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180
Chapter 5 Anomalies of Dorsal Induction
Table 5–1. NEURAL TUBE DEFECTS: DEFECTS OF
PRIMARY NEURULATION
Craniorachischisis totalis
Anencephaly
Myeloschisis
Encephalocele
Myelomeningocele, Arnold-Chiari malformation
Modified, with permission, from Volpe JJ. Neurology of the Newborn.
5th ed. Philadelphia: WB Saunders; 2008:3–50.
level will be within the normal limits. Prenatal diagnosis
in these cases will not be made on the basis of the serum
or amniotic fluid AFP. An ultrasound (US) examination
must therefore be performed in a timely fashion.
Acetylcholinesterase (AchE), unlike AFP, is not a normal component of the amniotic fluid. It is derived from
neural tissue and is always seen in the amniotic fluid in the
presence of an open NTD. Also, AchE may be present in
cases of abdominal wall defects in which a nerve plexus is
exposed to the amniotic fluid. It is essential to know that
AchE is normally found in fetal blood and may therefore be
found in amniotic fluid that at the time of amniocentesis
has been contaminated with fetal blood.
9 , 10
The occult dysraphic conditions affect the lower sacral
and coccygeal areas of the spine. These lesions are covered
by skin and may go on undetected, even after the birth of
the infant. The important issue is that 4.1% of siblings of
patients with these occult dysraphic conditions exhibit
disorders of primary neurulation, such as meningocele and
anencephaly.
11 , 12
EXENCEPHALY–ANENCEPHALY SEQUENCE
Table 5–2. NON–NEURAL TUBE MALFORMATIONS
ASSOCIATED WITH ELEVATED MSAFP
Fetal Conditions
Multiple pregnancy
Intrauterine fetal demise
Wrong dates (i.e. pregnancy more advanced)
Ventral wall defects: omphalocele, gastroschisis
Renal: congenital nephrosis, bilateral renal agenesis,
polycystic kidney or infantile
Intestinal atresia
Triploidy
Congenital skin disorders: epidermolysis bullosa or
aplasia cutis
Teratoma: sacrococcygeal, pharyngeal
Congenital cystic adenomatoid malformation
(congenital cystic adenomatoid malformation type III)
Turner syndrome with cystic hygroma
Oligohydramnios
Placental conditions
Hemangioma
Maternal Conditions
Maternal infection: parvovirus, cytomegalovirus, hepatitis
Maternal malignancy: hepatoma, ovarian teratoma
Abdominal pregnancy
Fetomaternal hemorrhage
Synonyms
Anencephaly, exencephaly, acrania
Definition
Exencephaly is the absence of the calvarium and skin
resulting in exposure of the brain. It appears to be the
embryologic predecessor of anencephaly. Anencephaly is
the complete absence of the calvarium, skin, meninges,
and forebrain.
Incidence
The reported incidence of NTDs of which anencephaly
is the most common is about 1 case per 1000 live births
worldwide.
ferent among different patient populations. In the United
States, the prevalence of NTDs is higher among Hispanic
women than among non-Hispanic white or non-Hispanic
black women.
residents are Hispanic, the prevalence of NTDs is 8.68 per
6 , 13 – 15
However, the incidence of NTDs is dif-
16 , 17
For example, in Puerto Rico, where most
10,000 live births, which is higher than in the mainland
United States, which is 5.59 per 10,000.
17
Pathogenesis
Anencephaly and related disorders are no longer theorized
to be simple NTDs, but are complex developmental malformations that primarily affect the production of mesenchyme. This results in skeletal defects and imperfect fusion
of the neural folds.
