extent of involvement
Polymicrogyria Cortex simplified, consists of 3-4 layers Cobblestone appearance grossly
Normal cortical layers polymicrogyria Small convolutions, numerous shallow sulci Three to four layers, not normal six layers
Heterotopia Foci of grey matter in white matter or beneath the ependyma Migrating neuroblasts from germinal matrix get stuck and don t proceed to the cortex
Cerebellar anomalies Arnold-Chiari malformations Causes are poorly understood Dandy-Walker malformation
Arnold-Chiari malformations TYPE I (Chiari malformation) Cerebellar tonsils extend through foramen magnum (chronic tonsillar herniation) Often associated with syringomyelia Not symptomatic until teen years (neck pain, ataxia) TYPE II Vermis, lower hemispheres, medulla extend into spinal canal Brainstem abnormalities-beaking of tectum Meningomyelocele 95% Hydrocephalus common
Chiari type I
Arnold-Chiari type II Pathogenesis unknown. Cerebellar herniation associated with lumbar myelomeningocele. Beaking of the tectum Elongation of medulla and fourth ventricle 22 wk fetus
Chiari II Extension of cerebellar vermis and medulla through foramen magnum into the spinal canal
Arnold-Chiari malformation II Extension of vermis and medulla into spinal canal Beaking of midbrain tectum Hydrocephalus
Dandy-Walker Malformation FoxC1 gene (normal cerebellar development) implicated in some cases Ataxia Hydrocephalus Absence of vermis
Dandy-Walker Malformation Cerebellar vermis is absent; cyst is an expanded 4 th ventricle that communicates with the subarachnoid space.
Syringomyelia-causes Syrinx is a tube Congenital Arnold-Chiari malformation Neural tube defects Idiopathic-occurring alone May be congenital? Role of the HOX genes Tumors (gliomas), later in like
Syringomyelia a fluid-filled cleft within the cord Disease often asymptomatic in childhood Dorsal half of cervical cord commonly involved Cyst expands during life Symptoms result from compression of normal spinal cord structures
Tracts of spinal cord Syringomyelia Symptoms in upper extremities Pain or loss of sensation-spinothalamic tract Weakness-pyramidal tract
Syrinx often surrounded by gliosis with Rosenthal fibers Cyst has no lining cells Syringomyelia
Syrinx T2
Learning objectives Correlate malformations with embryology of CNS List genes and their respective malformations Describe each malformation pathologically Explain the clinical features of each developmental disease Compare the malformations to each other Discuss how you would diagnose each developmental disease Characterize the outcome of each nalformation
The most common malformation
Contents B. PERINATAL DISORDERS - Periventricular leukomalacia - Germinal matrix hemorrhage - Porencephaly
Perinatal developmental lesions: susceptibility Susceptibility to hypoxia-ischemia, hemorrhage, etc. depends on age
Periventricular leukomalacia See bilateral symmetrical white matter lesions in cerebrum PVL is essentially a watershed infarction of subcortical tissue
Periventricular leukomalacia Occurs around time of birth Basically an ischemic/hypoxic lesion Affects cerebral white matter, not cortex Looks like there is loss of tissue, discoloration
Periventricular leukomalacia Sometimes there is cystic change in the white matter
Periventricular leukomalacia Palor of the subcortical structures Gliosis with microglia, astrocytes May be small areas of calcification
Germinal matrix Primitive stem cells next to lateral ventricle
Germinal Matrix Hemorrhage Premature infants Birth weight<1,500 gm or gestation <35 weeks. Hyaline membrane disease Occurs hrs after birth
Germinal matrix hemorrhage Fetal anoxia begins the process Acute venous congestion Dilation of terminal vein Capillary fragility in matrix Matrix substance is also loosely coherent Hemorrhage develops May rupture into ventricle Before ultrasound, it was thought to be uniformly fatal
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
Germinal Matrix Hemorrhage
WHAT IS SEEN HERE? Cystic structure in the brain, often communicates with ventricle Essentially an infarct occurring in utero Symptoms depend on size and location
Porencephaly Unilateral, cystic lesion, partially lined by ependymal or arachnoid