|
The term Neural Tube
Defect (NTD) includes all CNS developmental defects, which constitute
more than half of all congenital anomalies with an incidence of 1-2
per thousand births. Neural
tube closure defects are common congenital deformities. Advances in
genetics and molecular biology have led to a better understanding of
the control of central nervous system (CNS) development. Timely
prenatal diagnosis provides an opportunity to inform parents and
provide them with counseling on the likelihood of delivering an
affected baby and to make an informed decision about whether to
continue with the pregnancy or undergo selective therapeutic abortion
to avoid the birth of a disabled baby.
Neuroembryology:
Human
intrauterine development is divided into the embryonic period
includes the first 50 to 62 days post conception, and the fetal
period includes the subsequent 7 months of gestation. The embryonic
period has itself been divided into 23 stages, each stage encompasses
approximately 2 to 3 days.
Spinal
dysraphisms occur at the earliest point in gestation, typically
before the mother has confirmed that she is pregnant. During the
second and third weeks of gestation, the primitive streak is formed
along the dorsal surface of the embryonic disk. Cell migration along
the midline forms the notochord and provides the foundation for the
axial skeleton.
Gastrulation
is the formation of the streak, the development of the notochord, and
the differentiation of 3 distinct germ layers is termed. The 3 germ
layers, (embryonic ectoderm, embryonic endoderm, and embryonic
mesoderm) form the basis for specific tissue and organs. Anomalies of
notochord formation result in split notochord syndrome,
diastematomyelia.
Neurulation,
is the formation of the neural tube from neuroectoderm that occurs
during stages 8 through 20.
During stages 8 through 14 stages
the three major steps of the development of the central nervous
system occur. They are primary neurulation, and canalization of the
tail bud, and regression (secondary neurulation).
During primary neurulation, the flat
neural plate folds on itself into a neural tube which is covered by a
continuous layer of cutaneous ectoderm. The closure of the neural
tube begins in the upper cervical region and then extends caudally
and cephalically. During stage 12, the caudal portion of the neural
tube closes at the level L-1 or L-2. Errors during these stages may
lead to various congenital malformations such as myelomeningocele,
meningocele, lipomyelomeningocele, SCMs, the dermal sinus, and
intraspinal tumors such as dermoids and epidermoids. With the
completion of neurulation, the neural tube is totally covered by
cutaneous ectoderm.
Primary neurulation gives rise to
the spinal cord only down to the lumbar spine region. The spinal cord
caudal to this is formed by the process of canalization, and
regression.
The tail bud forms after completion
of primary neurulation. The formation of the neural tube caudal to
that formed during neurulation occurs by canalization of the tail
bud, which occurs during stages 13 through 20. This process consists
of the development of vacuoles within the tail bud, then coalescence of
these vacuoles to form the canal, which then connects with the
rostral neural tube formed during neurulation. Abnormalities that
develop during canalization of the tail bud can give rise to
ipomyelomeningocele. fibrolipomas of the filum terminale, tight filum
terminale, terminal myelocostocele, anterior sacral meningocele, and
caudal regression syndrome.
The terminal filum and cauda equina
are formed from the caudal portion of the neural tube by regression,
(secondary neurulation). The ventriculus terminalis marks the level
of the future conus medullaris and is a dilation of the central canal
that can be identified at stages 18 through 20 at which time it lies
at the coccygeal level. The tip of the vertebral coccygeal segments
contains an epidermal cell rest, the coccygeal medullary vestige. The
terminal filum is formed when the caudal neural tube regresses
between the ventriculus terminalis and the coccygeal medullary
vestige and is first present at stage 23. During the fetal period,
the vertebral canal grows faster than the neural tube, resulting in
the "ascent" of the spinal cord. At the time of birth, the
conus medullaris has reached the L2-3 space in the majority of
individuals, and it has reached the adult level by age 3 months.
The vertebral column grows faster
than the cord, so that at the 6th month of foetal life the caudal end
of the spinal cord lies at the level of the first sacral vertebra,
and at birth, at the lower border of the third lumbar. The adult
level, at the L1-L2 junction, is reached after the third year of life
with the roots taking a vertical course to exit from their respective
foraminae.
The anterior end of the neural tube
shows three primary vesicles, known as the prosencephalon
(forebrain), the mesencephalon (midbrain) and the rhombencephalon
(hind-brain). In addition, there are two flexures, the cervical at
the junction of the hindbrain and the spinal cord and the cephalic in
the midbrain region.
The prosencephalon grows more
rapidly than the rest of the CNS. It is divided into two parts, the
anterior telencephalon consisting of bilateral enlarging cerebral
vesicles around the central lamina terminalis, and a posterior
portion or the diencephalon when the embryo is five weeks old.
It extends forwards beyond the
anterior extremity of the notocord, the Rathke's pouch, and the
future buccopharyngeal membrane and gently folds back upon itself and
comes to rest upon the thalamus. As it folds back, the ventricle
approaches the area of potential union with the thalamus, the
cerebral substance disappears at the area of contact and all that
remains is a ventricular lining and the pia-arachnoid. As fusion
takes place, a double vascular layer persists and from itis derived
the blood supply of the lateral and third ventricles and the choroid
plexus. From the posterolateral portion of the hemisphere a bulge,
develops which grows anterolaterally and downwards to form the
future temporal lobe. It carries with it the ventricle, the vascular
septum (choroid fissure), the caudate tail and the fornix.
