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