The developmental sequence of events leading to
anencephaly was first elucidated in experimental animals
exposed to high doses of vitamin A. Subsequent studies in
the human embryo have suggested that in humans it progresses in a similar fashion.
development of anencephaly are (1) dysraphia or a failure
of the neural groove to close in the rostral region (new
evidence has suggested that the defect may occur as early
as 18 to 20 postovulatory days, as a mesenchymal defect,
far earlier than previously believed); (2) exencephaly, or
18 , 19
19 – 22
The three phases in the
45
40
35
30
Oligo VWB Other NTD
Chapter 5 Anomalies of Dorsal Induction
40.3%
181
25
20
Relative risk (%)
15
10
5
0
Figure 5–1.
bleeding, intra-abdominal echogenicity, hydronephrosis, echogenic bowel, dilated kidney, heart defect; NTD, neural tube defect; VWD, ventral wall
defect; Oligo, oligohydramnios; MoM, multiple of the median. (Reproduced, with permission, from Reichler et al. AJOG 1994;1071:1052.)7
3.4%
1.4%
2.5–2.9
Anomalies and oligohydramnios distribution as a function of elevated maternal serum alpha-fetoprotein (MSAFP). Other, subchorionic
7.8%
3.3%
3.0–3.9 4.0–4.9 5.0–7.0 >7
exposure of a well-developed and differentiated brain
outside the skull during the embryonic period; and
(3) disintegration of the exposed brain during the fetal
period, resulting in anencephaly
4 , 18 , 20 , 21
( Table 5–4 ). It
appears that early on during development the generation of the brain and the skull is relatively independent
of each other and that the brain of anencephalic fetuses
attains a high degree of differentiation before it disinte-
21
grates.
anencephaly from exencephaly has been observed and
reported.
corroborated by findings of primitive neuronal cells in the
amniotic fluid.
Using prenatal sonography, the development of
23
This breakdown of the brain tissue has been
24
Table 5–3. CLASSIFICATION OF NEURAL TUBE
DEFECTS
13.1%
1.6%
4.9%
MSAFP levels (MoM)
Etiology
Exencephaly/anencephaly, as well as other NTDs, can
be isolated or can be part of a malformation syndrome.
Isolated NTDs, which account for the majority of cases,
have a multifactorial origin involving both genetic and
environmental factors.
important factors is the maternal serum folic acid levels.
Maternal serum levels <200 μg/L have been associated
with a significant risk of NTDs. Syndromes associated
with NTDs can be the result of a chromosomal abnormality (eg, trisomy 13, 18, or 21) or a single gene disorder (eg,
Meckel-Gruber syndrome).
in a small number of cases of anencephaly and spina bifi-
26
da.
Maternal diabetes (pregestational) is associated with
a 2- to 10-fold increase in malformations (eg, NTDs), and
exposure to valproic acid and/or carbamazepine is associated with a 1% to 2% risk of spina bifida but not necessarily anencephaly.
Location
of Defect Open Closed
maternal obesity (patients with a body mass index [BMI]
18.2%
5.4%
10.9%
25
In these cases, one of the most
26
26
Other factors associated with NTDs are
17.3%
13.4%
Teratogenic exposure results
Cranial Anencephaly Cephalocele
Craniospinal Craniorachischisis Iniencephaly
Spinal Meningomyelocele Lumbosacral
lesions
Modified, with permission, from Lemire RJ. Anencephaly. In:
Myrianthopoulos NC. Handbook of Clinical Neurology Malformations.
Vol 6. Amsterdam: Elsevier; 1987.
Table 5–4. THREE PHASES IN THE DEVELOPMENT OF
ANENCEPHALY
Dysraphia
Exencephaly
Anencephaly
182
Chapter 5 Anomalies of Dorsal Induction
>29 kg/m
hyperthermia (2-fold increase).
2
having a 1.5- to 3.5-fold increase in risk) and
26
Associated Anomalies
Other malformations can also be seen in anencephalic
fetuses. However, due to the severity and lethality of this
malformation, searching for other malformations does
not alter the management or the prognosis for the fetus.
Among the other associated malformations are hypoplastic or anomalous folding of the ears; subcutaneous clefts
of the nose, cleft lip, and/or palate; diaphragmatic hernia; omphalocele; limb and cardiac malformations; and
hydronephrosis.
