CNS Malformations (Gianani)

Question 1

The most critical period for malformations and disruptions (prenatally)

Answer 1

is the third to eighth week of gestation, during which the brain and most organs take form.

Question 2

Malformation:

Answer 2

flawed development

• midline or bilateral and symmetric
• no gliosis
• carries a recurrence risk that can be calculated

Question 3

Disruption:

Answer 3

destruction of normal brain

• focal and asymmetric
• yes gliosis…inflammation/calcification if event occurs after first trimester
• do not recur unless exposure recurs or is continuous

Question 4

critical distinction between malformations and disruptions

Answer 4

Malformations carry a recurrence risk that can be calculated. Disruptions do not recur, unless the exposure recurs or continues.

Question 5

timing of exposure to teratogens

Answer 5

The timing of exposure is critical for both, malformations and disruptions. The earlier the exposure, the more severe the defect. For instance, fetal cytomegalovirus (CMV) infection before midgestation causes microcephaly and polymicrogyria. CMV infection in the third trimester causes an encephalitis, similar to postnatal CMV encephalitis.

Question 6

Types of neural tube defects (3)

Answer 6

NT closure defects
axial mesodermal defects
Tail bud defects

causes: defects in–
Folate (MTHFR C677T and MTHFR A1298C)
Hyperglycemia
Vit B12, Zinc

Maternal fever

Question 7

NT closure defects

Answer 7

anencephaly *
chranioraschischisis
myelomeningocele *

(spina bifida cystica, open spina bifida = meningocele)

Question 8

axial mesodermal defects

Answer 8

closed- split cord (high)

with herniation of neural tissue (encephalocele) *

= in the family of Ciliopathies

Question 9

Tail bud defects

Answer 9

spina bifida occulta *
split cord (low)
hydromyelia

not well understood

Question 10

Nongenetic factors linked to the causation of NTDs in human pregnancy

Answer 10

folate antagonists (carbamazepine, fumonisin, trimethoprim)

Glycemic dysregulation (hyperglycemia in DM, maternal obesity)- increased cell death

Histone deacetylase inhibitors (valproid acid)- disrupt signaling pathways

Micronutrient deficiencies (folate, inositol, vitamin B12, zinc)

Thermal dysregulation (hyperthermia- maternal fever in weeks 3-4)

Question 11

Failed cranial neurulation –>

Answer 11

exencephaly–> anencephaly

Question 12

failed spinal neurulation –>

Answer 12

early spina bifida –> myelo(meningo)cele

Question 13

Anencephaly

Answer 13

One of the most common neural tube defects
Initially brain protrudes through defect of cranial vault…subsequently destroyed (mechanical/chemical)

Elevated alpha-fetoprotein and acetylcholinesterase in amniotic fluid and maternal blood

Usually detected on ultrasound

Folic acid
Anencephaly is often accompanied by spina bifida.

Question 14

Craniorachischisis

Answer 14

the most severe NTD, is caused by defective closure of the hindbrain-cervical junction.

Question 15

Myelomeningocele

Answer 15

Herniation of CNS tissue through vertebral defect (menigocele is same thing but it does not contain CNS tissue)
Common neural tube closure defect
Can occur at any level, but&raquo_space; lumbosacral
Risk of infection
Some loss of sensation/paralysis
Folic acid
Surgical correction

Question 16

Spina bifida is

Answer 16

a set of malformations of the spinal cord caused by failure of closure of the neural tube and lack of fusion of the vertebral arches, soft tissues, and skin that cover the back.

Question 17

Encephalocele

Answer 17

• Defect of cranial mesodermal development

Herniation through an axial mesodermal defect of the skull

Meninges herniate with normal brain tissue…tissue in sac gets destroyed

75% occipital, less commonly fronto-ethmoidal
Ciliopathies ??

