Congenital Malformations, Perinatal, and Developmental Pathology of the Nervous System [3]

Question 1

Neural tube defects- definition and period during embryogenesis/development when they occur

Answer 1

Neural tube closure takes place during week 3 of development, so this is when these defects occur. They are all related to failure of the neural tube to close properly, or else failure of the neural tube to separate from the overlying ectoderm. Note that in the latter case, a tethered spinal cord will result.

Neural tube defects can be prevented with pre-conception folic acid supplementation

Examples: Cranioraschisi totalis, Anecephaly, Encephalocele,Myelomeningocele, Lipomyelocele, Dorsal dermal sinus tract, Spina Bifida Occulta

Question 2

Holoprosencephaly- definition and period during embryogenesis/development when they occur

Answer 2

The cleavage of the prosencephalon occurs during week 5 of fetal life.

Holoprosencephaly occurs when the single ventricle that exists in the early embryonic forebrain fails to form properly into the two lateral ventricles and one third ventricle. The disorder of cleavage may be complete or partial, and also results in some degree of failure of the two cerebral hemispheres to divide properly.

Question 3

Disorders of neuronal proliferation- definition and period

during embryogenesis/development when they occur

Answer 3

Neuronal proliferation takes place between weeks 8 and 19 gestation. Can result in…

1. Megalencephaly = too many neurons = abnormally large brain that usually functions abnormally
2. Microcephaly = too few neurons = head circumference is >2 sd smaller than mean. Can be assoicated with chromosomal abnormalities. Life expectancy is reduced and brain usually functions abnormally

Question 4

Disorders of neuronal migration- definition and period

during embryogenesis/development when they occur

Answer 4

Neuronal migration occurs between weeks 10 and 19 gestation.

Disorders can be due to the onset of migration, the process of migration itself, or the stopping of migration

Question 5

Disorders of elaboration of neurons and glia- definition and period during embryogenesis/development when they occur

Answer 5

x

Question 6

What is the association between Chiari I malformation and syringomyelia?

Answer 6

Finding of cerebellar tonsils that are elongated and pushed down through the foramen magnum, blocking the normal flow of CSF.

Can result in formation of a CSF-filled cyst that breaks out of the central canal and dissects into the substance of the cord (SYRINGOMYELIA)

Can also lead to an accumulation of CSF within the central canal (hydromyelia) or dysfunction of the grey or white matter of the spinal cord (myelopathy)

Question 7

What is the association between Chiari II malformation and myelomeningocele?

Answer 7

Elongation of the cerebaellar vermis (NOT the cerebellar tonsils), which is pushed down through the foramen magnum and can also block CSF flow

Causes abnormalities of the brainstem, including:
o “Beaking” of the midbrain tectal plate
o “Z-kink” in the medulla
o Causes abnormalities of the dural venous sinus including:
o Low-lying confluence of sinuses
o Osseous abnormalities of the skull
o Seen in conjuction with a thoraco-lumbar level myelomeningocele

Question 8

What are the normal levels at which the conus medullaris is found with respect to the vertebral column at different stages of development?

Answer 8

The conus medullaris is found at the level of the L3 vertebral body in the average newborn. The conus rises to the L2 vertebral body or higher by three months of age. In adulthood, the conus is found at the level of the L1 or L2 vertebral bodies. Many of the congenital neural tube defects can lead to tethering of the spinal cord, meaning that the conus medullaris is not allowed to rise during development.

Question 9

Understand the concept of tethering of the spinal cord that can be associated with neural tube defects. What are the symptoms/affects of such a defect?

Answer 9

The tethering of conus medullaris puts tension on the cord, which compromises its blood supply. Possible complications attributable to the tension on the cord include pain, signs of upper motor neuron injury (spastic paresis), and urinary incontinence.

Question 10

What symptoms result when a process such as syringomyelia occurs?

Answer 10

Determining the symptoms associated with syringomelia follows the same algorithm as determining the effects of a hemilesion:

• Symptoms of upper motor neuron loss will exist on the ipsilateral side
• Loss of fine touch and vibration sensation will exist on the ipsilateral side
• Loss of pain and temperature will exist on the contralateral side

Question 11

What are the principal causes and consequences of stroke in the perinatal period?

Answer 11

Perinatal stokes may be due to genetic/malformative causes or by trauma.

Possible genetic/malformative causes include vascular or cardiac malformations, neurocutaneous syndromes, clotting problems, sickle cell anemia, polycythemias, and primary vascular diseases.

A stroke in pre-term infants leads to hemorrhage into the subependymal germinal matrix that is forming neurons and glia. This is called a germinal matrix hemorrhage (GMH) and is the most common cause of cerebral palsy

Question 12

Cranioraschisis

Answer 12

Neural Tube Defect
Most severe defect. Complete failure of the NT to close, leaving a plate where the actual neural tube should be.

Not compatible with life.

Question 13

Anencephaly

Answer 13

Neural Tube Defect
Failure of the rostral neuropore to close. Forebrain neuroectoderm fails to separate from the cutaneous ectoderm, leaving a red area cerebrovasculosa protruding out of the top of the head.

