Neuroembryology

astrocytes

Provide structural and metabolic support for neurons.

disordered (over-) proliferation

hemimegalencephaly -- balloon neurons -- disorder migration -- contralateral hemisphere is affected assicated with: - Tuberous sclerosis, NF1, linear sebaceous nevus syndrome and other neurocutaneous disorders - megalencephaly-capillary malformation syndromes (PIK3CA) - isolated

plica choroidae

indents roof plate (10 wks) - anterior: choroid plexus - posterior: blake's pouch -- becomes permeable -> cisterna magna -- degenerates -> foramen of magendie (8-12-26 wks ga) foramina of Luschka form around 14-17 (26) WKS GESTATION

thalamus

the brain's sensory switchboard, located on top of the brainstem; it directs messages to the sensory receiving areas in the cortex and transmits replies to the cerebellum and medulla

sympathetic nervous system

the division of the autonomic nervous system that arouses the body, mobilizing its energy in stressful situations

parasympathetic nervous system

the division of the autonomic nervous system that calms the body, conserving its energy

corpus callosum

the large band of neural fibers connecting the two brain hemispheres and carrying messages between them

neurolemma

the outermost nucleated cytoplasmic layer of Schwann cells that surrounds the axon of the neuron. It forms the outermost layer of the nerve fiber in the peripheral nervous system.

peripheral nervous system

the sensory and motor neurons that connect the central nervous system to the rest of the body

dura mater

thick, outermost layer of the meninges surrounding and protecting the brain and spinal cord

pia mater

thin, delicate inner membrane of the meninges

meninges

three protective membranes that surround the brain and spinal cord

heterotopia

tissue occurring in an abnormal anatomical position hindbrain medulla, pons and cerebellum periventricular nodular heterotopia - genetically heterogeneous - FLNA mutations -- x-linked -- pleiotrophic and variable effects

chiari I

tonsilar hernia syringomyelia (cavitary lesion in CSF, cervical, causes capelike distribution pain/T loss of UE bc crossing tracks of spinothalamic tract affected)

cerebral commissures

tracts that connect the left and right cerebral hemispheres

cobblestone lissencephaly

type II lissencephaly

findings of rhombencephalosynapsis

usually discovered on fetal imaging due to hydrocephalus (25-90%) at 22 wks associated findings: - dentate and MCP fusion - collicular fusion - aqueductal abnormalities (75%) - thalamic fusion - callosal agenesis/other callosal anomalies - lobar holoprosencephaly - NTDS - DWM, hippocampal and cortical malformations

rhombencephalosynapsis clinical outcome

variable - normal cognition possible - characteristic facial phenotype -- hypertelerism, upturned nose, LS/PR ears, small jaw typical neurodevelopmental features: - ID - abnormal eye movements - behavioral phenotype - characteristic weaving/bobbing head movement - epilepsy

dandy walker malformation

vermian aplasia/hypoplasia - cystic dilation of 4th ventricle - CCW of the vermis - elevation of the tentorium/transverse sinuses/torcula - isolated or syndromic - may be seen in first tri - differentiate from blake's pouch cyst, mega cisterna magna, arachnoid cyst, or other causes of vermian dysgenesis

Neurulation

week 3 - development of the nervous system - induced by notochord - neural plate ectoderm becomes CNS and other structures - invagination begins on d. 18 - neural tube submerges beneath surface ectoderm

mechanism of rhombencephalosynapsis

- critical period: d. 28-42 different mechanisms: - vermian agenesis with cerebellar hemisphere fusion - normally unpaired cerebellar primordia with lack of vermian differentiation - abnormal unpaired cerebellar primordium - isthmus hypothesis frequence of 0.13% derived from consecutive MRI series

Rhombencephalosynapsis

- aplasia of vermis and fusion of cerebellar hemispheres - clinical severity likely proportional to degree of vermian aplasia - may have relative preservation of vermian lobes (nodules -> anterior-> posterior)

failure of prosencephalon development

- aprosencephaly/atalencephaly - holoprosencephaly - agenesis of corpus callosum - absent septum pellucidum

nerves in the spinal cord formation

- axons grow OUT from ventral motor neurons - axons grow INTO dorsal horns from sensory ganglia - neural crest cells do lots of things

clinical presentation of joubert syndrome

- clinical presentation includes GDD, oculomotor abnormalities, hypotonia, ataxia, abnormal respiratory drive - other recognizable facies - some genotype-phenotype correlation with non-neuronal phenotype --- polydactyly --- hepatic fibrosis --- nephonopthisis-tubulointerstitial nephritis with cysts --- retinal dystrophy DDx: COACH syndrome, MECKEL syndrome, other cliopathies

what does the spinal cord form?

