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410
Figure 14–3. Normal fetal eye at 22 postmenstrual weeks, imaged by
TVS. The straight hyaloid vessel is clearly demonstrated approaching
the lens.
Chapter 14 The Fetal Eye
high-resolution abdominal probes enables good visualization of these structures.
Figure 14–5. Fetal cataract diagnosed by lack of visualization of the
lens at 14 postmenstrual weeks. Termination of pregnancy (TOP) at 15
weeks demonstrated the cataracts.
Biometric Measurements
Nomograms have been constructed providing data on fetal
axial eye length, interocular distance, binocular distance,
lens diameter, and a timetable for hyaloid artery regression
and flow cessation.
18 – 24
Use of these nomograms may be
helpful in the detection of fetal hypo- or hypertelorism, as
well as other fetal eye and face malformations ( Tables 14–1
and 14–2 ). (See also Chapter 3 .)
Although the nomograms are useful and important, we do not routinely measure the ocular biometry
in low-risk pregnancies, but instead use a qualitative
approach comparing the two orbits and eyes in the same
plane. When a facial anomaly is suspected, as well as in
patients with a familiar history of malformations involving the eyes, we recommend a more extensive investigation that includes measurements and comparison with
nomograms.
PATHOLOGY OF THE LENS
The normal lens appears on the coronal ultrasonic facial
view as a smooth, hyperechogenic circular line with a
hypoechogenic content ( Figures 14–4 and 14–5 ). In the
axial view of the fetal head and orbits, the lenses are visualized as a pair of small dotted echoes originating from their
near and far margins ( Figure 14–2 ).
Cataracts
Cataracts are opacities of the lens that cause visual impairment. The mechanism of cataract formation is denaturation of lens protein and formation of an opaque insoluble
precipitate that causes loss of lens translucency.
may be unilateral or bilateral. It has been estimated that
this anomaly accounts for ~10% of the cases of blindness
in preschool children.
25 , 26
Approximately one-third of cataract cases are idiopathic, and many of these are familial.
Both autosomal dominant and autosomal recessive inheritance have been reported.
are intrauterine infections, chromosomal disorders, and
systemic syndromes.
25 – 28
26 , 27
Other possible etiologies
Cataracts may produce different US imaging patterns.
Thick, irregular, or crenate hyperechogenic borders, clusters of hypoechogenic material, or homogeneous opacities
may be observed ( Figures 14–8 , 14–9 , 14–10 , 14–11 , and
29 – 37
14–12 ).
In some cases of cataracts, we failed to dem-
onstrate the hyaloid artery. It is possible that the opacity
25
This
A B
Figure 14–4. The fetal optic nerve (A), (B) Visualization of the normal fetal optic nerve as two parallel lines ( arrows ) at 15 postmenstrual weeks by TVS.
Figure 14–6. The eyelids are visualized in a cross section of the fetal
face ( arrow ).
Chapter 14 The Fetal Eye
Figure 14–7. Eyelashes ( arrow ) observed in front of the fetal eye.
411
of the lens interfered with the visualization of this vessel. It can also be speculated that there is an association
between congenital cataract and pathologies of the hyaloid
38
artery.
It should be noted that demonstration of apparently
normal lenses on US does not exclude the presence of
cataract. Additionally, the transparency of the lens on
clinical examination is due to the free passage of light,
whereas sonolucency refers to free passage of US waves
through the lens. We have failed to diagnose some cases
of mild cataract.
31
Therefore, it is understandable and
can be summarized that at present the threshold for the
ultrasonic identification of cataract is still uncertain,
and mild to moderate or even severe cases might not
be sufficiently abnormal for sonographic detection and
recognition.
congenital cataracts, Monteagudo et al
32 , 33
As for the earliest possible detection of
33
reported an
early diagnosis using transvaginal scan at 14 weeks of
gestation.
PATHOLOGY OF THE EYELIDS
Because the normal eyelid and its opening and closure
can be detected, it is expected that a thorough, targeted examination of the eyelids can potentially detect
abnormalities. Figure 14–11A depicts a fetus with fixed,
partially open eyelids detected during ultrasonography.
Examination of the stillborn fetus confirmed this finding.
