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7/30/2019 Congenital Defects Cns
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GENERAL PRINCIPLES
Congenital abnormalities are among the leading causes of infant morbidity and
mortality and fetal loss. The leading sites of congenital abnormalities are the
skeleton, skin, and brain. Congenital abnormalities of the CNS can be divided into
developmental malformations and disruptions.
Developmental malformations result from flawed development of the brain. This
may be caused by chromosomal abnormalities and single gene defects that alter the
blueprint of the brain, or by imbalances of factors that control gene expression
during development. Gene defects may be in the germline or may develop after
conception by spontaneous somatic mutation or from the action of harmful physical
or chemical agents. Some malformations are caused by multiple genetic and
environmental factors acting in concert (multifactorial etiology).
Disruptions result from destruction of the normally developed (or developing) brain
and are caused by environmental or intrinsic factors such as fetal infection, exposure
of the fetus to harmful chemicals, radiation, and fetal hypoxia. For instance,
holoprosencephaly, a condition in which the forebrain is not divided into two
hemispheres, is a malformation. Hydranencephaly, in which massive destruction
reduces the hemispheres into fluid-filled sacs, is a disruption. The line between
malformation and disruption is sometimes blurred because an extrinsic factor (e.g.
radiation) may cause direct physical injury but also damage genes that are
important for development.
Developmental malformations are usually either midline or bilateral and symmetric
and do not show gliosis. On the other hand, most disruptions are focal and
asymmetric and are associated with gliosis and other reactive changes such as
inflammation, phagocytosis, and calcification. However, these reactions may not be
present if the disruption occurs in the first trimester, when the brain is immature.
For these reasons, it is hard, sometimes, to distinguish malformation from
disruption. This distinction carries important implications. Malformations carry a
recurrence risk that can be calculated. Disruptions do not recur, unless the exposurerecurs or continues.
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Congenital CMV: microcephaly
Congenital CMV: calcifications and hydrocephalus
Exposure to teratogens, viral infections, etc., can occur throughout pregnancy. 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. CMVinfection in the third trimester causes an encephalitis, similar to postnatal CMV
encephalitis. The most critical period for malformations and disruptions is the third
to eighth week of gestation, during which the brain and most organs take form.
NEURAL TUBE DEFECTS
The neural plate appears on the 17th day of gestation as a thickening of the
embryonic ectoderm over the notochord. Thisneuroectoderm gives rise to the
central nervous system. On day 18, the neural plate invaginates along the midline,
forming theneural groove with the neural folds on either side. By the end of the
third gestational week, the neural folds fuse forming theneural tube. Fusion begins
at the hindbrian-cervical junction and the hindbrain-forebrain junction and proceeds
rostrally and caudally from these two points. Then, the anterior and posterior ends
(neuropores) close, completing the process. The cranial end of the neural tube
closes by 24 days and the caudal by 25-26 days. Then, the neural tube is covered
dorsally by mesenchyme that forms the vertebral ardhes and skull. Closure of the
vertebral arches is completed at 11 weeks of gestation. Defective closure of the
neural tube results in neural tube defects (NTDs). Depending on the point of the
defect NTDs may affect the brain (anencephaly, encephalocele) or spinal cord (spina
bifida).
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The most severe NTD, craniorachischisis, is due to defective closure of the
hindbrain-cervical junction.
The conus medullaris, cauda equina, and filum terminale develop by a different
process from a solid rod of progentor cells, distal to the spinal cord proper. Duringdevelopment also, the spinal column elongates more than the spinal cord, such that
spinal cord levels end up higher than their corresponding vertebral levels.
Abnormalities of this caudal portion of the spinal structures cause the tethered cord
syndrome.
Exencephaly Anencephaly Anencephaly
In anencephaly, the brain initially protrudes through a defect in the cranial vault
(exencephaly) and is gradually destroyed because of mechanical injury and
vascular disruption. Eventually, all that is left is a small, vascular mass of
disorganized neural tissue (cerebrovasculosa) mixed with choroid plexus. The eyes
evaginate from the forebrain before it is destroyed and are preserved. The cranial
vault is either absent or collapses over the base of the skull. Damage of the
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hypothalamus results in adrenal hypoplasia. Anencephaly is incompatible with
survival.