- conus medullaris - cauda equina - filum terminali errors: result in tethered cord, other caudal spinal anomalies

prosencephalic development

- dorsal and ventral organizers - establishes individual cell population fates - recurring theme over length and depth of CNS

septum pellucidum

-thin membrane that separates lateral ventricles - development from medial inferior commissural plate - follows callosal formation but complete (albeit unfused) by 20 wks - fusion occurs in third trimester and postnatally

post-migrational development

22 weeks gestational age to two years of age - abnormalities result in gyral malformations, cortical disorganization defects include: - polymicrogyria - schizencephaly

neuronal migration

3rd-5th month of gestation (weeks 9-23)

mindbrain/hindbrain development

4-10 wks of gestation - pontine flexure differentiates metencephalon from myelencephalon - flexion creates thinned rhomboidal roof plate - floor plate> fourth ventricular floor

aqueductal stenosis

the abnormal narrowing of the cerebral aqueduct - improper folding of the neural tube - forking (two ependymal - lined channels) - glial overgrowth - hemorrhage - tumor - sequence of secondary injury due to forces, collapse - causes ventriculomegaly

moebius syndrome

Cranial nerve V and XII sometimes VII) problems - congenital bilateral facies paralysis with uni or bilateral abducens palsy - variable - association with Klippel-Fiel, Poland anomaly - genetic and vascualr hypotheses - PLXND1 mutation? - myopathic form due to MYMK gene

oligodendrocytes

Form myelin sheath in CNS

brainstem development at medullary level

GSE: XII motor SVE: Pharyngeal muscles GVE: autonmic efferent GVA: visceral sensory SVA: taste GSA: cranial cutaneous SSA: hearing/vestibular

ventricular zone

Hollow core of developing embryo, source of cells of nervous system

CNS membranes

Meninges - condensation of mesenchyme surrounding NT - dura mater - mesoderm - leptomeninges-neural crest-derived - arachnoid - pia mater

holoprosencephaly

Midline developmental anomaly, three forms (alobar, semilobar, lobar).

rhombencephalosynapsis associated syndromes

- VACTERL - Gomez-Lopez-Hernandez syndrome n.b. always look for rhombencephalosynapsis in cases of aqueductal stenosis without a defined cause

neuronal proliferation disorders

- neurogenesis mostly b/w wks 4-20(25) - decreased proliferation: microcephaly -- primary: ---usually simplified gyral patterns (vs. microlissencephaly) ---- e.g. ASPM, MCPH1 vs. NDE, TUBA1A --- zika virus, CMV, teratogens -- secondary: ---- post-proliferative (often postnatal injury) ---- genetic causes

neuronal proliferation

- neurogenesis mostly between 4-20 (25) - residual neurogenesis in VZ (Striatum) and HC (Dentate gyrus)

cerebellar agenesis

- rare - unilateral or bilateral - bilateral associated with pancreated dysgenisis (neonatal DM) - PTF1A - disruption more common than malformation - prognosis in unilateral likely dependent on midline involvement (vermian) - motor and often complex neuropbehavioral phenotype

Neural tube defects

- rashcisis - spina bifida occulta - spina bifida spectrum - encephalocele

prosencephalon development

- ventral induction (notochord, prechordal mesoderm, neuroepithelium) - prosencephalon forms just after anterior neuropore closure (end of week 4) - cleavage (evagination) mostly in wks 5-6 -- starts d. 35 -- neuroepithelium surrounding lamina terminalis cleaves and proliferates - optic evaginations d. 22 - olfactory bulbs visible d. 42 - midline development (commisures, chiasm, and hypothalamus)

cortical organization

-primary sensory areas -primary motor areas -association areas -limbic areas

diencephalon

-thalamus -hypothalamus (includes mammillary bodies) -Epithalamus (pineal gland, habenular and posterior comissure) -posterior pituitary gland (neurohypophysis)

Stages of CNS development

1. Neurulation 2. prosencephalic development 3. Neuronal proliferation 4. Neuronal migration 5. Postmigrational development 6. Myelination

neuronal maturation disorders

1. tuberous sclerosis 2. focal cortical dysplasia - FCD1 - migrational abnormalities, no balloon cells - FCD2a/b - abnormal cortical lamina and enlarged cells - FCD3a-d: other asscociated pathology - some FCDs, hemimegalencephaly cases associated with mutations in DEPDC5 or NPRL2/NPRL3 - GATOR1 complex disrutption and mTOR affects