The detected syndrome was the Neu-Laxova syndrome
( Figure 14–11B ); similar findings have been reported by
Shapiro and associates.
30
PATHOLOGY OF THE EYEBALL
Microphthalmia and Anophthalmia
Congenital microphthalmia can be sporadic or heredit ary.
46
Some sporadic cases are secondary to exogenous factors,
such as infections (eg, rubella, toxoplasma, and syphilis).
38 –
Sutcliffe and colleagues
41
reported two cases of bilateral
severe microphthalmia and one case of anophthalmia
associated with treatment of carbamazepine during pregnancy.
Microphthalmia may present as an isolated anomaly
or may be a component of multiple malformation syndromes. All patterns of mendelian inheritance have been
reported.
about equally affected.
44 – 46
Right and left eyes alone or together are
44
When bilateral, these patients
are blind or have poor vision due to disorganization of
the ocular globe as a whole or of one or more of its constituent parts. Common associated anomalies are cataract,
corneal scarring or vascularity, and colobomas of the iris
or choroid. The possibility of Fraser and Walker-Warburg
syndromes should be considered.
40 – 44
Anophthalmia, or the complete absence of ocular
primordial structure is considered the most extreme form
of microphthalmia. Clinical distinction between severe
microphthalmia and anophthalmia may be difficult or
even impossible in utero, and the accurate diagnosis can
be done only after pathologic examination.
42 , 43
The sonographic diagnosis of microphthalmia should
be suggested in cases of a small orbital diameter falling below the accepted nomograms of orbital growth
( Figures 14–10 , 14–13 , 14–14, 14–15 , and 14–16 ). The
prenatal diagnosis of microphthalmia has been reported
by several investigators.
38 – 46
Both isolated cases and
microphthalmia in multiple malformation syndromes have
been identified. The earliest gestational age of detection
was reported by Porges and collaborators,
44
who found the
anomaly in a fetus at 11 weeks of gestation.
Sonographic diagnosis of anophthalmia also has
been reported.
46 , 48 , 49
However, sonographers should
be cautious because fetal head position, especially in the
cephalic prone position with the head deep inside the
pelvis, may preclude visualization of the eyes. In such
cases, vaginal sonography may be of significant value
even in the advanced pregnancy. The sonographic diagnosis of anophthalmia should therefore be suggested in
412
Chapter 14 The Fetal Eye
Table 14 –1. GROWTH OF THE OCULAR PARAMETERS
Binocular Distance (mm) Interocular Distance (mm) Ocular Diameter (mm)
Age (postmenstrual weeks)
11 51320— —————
12 8 15 23 4 9 13 1 3 6
13 10 18 25 5 9 14 2 4 7
14 13 20 28 5 10 14 3 5 8
15 15 22 30 6 10 14 4 6 9
16 17 25 32 6 10 15 5 7 9
17 19 27 34 6 11 15 5 8 10
18 22 29 37 7 11 16 6 9 11
19 24 31 39 7 12 16 7 9 12
20 26 33 41 8 12 17 8 10 13
21 28 35 43 8 13 17 8 11 13
22 30 37 44 9 13 18 9 12 14
23 31 39 46 9 14 18 10 12 15
24 33 41 48 10 14 19 10 13 15
25 35 42 50 10 15 19 11 13 16
26 36 44 51 11 15 20 12 14 16
27 38 45 53 11 16 20 12 14 17
28 39 47 54 12 16 21 13 15 17
29 41 48 56 12 17 21 13 15 18
30 42 50 57 13 17 22 14 16 18
31 43 51 58 13 18 22 14 16 19
32 45 52 60 14 18 23 14 17 19
33 46 53 61 14 19 23 15 17 19
34 47 54 62 15 19 24 15 17 20
35 48 55 63 15 20 24 15 18 20
36 49 56 64 16 20 25 16 18 20
37 50 57 65 16 21 25 16 18 21
38 50 58 65 17 21 26 16 18 21
39 51 59 66 17 22 26 16 19 21
40 52 59 67 18 22 26 16 19 21
5th 50th 95th 5th 50th 95th 5th 50th 95th
From Romero and colleagues, 1988, 56 with permission.
