1. forebrain (prosencephalon)
    Prosencephalon --> telencephalon (cerebral hemispheres) and diencephalon

    • 1) Telencephalon--> cerebral cortex and basal ganglia
    • 2) Diencephalon --> thalamus, hypothalamus,optic nerves, and pineal gland
  2. The mesencephalon forms the ...........

    Image Upload 1
  3. The rhombencephalon forms ........
    the metencephalon (pons and granule cells of cerebellum) and myelencephalon (medulla)
  4. Hox genes
    Hox genes are a group of related genes that determine the basic structure and orientation of an organism.

    Hox genes are critical for the proper placement of segment structures of animals during early embryonic development (e.g. legs, antennae, and wings in fruit flies or the different vertebrate ribs in humans).

    Activation of correct Hox gene and segmental expression require retinoic acid
  5. Anencephaly
    • 1) Due to failure of anterior neuropore closure
    • 2) Defective notochord induction of the neuroectoderm
    • 3) More common in females
    • 4) Occasionally familial; certain populations may be athigher risk (France, Wales, Ireland)
    • 5) Replacement of most of the intracranial contents byarea cerebrovasculosa (vascular mass of small bloodvessels admixed with variable amounts of mature andimmature neuronal and glial cells)
  6. Meningomyelocele (spina bifida cystica)
    • 1) Herniation of spinal cord and meninges through avertebral defect
    • 2) Is often seen in Chiari type II malformation and is associated with hydrocephalus
  7. Spina bifida occulta
    • 1) A defect in one or more vertebral arches
    • 2) Spinal cord and meninges are normal
  8. Cranium bifidum
    • Defective fusion of cranial bones
    • 2) Most common in the occipital
    • 3) Associated with herniated cerebral tissue

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  9. Encephalocele
    • Extension of intracranial structures through the cranial vault from a defect in fusion of cranial bones
    • a) Meningocele: herniated meninges through skulldefect
    • b) Meningoencephalocele: herniated brain tissue and meninges through skull defect
    • c) Meningohydrocephalocele: herniated brain tissue, meninges, and ventricles through skull defect

    2) Most common in the occipital

    b) Both intracranial and herniated contents may show signs of migration abnormalities such as heterotopias

    Occipital encephalocele often contains vascular structures and is associated with Meckel-Gruber.
  10. Meckel-Gruber syndrome
    (autosomal recessive condition associated with occipital encephalocele, polycystic kidneys, liver fibrosis, cleft palate, and polydactylyImage Upload 3
  11. Chiari type I malformation may be associated with:
    • a) Hydrocephalus
    • b) Intermittent increase in intracranial pressure
    • c) Syringomyelia, syringobulbia
    • d) Klippel-Feil syndrome
    • e) Compression of brainstem structures and some rostral extension of the medulla

    1) Headaches, especially brought on by neck extension or the Valsalva maneuver (most common presenting symptom),

    2) Various cerebellar symptoms, lower cranial nerve dysfunction, diplopia and down-beat nystagmus,
  12. Chairi type II malformation associated with?
    • - Myelomeningocele
    • - Hydrocephalus
    • - Colpocephaly of the lateral ventricles (enlargement of occipital horns)
    • - Elongated fourth ventricle
    • - Interdigitating gyri (associated with hypoplasticfalx cerebri)
    • - Skull abnormalitie (lacunar skull)
    • - Tectal “beaking” of the midbrain due to pressurefrom herniated cerebellum

    Image Upload 4

    Treatment: surgical decompression and cerebrospinal fluid (CSF) shunt for hydrocephalus
  13. Chiari type III
    • Image Upload 5
    • low occipital/highcervical encephalocele with herniation of the cerebellum,occipital lobes, pons, medulla

    incompatible with life
  14. Chiari type IV malformation
    Likely a variant of Dandy-Walker malformation -- Hypoplastic brainstem and cerebellum
  15. Klippel-Feil syndrome
    characterized by the congenital fusion of any 2 of the 7 cervical vertebrae

    Image Upload 6
  16. Holoprosencephaly
    prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres. Hox genes, which guide placement of embryonic structures, fail to activate along the midline of the head.

    • Associated with midline defects and craniofacial anomalies
    • 1) Callosal agenesis
    • 2) Olfactory agenesis and arhinencephaly
    • 3) Craniofacial anomalies: cyclops (single eye), hypotelorism, and midline facial defects such as displaced nose.
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    Image Upload 8
  17. Septo-optic dysplasiaa.
    • Absence septum pellucidum + hypoplasia of the
    • optic nerve (sometimes involving theoptic chiasm) and pituitary infundibulumb.

    When you see septum pellucidum is gone check for optic N.

    May be associated with Schizencephaly
  18. Image Upload 9
    MRI appearances of septo-optic dysplasia.