Causes of aqueductal stenosis

20% isolated - hydrocephalus usually apparent by 18-20 wks - L1CAM mutations -- adducted thumbs may be present in first tri -- widespread neuronal involvement -- HSAS, MASA

Cerebellum

A large structure of the hindbrain that controls fine motor skills.

cerebellum

A large structure of the hindbrain that controls fine motor skills.

infundibulum

A stalk that attaches the pituitary gland to the hypothalamus.

microglia

Act as phagocytes, eating damaged cells and bacteria, act as the brains immune system

schizencephaly

Abnormal neuronal migration resulting in gray matter-lined clefts that invaginate brain. Extend from ventricular ependymal surface to pial cortical surface. Polymicrogyric clefts do not extend to ventricle. Open lip or closed lip (apposed walls) forms.

spinal cord formation

Alar (dorsal) and basal (ventral) regions - divided by sulcus limitans - ventricular zone -- neuroepithelial cells - intermediate zone - marginal zone

walker warburg syndrome

Autosomal Recessive: HARDE --> Hydrocephalus, Agyria, Retinal dysplasia, encephalocele

posterior fossa malformations

brainstem clefting athabaskan brainstem dysgenesis vermian-cerebellar hypoplasia brainstem disconnection syndrome

brainstem anatomy

gray matter surrounded by white matter

The nervous system

Central nervous system peripheral nervous system autonomic nervous system

Absent cavum septum pellucid

If not seen suspect agenesis of corpus callosum

caudate nucleus

One of the basal ganglia; it has a long extension or tail.

sulcation

The development of or resulting formations of sulci in a brain cortex.

Arnold-Chiari malformation

Type I: herniation of cerebellar tonsils, asymptomatic/headache Type II: herniation of cerebellum and medulla, often causes hydrocephalus.

polymicrogyria

a condition associated with errors in cortical organization in which children have too many folds (gyri) in the cerebral hemispheres

iniencephaly

a rare neural tube defect in which the brain tissue protrudes through a fissure in the occiput, so that the brain and the spinal cord occupy a single cavity

septo-optic dysplasia

absent septum pellucidum (>60%) pituitary dysfunction (>60%) optic nerve hypoplasia (25%) need 2/3 for dx genes: - hesx1, sox2, others - 1-2% positive genetic testing

filum terminale

anchors spinal cord to coccyx

adenohypophysis

anterior lobe of the pituitary gland

pituitary formation

anterior: ectoderm posterior: neuroectoderm d. 36 - hypophyseal diverticulum d. 56 - loses connection with oral cavity

Agenesis of corpus callosum

birth defect in which the corpus callosum is not fully formed or is only partially formed

central nervous system

brain and spinal cord

cerebellar development

cerebellum forms from dorsomedial alar area (rhombic lip) - wks 5-7: cerebellar primordia form at rhombic lips and develop in a rostral-caudal fashion, continues through wk 15 - cerebellar hemispheres reach medial extent in wk 9 - vermis completes first - hemisphere differentiation through age 2 - alternative hypothesis exist - neurons in alar and basal plates coalesce to form brainstem nuclear masses by d. 28

telencephalon

cerebrum

Joubert syndrome

ciliopathy - genetically heterogenous - vermian agenesis (complete or partial) - specific brainstem malformation (molar tooth sign) - other CNS anomalies - DT1 may show lack of decussation of SCPs and corticospinal tract

ganglia

clusters of cell bodies in the PNS

cauda equina

collection of spinal nerves below the end of the spinal cord

Hydranencephaly

congenital absence of the cerebral hemispheres caused by occlusion of the carotid arteries; midbrain structures are present, and fluid replaces cerebral tissue

spina bifida

congenital defects in the lumbar spinal column caused by imperfect union of vertebral parts

commissures

connect corresponding gray areas of the two hemispheres - lamina terminalis 10 weeks - commissures (clockwise from bottom) - optic chiasm - anterior commissure - hippocampal/formix commissure - corpus collasum - habenular commissure - posterior commissure

posterior fossa

contains the cerebellum and brainstem

timing of neural tube defects

d. 20-22: cranioraschisis totalis d. 24: anencephaly, myeloschisis/iniencephaly d. 26: myelomeningocele incidence: 1/2500-1/500 folic acid (0.4/4mg anticonvulsants: VPA, CBZ Thalidomide Chr anomalies Multifactorial/polygenic (>80 genes)