Chapter 14 The Fetal Eye
Table 14 –2. THE DIAMETER OF THE FETAL LENS (MM)
Centiles
GA (postmenstrual weeks) Mean 95% Cl 10 25 50 75 90
14 2.5 2.3–2.7 2.1 2.4 2.5 2.7 2.9
15 2.9 2.9–3.0 2.7 2.8 2.9 3.1 3.2
16 2.9 2.8–3.0 2.7 2.8 2.9 3.1 3.2
17–18 3.3 3.0–3.6 2.8 2.9 3 3.3 5
19–20 4.1 4.0–4.3 3.6 4 4 4.3 5
21 4.4 4.1–4.6 3.7 3.9 4 5 5
22 4.4 4.2–4.7 3.9 4 4.3 5 5
23 4.6 4.3–4.8 3.8 4 5 5 5
24 4.6 4.4–4.8 4 4.3 4.6 5 5
25 4.8 4.6–5.0 4.2 4.6 5 5.1 5.2
26 5 4.8–5.2 4.4 4.8 5.1 5.2 5.5
27 5 4.8–5.2 4.4 4.8 5.1 5.2 5.5
28 5.1 5.0.5.2 4.5 5 5.2 5.2 5.5
29 5.3 5.1–5.5 4.6 5.2 5.2 5.5 5.9
30–31 5.3 5.2–5.5 4.8 5.1 5.5 5.5 5.7
32–33 5.6 5.4–5.8 4.8 5.2 5.5 5.9 6.2
34–36 5.8 5.6–6.0 5.4 5.5 5.7 6 6.5
413
Cl, confidence interval; Ga, gestational age.
From Goldstein and colleagues, 1998, 20 with permission .
Figure 14–8. One of the suggestive findings of possible future develop-
ment of fetal cataract: edema of the fetal eyes (15 weeks, arrows ).
Cataract
Figure 14–9.
clusters of hypoechogenic material in the left eye (cataract). (From
Zimmer et al, 1993,
Homogeneous hyperechogenicity of the right lens and
26
with permission.)
414
Chapter 14 The Fetal Eye
LT Cataract
RT
A
Figure 14–10. Microphthalmia in utero and in the aborted specimen (A) Microphthalmia with cataract. A normal orbit and lens are imaged on the
right side (RT). On the left side, the orbit is small, and the lens contains hypoechogenic material. (B) An aborted fetus with microphthalmia.
cases in which a complete view of the fetal face failed
to demonstrate one or both orbits. However, we are
aware of two cases in which, although normal orbits
were observed during early pregnancy, the newborns
suffered from anophthalmia. The reason for this unexpected sequence of events is still unclear. In one of these
cases, we diagnosed bilateral anophthalmia at 15 weeks
of pregnancy ( Figure 14–15 ), and the newborn had congenital anophthalmia and a cardiac malformation. One
E,L.
B
of the patient’s sisters was followed in two successive
pregnancies. The first resulted in a normal newborn;
however, her next pregnancy resulted in a fetus with
unilateral microphthalmia that underwent termination
of pregnancy. The autopsy confirmed the diagnosis in
both cases ( Figures 14–15 and 14–16 ).
In cases of early microphthalmia, a high incidence of
associated anomalies, mainly cerebral, facial, and chromosomal disorders, are usually diagnosed by TVS.
43 – 45
It
A
Figure 14–11. Atrophy of the eyelids (A) Eyelids (EL). The upper and lower eyelids ( arrow) were small and open throughout the ultrasound (US)
examination. Partial atrophy was therefore suggested. (B) The aborted fetus with Neu-Laxova syndrome. There is partial atrophy of the eyelids, as well
as cataract.
B
Chapter 14 The Fetal Eye
415
Figure 14–12. Fetal cataract at 16 postmenstrual weeks, appearing as
concentric opacities ( arrows ), like “onion rings.”
should be noted, however, that normal measurements of
the fetal eyes in early and midpregnancy do not exclude the
possibility of subsequent development of microphthalmia.
The precise underlying causes for late-onset microphthalmia are not yet established.