The mesencephalon does not change
much and is separated from the rhombencephaion by a deep furrow. The
pontine flexure divides the rhombencephaion into two parts, the
anterior metencephalon, which later forms the pons and the cerebellum
and the posterior myelen-cephalon, destined to become the medulla
oblongata.
Etiology:
Both genetic and environmental
factors appear to be responsible for CNS anomalies.
There is a geographical variation in
the incidence of these malformations from one country to another and
in the different regions of a country itself. A high incidence,
exceeding 8 per 1000, has been reported from Northern Ireland, Egypt,
India and China. Prevalence in certain ethnic groups, a slight female
preponderance, and an increased incidence in offspring of
consanguineous marriages are traits of neural tube defects that have
suggested a genetic basis. The incidence of NTD in the off spring of
an affected parent is two to four per cent, and of an affected
sibling five per cent, compared to an average figure of 0.1 per cent
in the general population. Consanguinity and the presence of HLA-DR
locus further increases the frequency. Families with NTD transmitted
by X-linked inheritance and autosomal dominant inheritance have been
reported. Chromosomal anomalies such as trisomy 13, 18, and 21 can
be associated with a spectrum of CNS abnormalities. Most frequently
the abnormality is poly genie. Enough information is not yet
available to offer any firm genetic counseling.
Several studies have shown that
folic acid supplementation during the periconceptual period reduces
the incidence of NTD drastically. Periconceptional multivitamin
(including 0.8 mg of folic acid) supplementation reduced not only the
rate of neural tube defects but also the rate of other major
non-genetic syndromatic congenital abnormalities.
Exposure to valproic acid and other
drugs as well as maternal hyperthermia and diabetes mellitus have
been blamed. Hyperzincaemia is associated with a higher incidence of
anencephaly and spina bifida. Other factors associated with an
increased incidence of NTD include maternal age greater than 35
years, social class, alcohol abuse during the first month of
pregnancy, and poverty. Infections like rubella, cytomegalovirus and
toxoplasma, and irradiation are known to lead to CNS damage in human
embryos.
Pathogenesis:
There are many hypotheses, but so
far there is no generally accepted hypothesis. von
Recklinghausen, in 1886, suggested that the failure of closure of the
neural tube is the cause. Patten, in 1953, suggested that the
excessive overgrowth of neural tissue, so frequently observed in the
region of a spinal or cranial defect, prevents normal closure of the
neural tube.
Padget proposed that an abnormal cleft termed 'neuroschisis" may
develop after the closure of the neural tube. Escaping fluid blebs
which rupture through the surface ectoderm.
The 'hydromyelic theory' initially
proposed by Morgagni in 1769 and revived by Gardner states that every
embryo passes through a temporary period of internal hydrocephalus-hydromyelia
until the roof of the 4th ventricle opens and the subarachnoid
circulation of the CSF is established(34,36,37,39). Inadequate
permeability of the rhombic roof results in increased pressure within
the neural tube leading to either a rupture at sites of weakness, the
last portions to close (myelochisis), or a ballooning of the less
mature caudal end (syringomyelocoele) or a split (diastematomyelia).
Prenatal Diagnosis:
Prenatal screening tests should be
done before 20 weeks of gestation so that it is possible to carry out
a termination of pregnancy safely. Elevated serum a-fetoprotein (AFP)
testing during pregnancy helps identify the presence of open spinal
defects. The optimum time for screening is 16 weeks. A level 2.5
times normal indicates the need for additional studies.
If maternal serum AFP is elevated,
amniocentesis may be carried out to measure amniotic fluid levels of
AFP and acetylcholinesterase. Acetylcholinesterase is more specific
to the central nervous system, separating open spinal defects from
abdominal wall defects, which can also cause elevated AFP levels.
Fetal karyotype may be carried out on amniotic fluid to rule out
chromosomal abnormalities.
Fetal ultrasound is routinely used
to evaluate the fetus. Both prenatal ultrasound and prenatal magnetic
resonance imaging (MRI) can establish the diagnosis of open spinal
defects with nearly 100% accuracy and have the advantage of being
noninvasive. Magnetic resonance imaging is superior to ultrasound for
the prenatal evaluation of intracranial anomalies and may be useful
for parent counseling.
Transvaginal ultrasound and 3-D
ultrasound have been shown to enhance early diagnosis. The lemon sign
(scalloping of the frontal bones) and the banana sign (crescent
shaped lucency in cerebellum) seen in Chiari II malformation can be
seen as early as 12 to 14 weeks gestation. On antenatal ultrasound,
the majority of fetuses have ventriculomegaly by 21 weeks gestation.
If ventriculomegaly is diagnosed after 24 weeks it may be less severe.
Types:
NTDs may be , more commonly Spinal or Cranial;
they are discussed elsewhere.
|