27
Joo et al
28
reported that in a series of
743 cases of NTDs, 385 had anencephaly, 307 had spina
bifida, and 51 had encephalocele. They found that the
most commonly associated anomaly with anencephaly is
spina bifida (24%), a CNS anomaly; it can also be seen with
cephaloceles (10%). Non-CNS malformations seen with
anencephaly run the gamut of almost all organ systems,
such as congenital heart defects in 6.5% (eg, atrial septal
defect [ASD], ventricular septal defect [VSD], coarctation
of the aorta, and univentriculat heart), gastrointestinal
anomalies in 5.2% (eg, esophageal atresia, jejunal atresia,
and intestinal malformation), urogenital anomalies in
3.1% (eg, hydronephrosis and polycystic kidneys), facial
malformations in 19.2% (eg, hypo- and hypertelorism,
proboscis, and cleft palate), limb anomalies in 4.1% (eg,
clubfoot), and abdominal wall defects in 7.5% (eg, omphalocele, diaphragmatic hernia, and costal anomalies).
28
Among 77 anencephalic fetuses who underwent karyotype, 97.4% had normal chromosomes, with one case each
of trisomy 18 and 21.
Craniorachischisis refers to a defect in which the
open cranial defect (anencephaly) is in continuity with the
completely open spine (spinal dysraphism). In this defect
total failure of neurulation has occurred and is believed
to arise no later than 20 to 22 days after conception.
Most of the fetuses affected with this extensive malformation are spontaneously aborted early in pregnancy.
Craniorachischisisis presents in up to 10% of anencephalic
29
fetuses.
Sonography demonstrates the anencephaly and
11
the extensive spinal dysraphism ( Figure 5–2 ).
Polyhydramnios complicates up to 50% of anencephalic pregnancies, which usually develops during the second half of gestation. It is theorized that polyhydramnios
results from decreased fetal swallowing.
29 – 32
Risk of Recurrence
Anencephaly, like most NTDs, has a polygenic inheritance. In addition, several other factors, such as ethnicity,
geographic location, and nutritional deficiency (eg, folate),
may play significant roles in the occurrence of NTDs.
The risk of an NTD increases significantly if there is a
family history of an NTD. Deak et al
set of more than 1000 families affected by NTDs. They
found both sex-influenced and maternal (imprinting)
effects in the etiology of NTDs. Other factors associated
with increased risk of NTDs are diabetes and exposure to
15
reported on a data
valproic acid, thalidomide, and alcohol, as well as exposure
to hyperthermia.
33
Recurrence risk for NTDs is related to the family’s
history. If one of the parents has an NTD, the risk to the
offspring is as high as 4.5%.
34
If a previous full sibling is
affected, the recurrence risk is 4%; if two previous siblings
are affected, this risk increases to as high as 10%. The
recurrence risk among half-siblings is ∼0.5% to 0.8%.
risk for second-degree relatives (eg, grandparents and
grandchildren, uncles and aunts, nephews and nieces) is
0.5%, and for third degree (eg, first cousins), it is similar to
that of the general population.
concordance rate for NTDs is 7.7%; for dizygotic twins, it
15
is 4%
( Figure 5–3 ).
15
In monozygotic twins, the
Folic acid can help prevent 50% to 70% of the cases
of NTDs. Most studies suggest that folic acid works
by correcting a nutritional deficiency of folic acid;
however, exactly how it works is not known. Folates
have two main physiologic effects: as a cofactor for the
enzymes that synthesize DNA and RNA and for the
conversion of homocysteine to methionine. The gene for
5, 10-methylenehydrofolate (MTHFR) catalyzes the conversion of MTHFR into 5-methyl-tetrahydrofolate, which
is the major circulating form of folate. There are two mutations in the MTHFR gene that are associated with NTDs:
the C677T and the A1298C mutations. Specifically, C677T
has been linked to an increased risk of spina bifida and
anencephaly. This mutation causes a mild enzymatic dysfunction that results in mild hemocystenemia in persons
whose folate status is not optimal. Lower vitamin B
during pregnancy have also been associated with increased
risk of NTDs.
A decrease in folate intake has been shown to be
associated with an increased risk of NTDs.
1 , 35 , 36
37 – 39
of this association, the U.S. Centers for Disease Control
and Prevention (CDC) recommends that all women of
childbearing age should consume 400 μg of folic acid per
day for prevention of NTDs.
campaigns have not had a significant impact on the
prevalence of NTDs.