Myelomeningocele Craniorachischisis
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. The lesion is usually in the lumbosacral area but sometimes it
can be more extensive and may involve the entire spinal cord. In its mildestform, spina bifida occulta, the vertebral arches are absent, but there is a hairy
patch of skin over the defect. The spinal cord may be normal or the filum terminale
may be tethered to subcutaneous tissue. Meningocele is a bulge in the lumbosacral
area consisting of a meningeal sac protruding through the bone defect.
Inmeningomyelocele, the sac contains malformed spinal cord tissue. In severe
cases, there is no sac at all, and neural tissue from the open neural plate lies on the
dorsal surface of the fetus. Anencephaly is often accompanied by spina bifida.
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Encephalocele
Encephalocele is a protrusion of brain through a defect of the skull, usually in the
occipital area. The protruding part is destroyed because of mechanical disruption
and ischemia. The intracranial part of the brain around the defect is malformed and
disrupted. Large occipital encephaloceles are incompatible with life because of
damage of the brainstem.
NTDs are the most common congenital abnormalities of the CNS and, overall, the
second most common type of congenital abnormality after congenital heart disease.
They are a significant cause of fetal loss. Live-born babies with myelomeningoceles
may have paralysis of the legs and loss of bladder and bowel function. Open defects
allow entry of bacteria into the CNS. The same thing happens if the skin covering
the meningomyelocele becomes necrotic and infected. Some meningomyeloceles are
a component of a more complex malformation, the Chiari II malformation, which
includes hydrocephalus and abnormalities of the posterior fossa contents.
The tethered cord syndrome (TCS) is a frequent accompaniment of
meningmyelocele and other malformations of the lower spine and spinal cord. In the
TCS, the conus medullaris is pulled lower than the L2 vertebra or the L1-L2 disc
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space. This traction causes low back pain, scoliosis, lower extremity weakness and
sensory loss, and bowel and bladder dysfunction.
Neural tube defects can be detected in utero by determination of alpha-fetoprotein
(AFP) and acetylcholinesterase in theamniotic fluid and maternal blood.Alpha- fetoprotein, a circulating fetal protein produced by the liver, peaks at 12-14
weeks of gestation and subsequently declines. AFP leaks from the fetus into the
amniotic fluid through exposed capillaries of the NTD. This results in persistently
high levels of AFP in the amniotic fluid and in the maternal blood. Elevated AFP is
also seen in other lesions where fetal capillaries are exposed to the amniotic fluid
such as omphalocele and sacrococcygeal teratoma. Acetylcholinesterase leaks
directly from exposed neural tissue into the amniotic fluid.
NTDs develop during the third to fourth week of gestation and are due to acombination of genetic and environmental causes (multifactorial). The genetic
causes are largely unknown. Two polymorphisms of the folate dependent enzyme
5,10-Methylenetetrahydrofolate reductrase (MTHFR), MTHFR C677T and MTHFR
A1298C, are associated with an increased risk for NTDs. Environmental causes
include diabetes mellitus and the antiepileptic drug valproate. Administration of 0.4
mg of folic acid in the period from 4 weeks before to 8 weeks after conception
significantly reduces the occurrence of NTDs. The mechanism of action of folic acid
in preventing NTDs is not known. Women who have children with NTDs are not
overtly folate deficient. However, the rapidly dividing cells of the neural tubeprobably require a large amount of folate for DNA synthesis. Supply of folate may be
inadequate because of gene defects that result in subtle abnormalities of folate
metabolism.
HYDROCEPHALUS
Hydrocephalus is dilatation of the cerebral ventricles. This dilatation results from a
variety of causes, the common denominator of which is obstruction of CSF
circulation. Approximately 600-700 ml of CSF is produced daily by the choroid
plexuses. From the lateral ventricles, CSF enters the third ventricle through theforamina of Monro and then flows into the fourth ventricle through the aqueduct. It
exits from the fourth ventricle into the subarachnoid space through the foramina of
Luschka and Magendie. It bathes the spinal cord and flows over the cerebral
convexities to the arachnoid villi through which it is absorbed into the venous
circulation. Hydrocephalus may result from the following causes:
Hypersecretion of CSF: choroid plexus papilloma
Obstructive hydrocephalus
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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, intracranisl
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.
Hydrocephalus per se is not a malformation, but a deformation due to increased
pressure in the ventricles. As the above list shows, some forms of it are congenital
and others develop later in life. The most common congenital forms of
hydrocephalus are those that are associated with the Chiari malformation, variousaqueductal lesions, and the Dandy-Walker malformation (see further on).