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Embryology of the Nervous System

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Embryology of the Nervous System Neuroembryology and Brain Malformations Myriam Srour MDCM, FRCP(C) Pediatric Neurology Academic Half Day January 16th, 2013 Embryology ► 3% neonates have major systemic or CNS malformations ► 75% fetal deaths & 40% deaths within first year of life are associated with CNS malformations ► Most common CNS malformation involves neural tube closure and this happens by 28 days gestation, often before the woman knows she is pregnant Major Stages of Nervous System formation Primary neurulation 3-4 weeks Prosencephalic development 2-3 months Neuronal proliferation 3-4 months Neural migration 3-5 months Organization 5 mo – years Myelination birth-years NEURULATION Neurulation ►Definition: . Formation of the neural tube which will give rise to brain and spinal cord ►The notochord (d. 16-21) . Defines longitudinal axis of embryo . Induces overlying ectoderm to form neural plate ►Occurs in dorsal aspect of embryo Neurulation Neurulation ► Neuropores: openings at either end ► Cranial neuropore closes before caudal . Anterior closes at ~ d 24 . Posterior closes at ~ d 26 at lumbosacral level ► Caudal cord formed from a different process: secondary neurulation Neurulation ►Neural tube brain and spinal cord ►Neural crest cells peripheral nervous system (sensory ganglion cells, schwann cells)+ other ( pia, autonomic cells, melanocytes) Neurulation Alar ►Neural tube has 3 layers: plate ►ependymal ►mantle ►marginal ► Alar plate: (dorsal) sensory and coordinating neurons ► Basal plate: (ventral) motor control neurons Abnormalities in neurulation ►Craniorachischisis totalis ►Anencephaly ►Myeloschisis ►Encephalocele ►Myelomeningocele, Arnold-Chiari malformation Failure of anterior neural tube closure: Anencephaly Failure of posterior neural tube closure: Spina Bifida A- Normal B- Spina bifida occulta: Vertebra defect. May see small tufts dark hair overlying defect C- Meningocele D- Myelomeningocele Meningocele ►Sac contains meninges, NO nervous tissue Prosencephalic Development Prosencephalic development and Early brain structures (2-3 months) ► Following closure of anterior neuropore, there is rapid growth of neural tissue in the cranial region ► This occurs along with formation of the face Severe disorders of formation of brain development at this time result in facial anomalies ► Inductive role of Sonic Hedgehog and Retinoic acid ► Tissue in cranial region of neural tube enlarges to form 3 primary brain vesicles (week 4) ► Prosencephalon (Forebain) ► Mesencephalon (Midbrain) ► Rhombencephalon (Hindbrain) ► Then 5 Secondary Vesicles (week 5) ► Prosencephalon . Telencephalon (2 hemisheres;) Diencephalon (optic n, thalamus, hypothalamus;) ► Mesencephalon (midbrain) ► Rhombencephalon . Metencephalon (pons, cerebellum) . Myelencephalon (medulla oblongata) Prosencephalic development and Early brain structures ► Two flexures develop in the neural tube: . Cervical flexure – at rhonbencephalon/spinal cord junction . Cephalic flexure – at level of mesencephalon Disorders of Prosencephalic development ► Prosencephalic formation . Aprosencephaly . Atelencephaly ► Prosencephalic Cleavage . Holoprosencephaly . Holotelencephaly ► Midline Prosencephalic Development . Agenesis of CC . Agenesis of septum pelucidum . Septo-Optic dysplasia . Septo-optic-hypothalamic dysplasia Holoprosencephaly ►Failure of cleavage of telencephalon 18 weeks fetus 13 weeks Holoprosencephaly Holoprosencephaly (HPE) ► Continuity of the right and left hemispheres across all or part of the midline ► Associated with malformation of face and eyes ► 3 subtypes based on continuity of the hemispheres . Alobar . semilobar . lobar ► Alobar . Complete failure of division of forebrain . Absent interhemispheric fissure . Single horseshoe-shaped ventricle . Undivided thalamus and basal ganglia ► Semilobar . Presence of posterior interhemispheric fissure . Continuity of L and R frontal and parietal lobes . Continuity of thalamus and basal ganglia ► Lobar . Most of hemispheres separate . Continuity of posterior frontal region, sometimes thalamus and basal ganglia . Continuity of the rostral corpus callosum, giving an appearance on MRI of absence of the anterior CC Alobar Semi-lobar Lobar Holoprosencephaly ► Facial anomalies: . Hypotelorism . Cyclopsia . Cebocephaly . Midline cleft lip and palate . Single central incisor ► “face predicts the brain” in 70-90% ► Severe handicap and death within the first months of life in alobar HPE ► Semilobar HPE: also severe handicap ► Lobar HPE: . moderate to severe MR. Typically learn to walk and limited language . “forme fruste” normal intelligence or mild to moderate MR Holoprosencephaly ► All patients with HPE should have an endocrine evaluation as associated with pituitary defects ► In