    • (a) Anterior pituitary hypoplasia and absent infundibulum associated with bilateral optic nerve hypoplasia. The posterior pituitary is ectopic. There is an absence of
    • the septum pellucidum.
    • (b) Ectopic posterior pituitary, anterior pituitary hypoplasia, absence of the infundibulum and partial absence of
    • the septum pellucidum associated with optic nerve hypoplasia.

    CC, corpus callosum; AP, anterior pituitary; PP, posterior pituitary; SP, septum pellucidum; OC, optic chiasm.
  19. Arhinencephaly
    isolated olfactory aplasia or in association with other developmental abnormalitiessuch as holoprosencephaly or as part of Kallmann syndrome (X-linked or autosomal dominant anosmia, mental retardation, deficient gonadotropin hormones)
  20. Colpocephaly
    Dilatation of the occipital horns out of proportion to the remaining ventricles due to.

    Can be primary or secondary

    • 1) Primary congenital anomaly
    • 2) Secondary congenital anomaly from agenesis of the splenium of the corpus callosum

    Image Upload 10
  21. Image Upload 11
    • Holoprosencephaly. It is characterized by,
    • A. absence of the septum pellucidum and fused thalami and basal ganglia,and,
    • B. well-formed occipital horns.
    • C. cingulate gyrus crossing the midline and resting on the corpus callosum.
  22. Disorders of Migration
    • - Lissencephaly (pachygyria-agyria)
    • Image Upload 12

    Polymicrogyria: Usually occurs in context of intrauterine insult (usually ischemic) Also associated with intrauterine infections

    • Heterotopia:
    • Isolated heterotopia
    • Bilateral periventricular nodular heterotopia
    • Subcortical
    • Image Upload 13

    Image Upload 14

    • Schizencephaly
    • Two types: closed lip and open lipUsually due to fetal ischemic insult

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  23. Walker-Warburg syndrome
    Image Upload 17

    a) Also called HARD ± E syndrome (hydrocephalus, agyria, retinal dysplasia, and, in some cases, encephalocele)

    b) Presentation is usually in neonatal period with marked hypotonia, later development of spastic quadriparesis
  24. Muscle-eye-brain disease
    a) Neonatal presentation with congenital myopathy;severe neonatal hypotonia with progression to spasticity; in addition to seizures, mental retardation, abnormal EEG with progression
  25. 3 disease entities in Lissencephaly type 2
    • - Walker-Warburg syndrome
    • - Muscle-eye-brain disease
    • - Fukuyama muscular dystrophy: similar to Walker-Warburg syndrome and muscle-eye-brain disease,except with less prominent ocular involvement
  26. Notochorda
    - Notochorda is from --> Mesoderme

    - induce the formation of the neuralplate beginning at Hensen’s node

    - Gives rise to part of the vertebral column
  27. Development of the neural tube
    BMPs (bone morphog eneticprotein) and Wnt proteins are important for dorsal patterning and are expressed by dorsal neural tube.

    Shh (Sonic hedgehog) is an important ventralizing signal produced by the floor plate and notochord.

    Induction results from inactivation of bone morphogenetic proteins (BMPs), which normally act to change ectoderm to epidermis.3. Hensen’s node secretes factors, including chordin, noggin, and follisatin that inactivate BMPs and allow formation of the neural plate.

    Image Upload 18
  28. neuropores
    The initially unfused areas are termed “neuropores”

    • The anterior neuropore closes between days 24 and 26;
    • the posterior neuropore between days 25 and 28

    Image Upload 19
  29. Segmentation and Patterning
    Rostrocaudal: dependent on TGF-β family proteins Homeotic genes necessary for hindbrain patterning, depend on retinoic acid

    • Dorsoventral patterning
    • Ventral patterning (secreted from floor plate and notochord): Sonic hedgehog protein (SSH)

    Dorsal patterning (secreted from roof plate,dorsal ectoderm, and paraxial mesoderm): bone morphogenetic and Wnt proteins

    Image Upload 20
  30. Craniorachischisis
    congenital malformations of centralnervous system due to defective neural tube closure

    Image Upload 21
  31. Disorders of Neurulation (neural tube defects)?
    • Craniorachischisis
    • Anencephaly
    • Meningomyelocele (spina bifida cystica)
    • Spina bifida occulta
    • Cranium bifidum
    • Encephalocele
  32. Disorders of Forebrain Induction and MidlineMalformations
    Deficient lateral growth of the cerebral hemispheres or Abnormal differentiation of the telencephalon.

    • -Alobar holoprosencephaly
    • -Lobar holoprosencephaly
    • -Septo-optic dysplasia
    • -Arhinencephaly
    • -Colpocephaly
  33. Ventricular zone
    Responsible for initial proliferation of neuronal and glial cell precursors

    The orientation of the mitotic spindle determines the fate of daughter cells

    a. Vertical cleavage plane (perpendicular to the ventricular surface) --> The two daughter cells become neuroepithelial cells

    b. Horizontal cleavage plane (parallel to the ventricular surface) --> migrates toward the cortical plate, and becomes apostmitotic neuroblast

    younger neuroblasts migrate through the zones --> occupy the most superficial layers and eventually forms neocortical layers II-VI
  34. External Granule Layer of the Cerebellum
    Proliferative layer from which arise radial glial cells that migrate centripetally (opposit the ventrucular zone) (continues throughout first year of life)

    Granule neuroblasts are precursors of cerebellar granule cells, which form the external granule cell layer 4.