Diencephalon does develop, as evidenced from the “bug eye” appearance

Not compatible with life.

Question 14

Enecephalocele

Answer 14

Neural Tube Defect
Defect in the scull with protrusion of the leptomeninges and sometimes brain tissue. There is, however, an epidermal covering over this protrusion, and it can sometimes be reduced.

Infants have a possibility of surviving.

Question 15

Myelomeningocele

Answer 15

Neural Tube Defect
A skin-covered, CSF filled mass at the caudal end that is continuous with the CSF in the spinal cord. This can be fixed, but the tissues underneath are also malformed, so kids go on to have urinary problems and gait problems.

Usually the rest of the tissue of the spinal cord is normal.

The cord also needs to be untethered.

Question 16

Lipomyelocele/

Lipomyelomeningocele

Answer 16

Neural Tube Defect
A lipoma extends from the sub-Q tissue to the dorsal aspect of the cord, tethering it. Reflects premature separation of the Cutaneous ectoderm during neurulation that allows mesenchyme to enter the unclosed neural tube and differentiate into fat

Question 17

Dorsal dermal sinus tract

Answer 17

Neural Tube Defect
Ectoderm-lined tracts that can transgress the dura and allow communication between the skin and CSF. Can be associated with an intradural dermoid cyst.

Question 18

Spina Bifida Occulta

Answer 18

Neural Tube Defect
Occurs at the L5-S1 level. Occurs when the bony lamina of the vertebral body fails to close over a portion of the meningeal sac. Usually there are not symptoms, though there is often a Cutaneous abnormality indicative of the underlying spinal dysraphism.

Look for these along the midline: dermal dimple, hairy patch of skin, lipoma, etc.

Least severe defect – common incidental finding on radiographs in kids and adults.

Question 19

What are the three types of holoprosencephaly?

Answer 19

1. Alobar: No evidence of division of cerebral cortex
   Single forebrain, single ventricle.
   *Fusion of thalami
   *Barely any corpus callosum
   *Most severe form – not compatible with life
2. Semilobar: Only partial cleavage with the cerebral hemispheres fused at the frontal region.
   * Single, horseshoe-like ventricle
   * Variable degrees of fusion of the thalami
   * Absent olfactory bulbs and absent corpus callosum
   * May survive infancy, but not much longer

3.Lobar: Cerebral hemispheres are separated anteriorly and posteriorly, with some fusion of the structures. Least severe with normal life expectancy, but with severe mental and physical impairment

Question 20

Periventricular heterotopia

Answer 20

Disorder of ONSET of neural migration

• X-linked dominant inheritance – embryonic lethal in males
• Mutation in the filamin A gene (FLNA)
• Neurons have problems leaving the ventricular zone
• Female PH patients present with epilepsy without cognitive abnormalities. Possible X inactivation?

Question 21

Type 1 Lissencephaly

Answer 21

Disorder of Neuronal Migration

• Neurons exit the ventricular zone, but halt migration prematurely and do not make it to the cortical plate
• Brains of these patients are smooth (agyria) with a lack of layer specificity
• LIS1 is the affected gene – individuals are heterozygous = haploinsufficiency
• Results in severe mental retardation and epilepsy

Question 22

Double cortex syndrome

Answer 22

Disorder of Neuronal Migration

• Similar to type 1 lissencephaly, neurons are able to migrate out of the ventricular zone but fail to progress to the cortical plate
• Affected gene = DCX, found on the x-chromosome. *Males with DCX mutation are hard to differentiate from males carrying a LIS1 mutation (diagnosed with lissencephaly)
• Females with one mutant DCX gene have “double cortex” syndrome, characterized by epilepsy, mild mental retardation, and subcortical band heterotopia (band of heterotopic neurons midway between the ventricles and the brain surface
• Males have a more serious phenotype than females

Question 23

o Lissencephaly with cerebellar hypoplasia

Answer 23

Disorder of STOPPING neural migration
o Due to a mutation in the reeler gene
o Neurons cannot get off of the radial glia
o Normal “inside-out” pattern of the cortex is inverted
o Associated with cerebellar problems (reeling gait)

Question 24

Polymicrogyria

Answer 24

Disorder of Neuronal Migration, Non-specified

• Anomaly in neuronal organization – defect in the normal 6-layered structure of the cerebral cortex, with abnormal distribution of neurons into multiple small gyri
• May affect a variable portion of the cortex in one or both hemispheres, with the most common area of involvement being the posterior end of the sylvian fissure
• Associated with variably severe motor and intellectual dysfunction, depending on the extent of cortical involvement
• There is a close association between polymicrogyria and CMV infection

Question 25

What is syringomyelia?

Answer 25

Syringomelia is condition in which a cyst filled with CSF breaks out of the central canal of the spinal cord and dissects into the substance of the cord. Syringomyelia causes dysfunction of the grey or white matter of the spinal cord depending on where the dissection exists.