Sporadic or associated with other malformations…cardinal feature of Meckel-Gruber syndrome**

Question 18

Meckel syndrome (also known as Meckel–Gruber Syndrome, Gruber Syndrome,

Answer 18

a rare, lethal, ciliopathic, genetic disorder (autosomal recessive), characterized by renal cystic dysplasia, central nervous system malformations (occipital encephalocele), polydactyly (post axial), hepatic developmental defects, and pulmonary hypoplasia due to oligohydramnios.

Question 19

Hydromyelia

Answer 19

(over distension of central canal)

Pain in the neck; shoulders are usually numb
• headaches
• leg or hand weakness
• numbness or loss of sensation in the hands and feet
• problems with walking
• loss of bowel and bladder control
• spasticity and paralysis of the legs

Question 20

types of posterior fossa anomalies

Answer 20

(brain stem and cerebellum)

Chiari malformations I and II (small posterior fossa)

Dandy-Walker malformations (large posterior fossa)

Question 21

Chiari Type I

Answer 21

Herniation of a peg of cerebellar tonsil

Asymptomatic or neck pain, lower cranial nerve palsies, sleep apnea, sudden death

Cerebellar ataxia, late onset hydrocephalus, long tract signs, signs of syringomyelia

• Syringomyelia (90%)

Skeletal abnormalities suggesting that occipital dysplasia is a major pathogenic factor

• There is no neural tube defect

Question 22

Syringomelia

Answer 22

cape-like distribution of pain and temperature loss due to obstruction in the normal flow ofhte CNS eventuating in the dilation of the central canal of the spinal cord and the formation of a syrinx.

Question 23

Chiari Type II

Answer 23

(Arnold-Chiari malformation)

• Almost invariably with lumbosacral myelomeningocele
  Craniolacunia: shallow posterior fossa and enlarged foramen magnum, low tentorial insertion…herniation of vermis and tonsils
  Low torcula, short fenestrated falx
  Hydrocephalus (>80%)

small posterior fossa –> downward extension of vermis ghrough foramen magnum–> hydrocephalus and almost always myelomeningocele

Question 24

Dandy-Walker Malformation

Answer 24

large posterior fossa
absence of vermis
usually associated with hydrocephalus

Question 25

HYDROCEPHALUS

Answer 25

Hypersecretion of CSF: choroid plexus papilloma

or Obstructive hydrocephalus (many causes)

Question 26

Obstructive hydrocephalus:

causes

Answer 26

Obstruction of the foramina of Monro (colloid cyst, tuberous sclerosis).

Obstruction of the third ventricle (craniopharyngioma, pilocytic astrocytoma, germ cell tumors).

Obstruction of the aqueduct (aqueductal stenosis or atresia, posterior fossa tumors).

Obstruction of the foramina of Luschka or impairment of flow from the fourth ventricle (Chiari malformation, Dandy- Walker malformation, meningitis, subarachnoid hemorrhage, posterior fossa tumors).

Fibrosis of the subarachnoid space (meningitis, subarachnoid hemorrhage, meningeal dissemination of tumors), obliteration of the subarachnoid space by glioneuronal heterotopias in the Walker-Warburg syndrome.

Defective filtration of CSF: postulated for low-pressure hydrocephalus.

Hydrocephalus ex vacuo: dilatation of the cerebral ventricles due to loss of brain tissue. This is a common sequel of wasting brain diseases (leukodystrophies, multiple sclerosis, multiple strokes, Alzheimer’s disease, Huntington’s disease, etc.).

Idiopathic external hydrocephalus: a condition characterized by increased CSF volume and expansion of the subarachnoid space without ventricular dilatation, brain atrophy, intracranial hypertension, or other pathology. This entity is common in infants and causes a large head and rapid growth of the head. It is not accompanied by neurological abnormality and usually resolves without treatment (benign macrocrania). It is probably due to immaturity of the arachnoid villi.

Question 27

what forms the CSF?

Answer 27

choroid plexus

Question 28

Holoprocencephaly

Answer 28

incomplete separation of cerebral hemispheres
across the midline

Between the fourth to sixth week of gestation, the forebrain (prosencephalon) is divided into the two hemispheres.

• Absence of this cleavage results in a spectrum of malformations called holoprosencephaly (HPE).