Late-Onset Microphthalmia
Severe cataract and microphthalmia may be correctly
diagnosed by sonography.
detect moderate cataract in a case of repeat cataract in
a subsequent gestation.45 Also, anophthalmia may sometimes be secondary to a degenerative process in middle
and late pregnancy. In a retrospective group of late-onset
microphthalmia, we confirmed the normal eye measurements performed in early and midpregnancy.
31 , 43 , 45
However, TVS failed to
45
Like
Figure 14–13. Bilateral microphthalmia at 15 postmenstrual weeks.
The orbits are marked by an arrow and crosses.
late-appearing microcephalus, there may be a late arrest
of eye development, bringing about normal fetal screening at 15 and even 22 to 23 postmenstrual weeks, as well
as later development of microphthalmia.
Exophthalmos
Prominent eyes, or exophthalmia, are the result of shallow orbits or large eyeballs. The ultrasonographic diagnosis is done by imaging the protrusion of the eye on the
axial section, usually used for interorbital and binocular biometry ( Figure 14–17 ). Exophthalmos may appear
with various fetal abnormalities. Prenatal sonographic
diagnosis of exophtalmos has been reported in cases
of holoprosencephaly,
Crouzon syndrome,
hypokinesia sequence.
43
Saethre-Chotzen syndrome,
50
Roberts syndrome,
52
51
and akinesia-
49
A B C
D
Figure 14–14. Autosomal familial dominant cataract that affected the father and grandmother diagnosed at 15 postmenstrual weeks’ gestation as a
central homogeneous echogenicity of the fetal lens ( A)–(C ) and at 18 postmenstrual weeks ( D)–(F ) ( arrows ). Neonatal cataract was confirmed at delivery
as the only isolated neonatal malformation.
E
F
416
Figure 14–15. Bilateral familial anophthalmia at 15 postmenstrual
weeks. The patient’s sister was delivered of a neonate with congenital
anophthalmia and cardiac malformation. The next pregnancy in the
same patient was normal. However, the third pregnancy generated a
fetus with unilateral microphthalmia and was subsequently terminated.
The postmortem examinations validated the intrauterine-diagnosed
anophthalmia.
Chapter 14 The Fetal Eye
3
ABNORMALITIES OF HYALOID VASCULATURE
During early gestation, a conic net of blood vessels emerges
from the posterior portion of the eye to the anterior lens,
through the vitreous body, forming the primary vitreous
body. From the 7th through the 32nd week of gestation,
an apoptotic process causes this abundant blood vessel
network to degenerate, generating a bloodless vitreous
body, the secondary vitreous body ( Figure 14–18 ). Using
TVS, only the central part of the abundant blood vessels
network is visualized, as the hyaloid artery. Complete
or partial inhibition of the apoptotic process leading to
the degeneration of the vascular network may cause late
sequelae. Incomplete disruption of the vascular vessels in
the anterior end of the vitreous results in the formation
of the Mittendorf dot, whereas incomplete disruption
of the vascular vessels at its posterior end results in the
formation of the Bergmeister papillae. Both formations
are compatible with normal vision. Mittendorf dot, also
called the hyaloid body, is the embryonic remnant of
the hyaloid artery as it joins the tunica vasculosa lentis.
53
Although Mittendorf dot is present in normal eyes, representing the remains of the anterior portion of the hyaloid
artery, it may be associated with posterior lenticonus and
produce a posterior polar cataract, through extension of
the fetal vasculature through a gap in the lens.
be the pathophysiology of at least some forms of prenatal
and neonatal cataract.
54 , 55
The hyaloid artery does not
53
This may
always appear as a straight line connecting the retina to
the lens, but instead may have several normal variants
( Figures 14–19 and 14–20 ).
Persistent Hyperplastic Primary Vitreous
Persistent hyperplastic primary vitreous (PHPV) is an
infrequent developmental malformation of the eye characterized by the presence of a vascular membrane behind
the lens. The prevalence of this very rare fetal malformation in our population is about 1 in 60,000, occurring when
the hyaloid artery and the associated abundant vitreous
vessels fail to degenerate by 32 weeks’ gestation, resulting in the development of cataract and microphthalmia.