    After the initial proliferation of granule cells in the external granule cell layer at birth, the precursor cells migrate through the molecular and Purkinje cell layers

    Image Upload 22
  35. Neocortical development
    Image Upload 23

    VZ --> Daughter cells with the mitotic axis parallel to the ventricular surface differentiate and migrate (via radial glia).

    Neuroepithelial cells migrate to the superficial layer of the cortical plate (CP); thus, younger cells are in the most superficial layer andolder cells in deeper layers.

    Throughout this process, excess neuroepithelial cells degenerate via apoptosis.

    PP --> appears by 4 weeks of gestation and is eventually divided by the CP zone into a marginal zone (MZ) and a remnant of the PP zone,sometimes called the subplate zone (SPZ). See the pic This layer is transient

    MZ --> neocortical layer I (molecular)

    The cortical plate (CP) --> forms neocortical layers II through VI.

    intermediate zone (IZ) --> becomes white matter

    The subventricular zone (SZ)contains small interneurons and persists for several months postnatally.
  36. Defferent types of Lissencephaly
    Lissencephaly Type 1: disorder of undermigration associated with deletion of LIS1 gene on chromosome17, Miller-Dieker syndrome

    Type 2: disorder of overmigration causing poorly laminated, disorganized cortex, associated with Walker-Warburg syndrome, muscle-eye brain disease, and Fukuyama musculardystrophy
  37. Miller-Dieker syndrome
    Large deletions of LIS1 gene -- > neuroblast migration --> agyria,mental retardation, intractable seizures, and spasticity

    • Facial features: thin upper lip, high forehead, microcephaly, bitemporal hollowing,
    • Image Upload 24
  38. Lissencephaly type 2
    • 1) Poorly laminated, disorganized cortex with disoriented neurons
    • 2) Thickened cortex with an appearance resembling polymicrogyria (“cobblestone” appearance) and hypomyelination of the white matter

    3) Overmigration causing disrupted, discontinuous pia, and disoriented, disorganized neurons placed outside the pial surface, with no laminar organization

    • Image Upload 25
    • Cobblestone cortex (type 2
    • lissencephaly)
  39. Polymicrogyria
    • a. Excessive, numerous small gyri
    • b. May occur in combination with pachygyriac. Usually due to ischemic insult to the underlying parenchyma but can be due to defective migrationd. Other acquired intrauterine
    • insults include infectionssuch as toxoplasmosis and CMV (and others,including rubella and herpes simplex)

    e. Associated with X-linked dominant Aicardi’s syndrome
  40. Aicardi syndrome
    - Partial or complete absence of corpus callosum, the presence of retinal abnormalities.

    • - Infantile spasms.
    • - X-linked dominant inheritance, almost exclusivelyseen in girls (lethal in boys)

    • - Dorsal vertebral anomalies
    • - Optic nerve colobomas
    • - Associated with polymicrogyria and Mental retardation

    Image Upload 26Image Upload 27
  41. Megalencephaly etiology?
    • Primary causes
    • 1) Isolated familial megalencephaly (autosomal dominantor recessive)
    • 2) Isolated sporadic
    • 3) Associated with endocrine disorders, agenesis of corpuscallosum, and achondroplasiae.

    • Secondary causes
    • 1) Inborn errors of metabolism: GM1 and GM2 gangliosidoses, mucopolysaccharidoses, leukodystrophies such as Alexander disease and Canavan disease
    • 2) Neurocutaneous disorders such as neurofibro-matosis 1, tuberous sclerosis, linear sebaceous nevussyndrome
  42. Agenesis of the corpus callosum:
    - a disorder of apoptosis

    - The failure of apoptosis (cell death) of glial cells in the latter scenario acts as a barrier to the passage of axons

    - Does not present with disconnection syndrome thatoften occurs with acquired lesions of the corpus callosum

    - Associated with Aicardi’s and Andermann syndrome
  43. Andermann syndrome
    • 1) Autosomal recessive inheritance
    • 2) Mental retardation
    • 3) Agenesis of the corpus callosum
    • 4) Peripheral neuropathy
  44. Myelination of the Central Nervous System
    - as early as 14 weeks of gestation and continues to adulthood

    - Bulk of active myelination begins at third trimester and continues to about 2 years postnatally

    - Corticospinal tract myelinate throughout first 2 years of life
  45. Which CN continues myelination after birth
    Optic nerve myelinates postnally; most other cranialnerves myelinate prenatally
  46. Subcortical association fibers myelination?
    Certain subcortical association fibers (especially offrontal cortex) do not complete myelination until early adulthood
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