Heterogeneous group of conditions
- Maternal diabetes, toxoplasmosis, syphilis, rubella, fetal alcohol syndrome, genetic (AR, AD, X-linked)

~50% have a chromosomal anomaly, * most commonly (70%) trisomy 13 (Patau syndrome)

Mutation of the Sonic Hedgehog (Shh) gene in mice results in midline facial and CNS structural defects, and failure of ventral forebrain development (7q36)

Question 29

Agenesis of Corpus Callosum

Answer 29

Isolated defect or as part of other cerebral abnormalities

• Arnold- Chiari malformation(Type II)
• Dandy-Walker syndrome
• Andermann syndrome (motor and sensory neuropathy, K-Cl cotransporter)
• Schizencephaly

Sporadic or rarely familial

Entirely asymptomatic… subtle perceptual deficits…seizures…psychomotor retardation

Question 30

Neuronal Migration Defects

Answer 30

= MALFORMATIONS OF CORTICAL DEVELOPMENT

• ABNORMAL NEURONAL-GLIAL PROLIFERATION OR APOPTOSIS
• ABNORMAL NEURONAL MIGRATION
• ABNORMAL CORTICAL ORGANIZATION

Question 31

ABNORMAL NEURONAL-GLIAL PROLIFERATION OR APOPTOSIS

–>

Answer 31

Microcephaly

Megalencephaly

Question 32

ABNORMAL NEURONAL MIGRATION–>

Answer 32

Periventricular nodular heterotopia
Lissencephaly /subcortical band heterotopia
Cobblestone cortex/congenital muscular dystrophy

Question 33

ABNORMAL CORTICAL ORGANIZATION–>

Answer 33

Polymicrogyria

Focal Cortical Dysplasia

Question 34

Five outcomes are possible in the MCDs: (alone or in combination)
* THIS IS LOW YIELD FOR GIANANI

Answer 34

1. Fewer or more than normal neurons are produced (microcephaly, megalencephaly).
2. Neurons do not migrate at all from the ventricles (periventricular heterotopia) or migrate half way (subcortical band heterotopia).
3. Some neurons reach the cortex but large numbers do not. No normal cortical layers are formed (lissencephaly, pachygyria, cobblestone cortex).
4. Neurons over-shoot the cortex and end up in the subarachnoid space (marginal-leptomeningeal glioneuronal heterotopia, cobblestone cortex).
5. The late stage of migration and cortical organization is disrupted (polymicrogyria).

Question 35

Lissencephaly

* low yield for gianani

Answer 35

(Smooth brain)

Defective neuronal radial and tangential migration
Absence of normal convolutions (smooth brain)
Several underlying genetic abnormalities
-LIS1 mutation
Some of these genes are associated with microtubule motor proteins and some disrupt microtubule dynamics

Question 36

Polymicrogyria * low yield for gianani

Answer 36

Diffuse or focal, bilateral or
unilateral, symmetric or asymmetric

Variable neurologic disability
- Seizures, severe psychomotor retardation, spasticity

Caused by disruptions after neuronal migration
- Intrauterine ischemia, twinning, infections
Rarely in inherited metabolic syndromes

Question 37

Focal cortical dysplasia (FCD)

* low yield for gianani

Answer 37

• The most frequent pathology in brain tissue removed in epilepsy surgery in children is focal cortical dysplasia.

FCD is a sporadic developmental malformation of the cerebral cortex that causes intractable seizures and cognitive impairment.

The core pathology of FCD is an abnormal cortical cytoarchitecture characterized by loss of normal layering.

Glioneuronal tumors (ganglioglioma, dysembryoblastic neuroepithelial tumor), vascular malformations, and other lesions are less frequent.

A significant proportion have hippocampal sclerosis (HS), which is the most frequent lesion in older patients.

Question 38

Fetal alcohol syndrome- face

Answer 38

• low nasal bridge
• minor ear abnormalities
  indistinct philtrum
• micrognathia
  epicanthal folds
  short palpebral fissures
  flat midface and short nose
  thin upper lip