anencephaly

defect in closure of the cephalic portion of the neural tube that results in incomplete development of the brain and bones of the skull; the most drastic neural tube defect usually results in a stillbirth

pontine tegmental cap dysplasia

defective neuronal migration or axonal guidance typical radiographic findings: - tegmental cap - flattened belly of pons - hypoplastic/absence middle cerebellar peduncles - absent inferior olivary prominence - molar-tooth like sign clinical features: - GDD - cranial nerve deficitiency - ataxia - epilepsy

abnormal posterior fossa development

different classification schemes - developmental - genetic - radiographic

basal plate

differentiates into motor neurons

alar plate

differentiates into sensory neurons

spinal meninges

dura mater, arachnoid mater, pia mater

lhermitte duclos disease

dysplastic cerebellar gangliocytoma - hamartoma - associated with Cowden syndrome (PTEN) - clinical presentation related to ICP

conus medullaris

end of spinal cord

marginal zone

faces the overlying pia

prosencephalon

forebrain

Prosencephalon

forebrain - made of telencephalon (cerebral hemispheres) and - diencephalon (thalamus, hypothalamus, pituitary gland, epithalamus)

intermediate zone

gray matter between the dorsal and ventral horns

subventricular zone

lining of neural stem cells surrounding the ventricles in adults

neuronal migration disorders

lissencephaly heterotopia

rhombencephalon

made of: metencephalon (pons) myelencephalon (medulla)

HPE (Holoprosencephaly) causes

maternal diabetes carries 1% risk chr anomalies associated in 25-50% of cases - T13, T18 and others Smith-Lemli-Opitz syndrome specific genes: - SHH, SIX3, ZIC2, TGIF, GLI2, and others

myelencephalon

medulla oblongata

ependyma

membrane lining the central canal of the spinal cord and the ventricles of the brain

lamina terminalis

membrane where the third ventricle ends anteriorly

mesencephalon

midbrain

brain development

midbrain and cervical flexures precede pontine flexure - spinal organization gives way as one moves rostrally through brainstem

arachnoid membrane

middle layer of the three membranes (meninges) that surround the brain and spinal cord

Neural crest cells

neural crest starts as ectoderm - cells undergo mesenchymal transformation - migrate to form various structures

Primary neurulation

neural tube closes in sequential fashion - multiple sites of closure - closure complete with rostral (d.24-25) and caudal (d. 26-28) neuropore closure

brain developement

neuroepithelium mesenchyme

myelination

occurs in a specific sequence - CNS myelination produced by oligodendrocytes - one oligodendrocyte myelinates several central axons

normal posterior fossa development

occurs in response to ventral induction

cranial nerves

olfactory - sense of smell optic - visual acuity oculomotor - extraocular movement of eye trochlear - pupil constriction and dilation, upward and downward movement of eyeballs trigeminal - sensory nerve to skin of face, motor nerve to jaw muscles abducens - lateral movement of eyeballs facial - facial expressions auditory - hearing glossopharyngeal - taste, ability to swallow vagus - sensation of pharynx, movement of vocal cords spinal accessory - movement of head and shoulders hypoglossal - position of tongue

chiari malformation

part of cerbellum herniates down through foramen magnum - heterogenous three types sharing tonsilar ectopia - chiari 1: developmental anoamly of mesoderm -- over 50% with syrinx - acquired chiari 1 due to intracranial pressure abnormalities - chiari II, III arise from NTDs

dandy walker caused by

plica choroidae fail to subsume the anterior membraneous area of the rhomencephalic roof - CSF forces expansion of this into a cystic structure - formina of magendie and luschka are absent - vermis fails to form to varying degrees

metencephalon

pons and cerebellum

neurohypophysis

posterior lobe of the pituitary gland

choroid plexus

produces CSF

meningomyelocele

protrusion of the meninges and spinal cord

Spinal cord formation - secondary neurulation

remnant of primitive strick area - cluster of neuroectodermal cells form (caudal cell mass) - central canal w/in this mass becomes continuous with more cephalic NT canal - d. 28-32 followed by 3 weeks of canalization then regressive differentiation

aprosencephaly, atelencephaly

rudimentary tissue rostral to brainstem

sulcus limitans

separates alar and basal plates

lissencephaly

smooth brain Type 1: spectrum and gradient of smooth four-layer cortex - LIS1, tubullin associated genes, ARX, DCX Type 2: cobblestone pattern, dystroglycanopathies - muscle-eye-brain disorders

chiari II malformation

• cerebellar vermis and medulla herniation through foramen magnum • hydrocephalus d/t aqueductal stenosis