26
Approximately 40% of women of
40
However, public health
childbearing age report taking folic acid, although racial
and ethnic differences are noted, with Hispanic women
who have the highest rate of NTDs reporting the lowest
rate of consumption of folic acid.
41
In 1998 the U.S. Food
and Drug Administration (FDA) mandated that folic acid
should be added to all grain products in the United States;
since that time, many other countries have followed suit.
Over the last 10 years since the fortification of cereal grain
products was mandated, there has been a 26% decrease
in NTDs in the United States.
41
On the other hand, the
amount of folic acid in these foods is small, and women of
childbearing age still need to continue to supplement their
diet with folic acid. Worldwide, as reported in 2007 by the
CDC, the percentage of wheat flour fortification increased
from 18% in 2004 to 27% in 2007.
43
Oakley
reported that the Flour Fortification Initiative
42
More recently, Bell and
now includes 67 countries that fortify wheat flour and
6 countries that fortify both wheat and maize (corn) flour;
this has resulted globally in a 9% decrease of folic acid–
preventable NTDs.
15
The
levels
12
In view
Chapter 5 Anomalies of Dorsal Induction
183
A
C
D
B
E
F
G
H
I
Figure 5–2. Exencephaly at 17 postmenstrual weeks. (A) Coronal section demonstrating the eyes (lens) showing strabismus and the brain tissue with-
out the calvarium. (B) The splayed upper part of the spinal column ( arrow ). (C) Coronal section highlighting the orbit with the lens pointing downward
(strabismus). ( D) A median section showing the flat profile ( arrow ). (E) and (F) Horizontal sections of the brain. No hyperechoic bony structure sur-
rounding the brain tissue is seen. (G), (H), and (I) Pictures of the aborted specimen from the front, side, and back, respectively. Note the resemblance
of the specimen to the respective sonographic pictures.
184
Figure 5–3. Discordant dizygotic twins concordant for anencephaly.
Pregnancy following invitro fertilization and intracytoplasmic sperm
injection. (Courtesy of Gustavo Malinger.)
Chapter 5 Anomalies of Dorsal Induction
Recurrence risk can be significantly decreased with
the use of periconceptional folic acid. For women who
have had a prior child with an NTD, the recommended
dose of folic acid is 4 mg daily started at least 1 month
before conception and to be continued for the first
12 weeks of pregnancy.
40
Doses of folic acid >1 mg must be
taken under the supervision of a physician in order not to
mask an underlying condition, such as pernicious anemia
(vitamin B
deficiency).
12
Sonographic Diagnosis
Anencephaly is a historically important malformation in
the field of US, as it was the first malformation reported
using transabdominal sonography in a fetus at 17 postmenstrual weeks.
first malformation reported using transvaginal sonography
(TVS) in a fetus at 11 weeks, 5 days (postmenstrual).
Using TVS, the integrity of the cranium can be
assessed as early as the first trimester of pregnancy. This
is because ossification of the fetal cranium begins and
subsequently accelerates after 9 postmenstrual weeks.
Abnormal mineralization of the cranial bones can be
sonographically determined by the early second trimester
by assessing the degree of echogenicity of the bone.
mineralized bone is highly echogenic. Absence of an echogenic outer border surrounding the fetal brain must raise
the suspicion of the presence of exencephaly-anencephaly
sequence ( Figures 5–4 and 5–5 ). The visualization of
echogenic “milky” amniotic fluid during the first or early
second trimester is considered diagnostic for the presence
of anencephaly ( Figures 5–6 and 5–7 ).
Exencephaly refers to a “transient” malformation in
which the brain is exposed to the amniotic fluid. It is the second stage of the development of the clinically apparent anencephaly in humans.
amount of well-developed brain is present in the absence
of a fetal cranium, with significant portions of the cranium
missing, but there is preservation of the face and bones of
the base of the skull. Preservation of the bones of the face
and skull is also seen in anencephaly, although during the
44
Almost 20 years later, it became the
45
48
Well-
31 , 48 – 53
In exencephaly a relatively large
46 , 47
Figure 5–4. Anencephaly at 20 postmenstrual
weeks. (A) Median section depicting a relatively
normal profile of the fetal head. However, the skull
is totally missing. (B) A coronal section of the face
showing the fetal orbits with the lenses within. The
arrow points to the two-vessel cord present in this
fetus. (C) and (D) are two views of the hands of the
fetus. Note that the hands are clenched with overlapping digits.