presence of hydrocephalus, prognosis should be differed until shunt has been placed because of difficulty with identifying between alobar, semi and lobar ► Associated with . maternal diabetes, retinoic acid exposure, CMV, and rubella . Chromosmal abnormalities (trisomies 13 and 18) Holoprosencephaly ► Genetics: . Mostly sporadic . Familial cases ► AD with incomplete penetrance and variable expressivity ► Also AR and X-linked forms . Molecular basis understood in 10% of patients ► Most common HPE genes: SHH, ZIC2, SIX3, TGIF ► Expressed inventral portion of rostral neural tube ► Role in ventral neural tube induction . Empiric recurrence to future sibs in sporadic HPE is 6% De Morsier syndrome Septo-optic dysplasia (de Morsier syndome) ► Characterized by 1. Absence of septum pellucidum 2. optic nerve hypoplasia 3. hypothalamic dysfunction ► For diagnosis, need 2 of the above ► Whenever one of triad discovered, look for others ► Two distinct syndromes: 1. Isolated SOD 1. Usually present with pituitary insufficiency 2. Usually mild development delay, or normal 3. Seizures uncommon 2. SOD associated with schizencephaly 1. Usually present with visual loss and neurologic abnormalities 2. Dev delay, MR, hemi or quadriplegia ► Equal frequency ► Sporadic Neuronal Proliferation Neuronal Proliferation ►All neurons and glia and derived from the ventricular zones ►“To-and-fro” migration . Cells from periphery of ventricular zone migrate to luminal surface and divide . The two daughter cells then migrate back to the periphery of the ventricular zone “to and fro” migration and division Disorders of Neuronal Proliferation ►Microcephaly . Micrencephaly vera ►Macrocephaly . Isolated macrocephaly . Hemimegalencephaly Hemimegalencephaly Hemimegalencephaly Hemimegalencephaly ► Enlargement and dysplasia of one cerebral hemisphere ► Associated with other anatomic abnormalities: . Thick cortex . Abnormal signal of white matter on T2 . Heterotopias . Enlarged ventricles ► Clinical presentation: . Variable developmental delay and MR . Unilateral neurologic signs . Seizures severe and intractable ► Partial with 2y generalization ► Isolated vs. associated with neurocutaneous disorders: . Klippel-Trenaunay, epidermal nevus syndrome, hypomelanosis of Ito, Proteus syndrome… Hemimegalencephaly ► Management . Aggressive management of epilepsy . Should consider surgical options ► Hemispherectomy ► Genetics . Somatic mosaicism with mutations in AKT gene (mTOR pathway) . No examples of familial recurrences . Low recurrence risk in siblings Primary microcephaly (microcephaly vera) Affected 13 year old Normal 11 year old Primary microcephaly (microcephaly vera) ► Defined as congenital microcephaly (HC < 2 SD) and otherwise normal brain structure . Usually HC <4SD ► Clinical course and prognosis: Variable . Some children only have moderate developmental delay and moderate to severe MR . Others profound MR and spastic quadriparesis and epilepsy ► Genetics . AR . X-linked Neuronal Migration Migration to cerebral cortex and deep nuclei ►Neuron migrate by following radial glia guides ►Early-arriving neurons take deep positions in cortex, and later arriving neurons take superficial positions . “inside-out” pattern Migrating neuron Glial fiber “inside-out” migration pattern Identified key proteins ► Filamin-1 gene encodes actin-cross-linking phosphoprotein ► Key function in growth-cone extension of the migrating neuron along radial glial cells • LIS1 has a role in stabilizing microtubules • DCX encodes a microtubules-associate protein expressed in migrating neuroblasts • TUBA1A (tubulin A1A) assemble to form microtubules essentual for neuronal migration, neurite outgrowth… ► Termination of neuronal migration linked to reelin protein and mDab1 protein Disorders of Neuronal Migration (Volpe) ►Schizencephaly ►Lissencephaly-Pachygyria ►Polymicrogyria ►Heterotopia ►Focal dysgenesis Lissencephaly smooth brain Brain of 18 week fetus Lissencephaly (LIS) or agyria- pachygyria ► Lissencephaly= smooth brain ► Should be considered as an agyria-pachygyria spectrum . Subcortical band heterotopia/double cortex part of same spectrum ► Two types: . Classic lissencephaly (type 1) . Cobblestone lissencephaly (type 2) Classic Lissencephaly Lissencephaly (LIS) or agyria- pachygyria ► Most have normal facial appearance . Some with cranioafacial abnormalities . Miller-Dieker syndrome ► Prominent forehead, bitemporal hallowing ► Short nose with upturned nares, prominent upper lip and small jaw ► Clinical Course of Lissencephaly . Intractable seizures ► Infantile spasms early on ► Multiple seizure types . Profound MR . Early hypotonia then spastic quadriparesis . Gastrostomy . Repeated aspiration pneumonia Miller-Dieker syndrome Genetics of LIS-SBH ► 6 genes account for 80% ► LIS1, DCX, ARX, RELN, TUBA1A, VLDLR ► Isolated Lissencephaly: LIS1,
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