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Home , Anencephaly, Flexure (embryology), Lissencephaly, Schizencephaly, Ventricular zone

Neuroembryology and Malformations

Myriam Srour MDCM, FRCP(C) Pediatric Academic Half Day January 16th, 2013

► 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 closure and this happens by 28 days gestation, often before the woman knows she is pregnant Major Stages of formation

Primary 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 ►The (d. 16-21) . Defines longitudinal axis of . Induces overlying ectoderm to form

►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 ► 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 ► Basal plate: (ventral) motor control neurons

Abnormalities in neurulation

►Craniorachischisis totalis ► ►Myeloschisis ► ►Myelomeningocele, Arnold- Failure of anterior neural tube closure: Anencephaly Failure of posterior neural tube closure:

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 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 () ► Rhombencephalon ()

► Then 5 Secondary Vesicles (week 5) ► Prosencephalon . Telencephalon (2 hemisheres;) Diencephalon (optic n, thalamus, hypothalamus;) ► Mesencephalon (midbrain) ► Rhombencephalon . (, ) . ()

Prosencephalic development and Early brain structures

► Two flexures develop in the neural tube: . Cervical – at rhonbencephalon/spinal cord junction . Cephalic flexure – at level of mesencephalon

Disorders of Prosencephalic development ► Prosencephalic formation . Aprosencephaly . Atelencephaly ► Prosencephalic Cleavage . . 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 . 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 , 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

► : . 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 Septo-optic dysplasia (de Morsier syndome)

► Characterized by 1. Absence of septum pellucidum 2. 3. hypothalamic dysfunction ► For diagnosis, need 2 of the above ► Whenever one of triad discovered, look for others ► Two distinct : 1. Isolated SOD 1. Usually present with pituitary insufficiency 2. Usually mild development delay, or normal 3. uncommon 2. SOD associated with 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

► . Micrencephaly vera ►Macrocephaly . Isolated macrocephaly . Hemimegalencephaly

Hemimegalencephaly Hemimegalencephaly

► Enlargement and dysplasia of one cerebral hemisphere ► Associated with other anatomic abnormalities: . Thick cortex . Abnormal signal of 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 . 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 and deep nuclei

► 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 • TUBA1A (tubulin A1A) assemble to form microtubules essentual for neuronal migration, neurite outgrowth… ► Termination of neuronal migration linked to protein and mDab1 protein Disorders of Neuronal Migration (Volpe)

►Schizencephaly ►- ► ►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 types . Profound MR . Early 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, DCX and TUBA1A ► Can be associated with cerebellar hypoplasia (esp. TUBA1A) ► LIS1: posterior> anterior gradient ► DCX: anterior>posterior gradient ► All patients with Miller-Dieker have large deletions of 17p13.3, which includes LIS1 . 70% cytogenetically visible ► In patients with classical LIS but no other anomalies: . 40% microdeletions of 17p13.3 . 24% intragenic mutations of LIS1 . 12% intragenic mutation of DCX Posterior>>Anterior Mutation in LIS1

Anterior>>Posterior Mutation in DCX

►RELN: Lissencephaly with cerebellar hypoplasia

►ARX: X-linked lissencephaly with abnormal genitalia Subcortical band heterotopia Subcortical Band Heterotopia

►Course and prognosis . Variable . Severe MR to normal ►Most mild to moderate MR . Variable seizure frequency and severity . Neurologic outcome depends in part on thickness of the heterotopic band ►Genetics . Mutations in DCX in 100% of girls with family history, 80% sporadic females and 25% males Cobblestone lissencephaly

► Cortex is smooth ► Distinction from classic lissencephaly based on clinical association with eye abnormalities, muscle and progressive hydrocephalus ► “cobblestone” refers to pathologic examination ► Cells pass their stopping point and erupt over the surface of the cortex into subarachnoid space . Walker-Warburg . Muscle-eye brain . Fukuyama Walker Warburg syndrome Periventricular heterotopias