A
AND
C
B
D
Chapter 5 Anomalies of Dorsal Induction
185
5/7
weeks
A
B
C
GA g
Figure 5–5. The fetal head is seen in three different views in this fetus with exencephaly at 9 weeks, 5 days. (A), (B) Using two-dimensional (2D)
sonography, the exposed brain is shown as disorganized and lacking any of the anatomical landmarks usually seen at this gestational age. (C) Threedimensional (3D) reconstruction of this pathology. The typical appearance of the “Mickey Mouse”–shaped head is evident.
AF
EES
AF
A
B
GA 13
3/7
weeks
Figure 5–6. A fetus with exencephaly-anencephaly sequence at 13 weeks, 3 days. (A), (B) The amniotic fluid (AF) appears echogenic when compared
with the extraembryonic space (EES), which is anechoic; due to the disintegrating brain tissue, eventually no brain tissue will be seen, and the typical
anencephalic appearance will be evident.
186
Chapter 5 Anomalies of Dorsal Induction
A
Figure 5–7. Transvaginal sonography at 13 weeks, 2 days in an anencephalic fetus. (A) “Milky” amniotic fluid. (B) Anencephaly, most probably due to
amniotic band sequence. Note the continuity between the amnion and the brain remnants ( arrow ). (Courtesy of Gustavo Malinger.)
first trimester, specific structures, such as the ventricles and
the choroid plexus, may be apparent ( Figure 5–8 ). Usually,
the first trimester exencephalic fetus has an apparently wide
fetal head, with sonolucent spaces within the disintegrating
29
brain.
The outer shape of the head is bilobed; we, as well as
other authors, have referred to this appearance as a “Mickey
Mouse”–shaped head
54
(see Figure 5–5 ). Exencephaly is
rarely observed in human infants due to the disintegration
of the exposed brain that occurs during intrauterine life.
Most cases of exencephaly diagnosed in utero will have
the typical anencephalic appearance at the time of delivery
( Figure 5–9 ). Like anencephaly, exencephaly is a lethal malformation incompatible with postnatal life.
The anencephalic fetus is easy to detect using sonography due to the severity of the malformation. This is especially
true during the second and third trimesters of pregnancy.
During the first trimester, the typical anencephalic phenotypic picture may not be sonographically apparent. Instead,
an exencephalic fetus with an abnormally shaped head and
some brain tissue may be imaged by sonography.
B
obviously missing ( Figure 5–10 ). A coronal view demonstrates the absence of the cranium above the prominent
orbits with preservation of the base of the skull and
facial features.
55
The prominent, bulging eyes give the
anencephalic fetus its typical “frog’s facies.” Several other
abnormalities involving the eye and orbit of anencephalic
fetuses have been described in pathologic specimens, such
as coloboma, corneal dermoids, and anophthalmia.
27
In
addition, it has been reported that although the eyes of the
anencephalic fetus may appear normal, often they have no
connection to the brain centrally. Using sonography, we
have noted the lenses of the anencephalic fetus to have an
apparent strabismus, with both lenses located in the lower
lateral aspect of the orbits. In most cases of anencephaly,
a soft, spongy, red-colored vascular glial tissue simulating
cerebral content is seen to protrude or to be exposed at the
site of the defect. This tissue is commonly referred as the
area cerebrovasculosa.
Anencephaly can be further divided in two types,
depending on the severity of the skull defect:
Anencephaly is characterized by the symmetric partial
or total absence of the cranial vault above the orbits. In
addition, a variable degree of disintegrating brain tissue
may be present. The parts of the brain that are missing
are the prosencephalon, the mesencephalon, and the rostral part of the rhombencephalon.
18
In a sagittal view of a
fetus with anencephaly, the profile of the chin, lips, nose,
and orbits appears relatively normal, but superior to the
area of the orbital ridges, the forehead and calvarium are
1. Holoacrania (Greek holos, “entire”), in which most or
all of the calvarium is missing to the level of the foramen magnum. This is the typical anencephaly that
is easily recognized by sonography.