This anomaly is usually sporadic and unilateral, but when
bilateral, trisomies 13 and 18 should be ruled out. Only
one case report has been published in which the diagnosis was made at 23 weeks.
this case report
54
is equivocal, as PHPV can be diagnosed
54
The accurate diagnosis in
A B
Figure 14–16. Unilateral microphthalmia: (A), (B) Unilateral microphthalmia at 15 postmenopausal weeks. One of these two fetuses is from the third
pregnancy of the patient described in Figure 14–15.
Chapter 14 The Fetal Eye
417
A
Figure 14–17. (A) Exophthalmos of the right eye in a fetus at 19 postmenstrual weeks. (B) Bilateral exophthalmos in a fetus with Raine syndrome at
21 postmenstrual weeks.
only during the third trimester, when physiologically,
the apoptotic regression of the vitreous blood vessels is
completed. In contrast to this case report, Figure 14–21
describes a true case of PHPV at 34 weeks, with bilateral
cataract and microphthalmia associated with trisomy 13
(see also Figure 14–22).
PATHOLOGY OF THE
INTERORBITAL DISTANCES
Hypotelorism
Hypotelorism is defined as a decreased interorbital distance ( Figure 14–23 ) (see Chapter 2 ). It is usually associated
with other fetal abnormalities, mainly holoprosencephaly
(arhinencephaly).
form of the spectrum and is usually associated with
midline deficiencies in facial development and incomplete morphogenesis of the forebrain. There is a single
eye or partially divided eye in a single orbit and arhinia
with proboscis. In most cases, other malformations are
present.
57 – 65
cyclopia, trisomy D has been described with the greatest
frequency.
Environmental factors such as viremia and salicylates
have been suggested as a possible cause of this abnor-
65
mality.
In ethmocephaly, there is extreme hypotelorism
but separate orbits, as well as arhinia with proboscis. In
cebocephaly, hypotelorism is associated with a proboscislike nose or a single-nostril nose, but there is no median or
49 , 55 , 56 , 66
cleft lip.
three different types of orbital anomalies is not easy. It may
be difficult to differentiate between a single orbital cavity
and very close or fused orbits. Furthermore, in some cases
the observers failed to identify the orbits, and the diagnosis
relied on the demonstration of a proboscis in a fetus with a
55 , 56
Cyclopia represents the most severe
Of the various karyotypes associated with
62 – 64
An accurate sonographic diagnosis of these
B
brain anomaly.
ful in detecting cyclopia and proboscis, as demonstrated in
a fetus at 13 weeks’ gestation.
58 , 60
Three-dimensional (3D) US may be use-
67
Hypotelorism has been described in fetuses with
microcephaly, oculu-dento-digital dysplasia and medical
syndrome.
56
Hypertelorism
Hypertelorism is a craniofacial defect that consists of
abnormally spaced orbits. The sonographic diagnosis
therefore relies on the measurement of an abnormally
large interorbital distance. Hypertelorism may be isolated or associated with many malformation syndromes.
Romero and colleagues
56
summarized nearly 150 fetal syn-
dromes with hypertelorism.
Prenatal diagnosis was reported by several investigators
in fetuses with diverse associated malformations.
42 , 56 , 68 , 69 – 74
Recently, mycophenolate mofetil (CellCept), an immunosuppressant drug used by young women with autoimmune
diseases, such as systemic lupus erythematosus, has been
found to be teratogenic and capable of producing hypertelorism.
72
Retinal Disorders
Prenatal sonographic diagnosis of retinal detachment
and dysplasia is extremely rare and has been reported in
only a few cases, (Figure 14–24) most of them associated
with Walker-Warburg syndrome.
Walker-Warburg syndrome, recurrence can be suspected
as early as the first trimester, but the diagnosis cannot
be excluded on the basis of normal appearance on US
until later in pregnancy.
73 – 76
ized by the presence of cobblestone lissencephaly with
other brain malformations, eye anomalies, and muscular
73 – 76
In some cases of
This syndrome is character-
418
Chapter 14 The Fetal Eye
Neural
fold
Neural
groove
Lens
plate
Forebrain
Forebrain
Invaginating
optic vesicle
Optic vesicle
3 weeks. Dorsal view.
Neural folds beginning
to close.
