CNS Malformations (Gianani) Flashcards
The most critical period for malformations and disruptions (prenatally)
is the third to eighth week of gestation, during which the brain and most organs take form.
Malformation:
flawed development
- midline or bilateral and symmetric
- no gliosis
- carries a recurrence risk that can be calculated
Disruption:
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
critical distinction between malformations and disruptions
Malformations carry a recurrence risk that can be calculated. Disruptions do not recur, unless the exposure recurs or continues.
timing of exposure to teratogens
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.
Types of neural tube defects (3)
NT closure defects
axial mesodermal defects
Tail bud defects
causes: defects in–
Folate (MTHFR C677T and MTHFR A1298C)
Hyperglycemia
Vit B12, Zinc
Maternal fever
NT closure defects
anencephaly *
chranioraschischisis
myelomeningocele *
(spina bifida cystica, open spina bifida = meningocele)
axial mesodermal defects
closed- split cord (high)
with herniation of neural tissue (encephalocele) *
= in the family of Ciliopathies
Tail bud defects
spina bifida occulta *
split cord (low)
hydromyelia
not well understood
Nongenetic factors linked to the causation of NTDs in human pregnancy
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)
Failed cranial neurulation –>
exencephaly–> anencephaly
failed spinal neurulation –>
early spina bifida –> myelo(meningo)cele
Anencephaly
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.
Craniorachischisis
the most severe NTD, is caused by defective closure of the hindbrain-cervical junction.
Myelomeningocele
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»_space; lumbosacral
Risk of infection
Some loss of sensation/paralysis
Folic acid
Surgical correction
Spina bifida is
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.
Encephalocele
- 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**
Meckel syndrome (also known as Meckel–Gruber Syndrome, Gruber Syndrome,
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.
Hydromyelia
(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
types of posterior fossa anomalies
(brain stem and cerebellum)
Chiari malformations I and II (small posterior fossa)
Dandy-Walker malformations (large posterior fossa)
Chiari Type I
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
Syringomelia
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.
Chiari Type II
(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
Dandy-Walker Malformation
large posterior fossa
absence of vermis
usually associated with hydrocephalus
HYDROCEPHALUS
Hypersecretion of CSF: choroid plexus papilloma
or Obstructive hydrocephalus (many causes)
Obstructive hydrocephalus:
causes
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.
what forms the CSF?
choroid plexus
Holoprocencephaly
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)
Agenesis of Corpus Callosum
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
Neuronal Migration Defects
= MALFORMATIONS OF CORTICAL DEVELOPMENT
- ABNORMAL NEURONAL-GLIAL PROLIFERATION OR APOPTOSIS
- ABNORMAL NEURONAL MIGRATION
- ABNORMAL CORTICAL ORGANIZATION
ABNORMAL NEURONAL-GLIAL PROLIFERATION OR APOPTOSIS
–>
Microcephaly
Megalencephaly
ABNORMAL NEURONAL MIGRATION–>
Periventricular nodular heterotopia
Lissencephaly /subcortical band heterotopia
Cobblestone cortex/congenital muscular dystrophy
ABNORMAL CORTICAL ORGANIZATION–>
Polymicrogyria
Focal Cortical Dysplasia
Five outcomes are possible in the MCDs: (alone or in combination)
* THIS IS LOW YIELD FOR GIANANI
- Fewer or more than normal neurons are produced (microcephaly, megalencephaly).
- Neurons do not migrate at all from the ventricles (periventricular heterotopia) or migrate half way (subcortical band heterotopia).
- Some neurons reach the cortex but large numbers do not. No normal cortical layers are formed (lissencephaly, pachygyria, cobblestone cortex).
- Neurons over-shoot the cortex and end up in the subarachnoid space (marginal-leptomeningeal glioneuronal heterotopia, cobblestone cortex).
- The late stage of migration and cortical organization is disrupted (polymicrogyria).
Lissencephaly
* low yield for gianani
(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
Polymicrogyria * low yield for gianani
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
Focal cortical dysplasia (FCD)
* low yield for gianani
- 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.
Fetal alcohol syndrome- face
- low nasal bridge
- minor ear abnormalities
indistinct philtrum - micrognathia
epicanthal folds
short palpebral fissures
flat midface and short nose
thin upper lip
