Abnormal Development of the Nervous System Chris Pierson, MD, PhD Neuropathologist, Nationwide Children’s Hospital Assistant Professor of Pathology

Objectives  Identify the location and describe the pathological findings, symptoms, and the appropriate intervention (pharmacological, surgical, other) for CNS tumors.  Describe how primary brain tumors differ pathologically and clinically from metastatic brain tumors.

Outline  Introduction  Incidence/prevalence, general pathogenesis  Malformations  Neural tube defects Anencephaly, myelomeningocele, encephalocele  Chiari malformation (type II)  Disorders of forebrain induction Holoprosencephaly  Disorders of neuronal migration Agyria (Lissencephaly), Pachygyria, Polymicrogyria  Microcephaly & megalencephaly

Outline (continued)  Acquired Lesions  Introduction with reference to premature birth  Germinal matrix hemorrhage & intraventricular hemorrhage  Periventricular leukomalacia  Cerebral palsy

Introduction to malformations  Congenital structural defects due to abnormalities in development  Wide range in severity  Prevalence of CNS malformations is 5 to 10/ 1000 births  Affects 10% of stillbirths

General pathogenesis  Etiology is highly variable  Genetics, infections, toxins, idiopathic  Timing is key  Different insults can lead to the same malformation if the insult occurs in the window of vulnerability  Some insults can cause different types of malformations depending on when they were introduced

Classification of neural tube defects

Neural Tube Defects: Anencephaly with complete rachischisis 20 week old fetus F>M, 1-5/1000 live births, occasionally familial Pathology: Failure of anterior end of neural tube to close. Brainstem may be present. Skull vault is absent, skull base is thick and flat, shallow orbits

Neural Tube Defects Meningocele Myelomeningocele - Likely due to failure of posterior neuropore to close.

Defects of Neural Tube Closure: Lumbosacral myelomeningocele ABC

Encephalocele -Herniation of neural tube through axial mesodermal defect -Midline lesions and most are occipital (rest are frontal) -Females predominate -Can be huge and even contain a cerebral hemisphere. See brain/meninges underlying dermis -Cortex may show polymicrogryia/heterotopias

Chiari Malformations

Disorders of Forebrain Induction (Cleavage) - Holoprosencephaly  Mostly sporadic, occasionally familial  1:250 abortions; 1:20,000 to 1:30,000 live births  Heterogeneous  Maternal: diabetes, toxoplasmosis, syphilis, rubella, fetal alcohol syndrome, chemicals/toxins  Genetic: AD, AR and X-linked (several implicated genes) 50% of cases have chromosomal aberrations (trisomy 13 & 18, triploidy) Seen in 70% of trisomy 13 cases

Alobar Holoprosencephaly Severest end of spectrum, very small brain termed holosphere, undivided (one ventricle) No gyri recti, longitudinal fissure, corpus callosum & thalami are fused; basal ganglia in floor of ventricle

Alobar Holoprosencephaly

A B C D

Lobar Holoprosencephaly Milder end of spectrum Near normal brain mass and cerebral lobes have a nearly normal gyral pattern Hemispheres appear separated, but cortex is continuous across midline A B

Semilobar Holoprosencephaly Intermediate form Brain is small, but not as small as in alobar form Shallow longitudinal fissure, cortex continuous across midline Rudimentary cerebral structure

Disorders of Neuronal Migration  Cortical malformations, neuronal proliferation and migration starts at 2 gestational months and lasts until birth  Three broad categories:  Agyria, lissencephaly –completely (or almost completely) smooth or unconvoluted brains  Macrogyria or pachygyria - reduced numbers of coarse or widened convolutions  Polymicrogyria - more in a moment

Zellweger’s Disease

Agyria, lissencephaly A B

Polymicrogyria Unifocal PolymicrogyriaSymmetric Polymicrogyria A B C

Polymicrogyria  Etiologically very heterogeneous:  Acquired: intrauterine ischemia, twinning, intrauterine infections (CMV, VZV, toxo, syphilis)  Inherited familial syndromes  Metabolic disorders  Peroxisomal disorders  Some may have a hypoxic-ischemic pathogenesis as suggested by:  Topography, bilateral symmetry, frequent nature of MCA distribution  Clinical cases of catastrophic intrauterine events indicate that it develops in 4 th to 5 th gestational months

Polymicrogyria  Varying degrees of neurologic disability depends on extent and associated findings:  Profound pyschomotor retardation, mental retardation if extensive, seizure disorder, bilateral lesions with microcephaly  Spastic paraplegia if central sulcus is involved  May even be asymptomatic if focal, especially if insula is involved

Microcephaly with associated malformations without associated malformations

Megalencephaly Less common than microcephaly, brain is 2.5 standard deviations above normal for weight and gender Can be familial, isolated or associated with metabolic disorders/ syndrome, Males: females = 2:1 Seizures and or developmental delays may be evident

ACQUIRED LESIONS: PERIVENTRICULAR LEUKOMALACIA AND GERMINAL MATRIX HEMORRHAGES/ INTRAVENTRICULAR HEMORRHAGES

Premature Birth: Magnitude of the Problem  Largest contributor to infant mortality accounts for 1/3 of all infant deaths  Franklin county’s preterm birth rate is 13% or about 2000/year  It is 20% in at risk populations  Contributing factors include: lack of health care, smoking, back-to-back pregnancies, increased C-section deliveries, and early induced labor.

Timing of hypoxic-ischemic injury GMH PVL

Perinatal hypoxic-ischemic injury Mean Arterial Pressure Cerebral Blood Flow (% of normal) Mean Arterial Pressure Cerebral Blood Flow Passive Pressure Circulation Premature infantChild Loss of cerebral autoregulation results in a passive pressure circulation

Periventricular Leukomalacia Pathogenesis Impaired perfusion at boundary zone where metabolic requirements of myelinating white matter are high

Pathology of PVL Two components:  Focal (cavitating) necrosis  Diffuse white matter gliosis A B

Long standing white matter lesions of PVL Cyst formationPoor myelination A B C

Hemorrhages  Commonest pathology in fetal/neonatal brains  Can start in any intracranial compartment, and can rapidly spread  Pathogenesis is multifactorial

Germinal Matrix Hemorrhages - Pathogenesis Controversial Persistence until 34 weeks of a large matrix with fragile microcirculation with little supporting stroma

Germinal Matrix Hemorrhages  Grading done on cranial ultrasound – not neuropathology GradeHemorrhage Distribution 1Confined to germinal matrix 2Germinal matrix and lateral ventricle, no ventricular dilation 3Germinal matrix and lateral ventricle, which is distended by hematoma 4As above with extension of hemorrhage into adjacent brain parenchyma Papile LA, et al. J Pediatr 1978; 92: Poor Outcome Good Outcome

Germinal Matrix Hemorrhages A) Grade 1 B) Grade 2 C) Grade 3 D) Grade 4

Cerebral Palsy - 7 Basic Forms  Spastic hemiparesis (hemiplegia) - unilateral lesion of corticospinal system. Stroke, GMH/IVH, PVL  Spastic diaparesis (diplegia) - tends to involve arms>legs, often due to GMH/IVH, PVL  Spastic quadriparesis - most severe, diffuse damage to brain, associated with cognitive difficulties  Hypotonic CP- Floppy infants, pathogenesis not understood. Often have severe cognitive issues and severe brain injury  Dyskinetic CP - Lesions in basal ganglia  Ataxic CP - Cerebellar injury  Mixed CP - Mostly a combination of spastic & dyskinetic or ataxic forms. Used for children who don’t meet strict criteria for other forms.

Summary

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