Surface ectoderm
Outer neural ectoderm
Invagination
of lens vesicle
Inner neural
ectoderm
Mesenchyme
5 weeks. Cross-section. Development of
optic cup and lens vesicle.
Pigment epithelium of retina
Neural retina
Lens
vesicle
Surface
ectoderm
7 weeks. Cross-section. Differentiation of
layers of neural ectoderm into pigment
epithelium and neural retina and expansion
of lens vesicle.
Figure 14–18. The apoptotic degeneration of the conic vascular network in the primary vitreous, in the seventh and ninth weeks (left), to the “blood
vessel–free” secondary vitreous body, after the seventh month of gestation (right). (Reproduced with permission from Riordan-Eva P, Whitcher JP.
Vaughan & Asbury’s General Ophthalmology 17th ed. New York: McGraw-Hill, 2008. Fig. 1–28.)
Hyaloid system developing
4 weeks. Transverse section.
Formation of optic vesicles
and lens plates.
Optic stalk
6 weeks. External view. Closure of optic fissure
through which hyaloid vessels enter the optic cup.
Hyaloid
remnants
Conjunctival
sac
Lids
closed
Cornea
Anterior
chamber
Invaginating
lens plate
1
4
/2 weeks. Transverse section.
Invagination of optic vesicles
and lens plates.
Optic cup
Optic stalk
Optic fissure
Neural retina
Lens
Mesenchyme
8 weeks. Cross-section. Fusion of lids
and development of extraocular muscles
from mesenchyme.
Pigment
epithelium
of retina
Extraocular
muscle
Optic
nerve
dystrophy. Ultrasound of the fetal eye reveals a conical
structure within the globe with its base toward the lens
and its apex pointing posteriorly toward the optic nerve.
In one case,
eye only. However, at the time of autopsy, the anomaly
was identified in both eyes. Monteagudo et al
73
this ultrasonic image was obtained in one
74
described
this syndrome at 34 postmenstrual weeks in a fetus presenting with hydrocephaly and retinal detachment. (See
also Chapter 16 .)
In another case,
77
a similar conical structure was seen
on US of the fetal orbits; examination of the newborn
showed disorganized fibrous structures within the vitreous
Chapter 14 The Fetal Eye
A
B
419
C D
Figure 14–19. Variants of a hyaloid artery. (A), (B) Wide bifurcated hyaloid artery at 15 postmenstrual weeks’ gestation. (C), (D) Threadlike structured
hyaloid artery at 23 weeks’ gestation.
cavity. On physical examination, absence of the irises and
pupils was noted.
Bilateral retinal detachment was also imaged by US
in a fetus with Norrie disease.
78
The principal feature
of this disease is retinal dysplasia with resultant retinal
detachment (Figure 14–24).
Maat-Kievit and colleagues
79
reported on the detec-
Recent studies
lar techniques to screen prenatally for retinoblastoma,
and others have reported on the first newborn delivered
following preimplantation genetic exclusion of retinoblas-
83
Prenatal diagnosis of other rare disorders has been
toma.
reported, including orbital heterotopic brain tissue
orbital teratoma.
81 , 82
have reported on the use of molecu-
86
84 , 85
and
tion of a large retinoblastoma in a fetus at 21 postmenstrual weeks’ gestation. The oval-shaped tumor protruded
from the right side of the fetal face. The right orbit, as well
as the fetal nose and mouth, could not be imaged, and a
deformity of the normal anatomy of the facial bones was
noted. Another case of fetal ocular neoplasm, rhabdomyosarcoma, is shown in Figure 14–25 . Retinoblastoma is a
very rare tumor, with an estimated annual incidence of
between 1 in 15,000 and 1 in 34,000 in childhood, and
about 1 in 30,000 prenatal incidence.
79 , 80
CONGENITAL NASOLACRIMAL DUCT CYST
The presence of fetal periorbital cystic structures raises
the possibility of dacrocystocele;
apparent only in late pregnancy. Congenital nasolacrimal
obstruction occurs in 1.75% to 6% of newborns.
abnormality may be unilateral or bilateral. Epiphora is the
only clinical sign in most cases, and spontaneous resolution occurs during infancy. However, in some cases, cysts
87
this condition is usually
88 – 95
The