21 , 27 , 29
In addition,
in holoacrania variable degrees of spinal rachischisis
may be present.
2. Merocrania (Greek meros, “part”), in which there is
a partial or incomplete median cranial defect with
Figure 5–8.
Although the coronal plane ( A ) may produce the false
impression of holoacrania, the medial plane ( B ) shows the
presence of cranial bone. Note the relatively small anterior
fontanelle with uncovered freely floating brain ( arrows ).
(Courtesy of Gustavo Malinger.)
Merocrania in a fetus at 15 weeks, 6 days.
A
B
Chapter 5 Anomalies of Dorsal Induction
A
187
B
C
D
E
F
Figure 5–9. Anencephaly at 31 postmenstrual weeks. (A)–(C) Subsequent coronal sections from the front to the back showing the widely spaced
orbits (hypertelorism), the lens in the dislocated position (strabismus), and the scant tissue at the base of the skull. (D), (E) Median views showing
the upper end of the vertebral column covered by a small amount of tissue (cerebrovasculosa). (F), (G) Lateral and posterior views of the specimen
after birth.
ectopia of the brain. The foramen magnum is not
involved and no cervical lordosis is present. Merocrania
may be confused with a cephalocele; however, it can be
differentiated from it by the presence of cranial bones,
sutures, and fontanelles and the absence of skin covering the ectopic brain
21 , 27 , 29
( Figure 5–8 ).
G
Three-dimensional (3D) US is not essential to make
the diagnosis of exencephaly-anencephaly sequence
because two-dimensional (2D) US will provide all of the
information needed for the diagnosis. However, it plays
a key role in the counseling of the couple whose fetus has
this anomaly as it will help the patient understand the
188
Chapter 5 Anomalies of Dorsal Induction
A
21 4/7 weeks
Figure 5–10.
that demonstrates the typical bulging eyes, as well as the lack of calvarium above the fetal orbits. (B) The nose, lips, and chin appear normal, but the
calvarium is missing just above the prominent fetal eyes.
A 3D reconstruction of the fetal face (using the surface rendering display) of a fetus with anencephaly at 21 weeks, 4 days. (A) Profile
severity of the anomaly. In addition to the reconstruction
of the face ( Figures 5–10 and 5–11 ), tomographic sections
of the brain can be obtained to clearly define the defect
( Figures 5–12 and 5–13 ).
B
Differential Diagnosis
Anencephaly or exencephaly may result as a consequence
of amniotic bands (see Figure 5–7 ). This nonrecurring
cause of anencephaly can be differentiated from the
A
Figure 5–11.
(A) Frontal view of the face displaying a significant amount of abnormal-appearing brain tissue. (B) Lateral view.
Using the surface-rendering modality of the 3D US machine, the face of a fetus with exencephaly-anencephaly sequence is displayed.
B
Chapter 5 Anomalies of Dorsal Induction
Figure 5–12. A typical-appearing fetus with exencephaly-anencephaly sequence is shown using the tomographic feature. Note that, compared with
Figures 5–13 and 5–14 , there is less visible brain tissue.
189
anencephaly occurring as a result of failure of the neural
tube to close, in that the cranial lesion is asymmetric,
and multiple amputations of the fingers or toes, as well as
defects of the abdominal wall, may also be present. The key
sonographic finding in making this diagnosis of amniotic
band syndrome is the presence of a band between the fetal
defect and the placenta.
53 , 56
Prognosis
Anencephaly is a lethal condition that more commonly
affects female fetuses. It has been estimated that ∼75% of
fetuses with anencephaly are stillborn. Most infants born
alive with anencephaly will die within the first 48 hours
and the remaining within the first week of life,
57 , 58
although
Figure 5–13. Using 3D US, the volume of a fetus with exencephaly-anencephaly sequence is displayed using the tomographic feature of the US machine.
Serial sagittal sections are displayed that clearly show the absence of the bony skull, as well as the exposed and abnormal-appearing fetal brain.