+ corpus callosum agenesis

+ bilateral periventricular heterotopia Periventricular Heterotopia ► Nodular or diffuse ► Contiguous bilateral periventricular nodular heterotopia (BPNH) . FLNA: Filamin A . Large actin-binding phosphoprotein that stablizes the cytoskeleton . Failure of the neuron to attach to radial glia . X-linked . Explain almost all females with + family history and 25% of sporadic females . Explain approx 7% males . Other associated abnormalities: coagulopathy and cardiovascular abnormalities ► Most patients with nodular heterotopias are of normal intelligence . Subcortical heterotopias tend to have lower IQ ► Seizures ► PNH with severe congenital microcephaly: ARGEF2 Disorders associated with Neuronal Heterotopias

► X-linked disorders- BPNH and X-linked double cortex ► Metabolic disorders- neonatal ALD, glutaric aciduria type II, non-ketotic hyperglycinemia, Leigh disease, Menkes, GM2- gangliosidosis, Hurler disease ► ► Neurocutaneous syndromes- NF, TS, incontinentia pigmenti, Ito’s hypomelanosis, linear nevus sebaceus ► Multiple congenital anomaly syndromes- Smith-Lemli-Opitz, de Lange, Potter ► Chromosomal syndromes- trisomy 18, trisomy 13, deletion 4p ► Fetal toxic exposures- carbon monoxide, isotretinoic acid, ethanol, organic mercurial Schizencephaly Schizencephaly-Polymicrogyria complex

► Disorder of migration . “Malformations due to abnormal cortical organization (including late neuronal migration)”, under Barkovich classification ► Deep clefts lined by polymicrogyria from the pial surface to the ependymal surface of the lateral ventricle ► Open-lip and closed-lip ► Unilateral in 63% ► There is NO reported case of schizencephaly WITHOUT polymicrogyria . lining clefts help differentiate from porencephalic cysts ► Other causes: . TORCH infections, especially CMV . Early vascular event Schizencephaly

Clinical . Developmental delay and MR ► In 2 series, cognitive disturbances only in 24% of unilateral lesions . Spastic hemi or quadriparesis . Epilepsy . Distribution and severity related to size and location of clefts . Open-lipped and bilateral clefts are more severe

Schizencephaly

Genetics . Sporadic . Some familial forms . EMX2 homeobox-containing gene ► Expressed in neuroblasts of the ventricular zone . Disorder of segmentation vs migration? Polymicrogyria

► Cerebral cortex with multiple excessive small convolutions ► Cortex appears thickened – but microscopically, is not truly thickened ► May be misdiagnosed as pachygyria ► Classified based on distribution and bilaterality . Bilateral perisylvian –> pseudobulbar, speech delay, ID . Unilateral perisylvian . Generalized . Frontal . Parasagital parieto-occipital Bilateral perisylvian dysplasia Unilateral perisylvian syndrome Focal cortical dysplasias (FCD)

►Key feature is presence of abnormal cortical lamination ►Classified based on absence (type I) or presence (type II) of balloon cells ►FCDI: may not be detectable on MRI ►FCDII: increased cortical thickness, blurring of grey-white junction, abnormal sulcatiom, high T2 or FLAIR signal at base of the lesion Organization Organization

►Lamination: alignment, orientation and layering of cortical neurons ►Neurite outgrowth: dendritic and axonal ramification ►Synaptogenesis ► death and selective elimination of neural processes and synapses Disorders of Organization

►Primary disturbance . Mental Retardation . Down Syndrome . Angelman syndrome . Infantile Autism ►Potential disturbance . Premature . Nutrition . Other perinatal and postnatal insults

2012 Developmental and genetic classification of malformations of cortical debelopment- Barkovich et al, Brain 2012 ► Group 1: due to abnormal neuronal and glial proliferation or apoptosis . Microcephalies . Megalencephalies . Cortical dysgeneses with abnormal cell proliferation ► Group 2: due to abnormal neuronal migration . Heterotopias . Lissencephaly . Subcortical heterotopias . Cobblestone malformations ► Group 3: due to abnormal post-migrational development . Polymicrogyria and schizencephaly . Focal cortical dysplasias Questions? ►http://laxmi.nuc.ucla.edu:8888/Teachers/pp helps//Published_Trays/PS107-Fall98- Lec2/Pindex.html