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300
Chapter 8 Anomalies of the Cerebellum
pregnancies, most cases will escape detection. In some
cases, an open fourth ventricle can be identified. After
20 weeks’ gestation, this finding requires an expert evaluation by either neurosonography or MRI.
Prognosis
Most infants have severe intellectual impairment, and
early death is common. Neurologic dysfunction typically
includes ataxia, abnormal breathing patterns (hyperpnea
intermixed with central apnea in the neonatal period), and
abnormal behavior (temperament, hyperactivity, aggressiveness, and dependency).
51 , 54
Obstetric Management
When a confident diagnosis is made, termination of pregnancy may be offered to the couples. Otherwise, no modification of standard obstetric management is indicated.
UNILATERAL CEREBELLAR LESIONS
Definition
Echogenicity of one cerebellar hemisphere usually evolving
into unilateral hypoplasia
Excludes
Global cerebellar hypoplasia
Etiopathogenesis
Echogenicity of one cerebellar hemisphere has been found
as a consequence of hemorrhage, although in some cases
the lesion may have an ischemic cause; in time the affected
hemisphere becomes atrophic.
27 , 57
Two of the cases thus
far described have occurred in severely anemic fetuses
that were salvaged with intrauterine transfusions. 57 An
association with cytomegalovirus (CMV) infection has
been reported. 58 We have also documented this finding in
otherwise normal fetuses, typically in the second trimester
of gestation.
Diagnosis
One of the cerebellar hemispheres is initially brightly
echogenic and in the following weeks becomes hypoplastic
and/or develops into a cystic lesion ( Figure 8–23 ).
Differential Diagnosis
Global cerebellar hypoplasia characterized by an overall
reduction in cerebellar size .
Associated Anomalies
Intracranial hemorrhage at other sites, CMV infection .
Prognosis
The experience thus far is limited, and it is impossible to
draw on specific figures. The handful of cases we have
3v
AB C
Figure 8–23.
alloimmunization. It was resuscitated with intrauterine transfusions but developed an intense echogenicity of one cerebellar hemisphere that eventually became atrophic. The vermis and contralateral hemisphere appeared intact. The neurologic and intellectual development was normal at long-term
postnatal follow-up. (Reproduced, with permission, from Ghi T, Brondelli L, Simonazzi G, Valeri B, Santini D, Sandri F, Ancora G, Pilu G. Sonographic
demonstration of brain injury in fetuses with severe red blood cell alloimmunization undergoing intrauterine transfusions. Ultrasound Obstet Gynecol.
2004;23(5):428–431.)
Acquired intrauterine lesion of one cerebellar hemisphere. This fetus developed severe anemia and hydrops as a consequence of anti-D
57
Chapter 8 Anomalies of the Cerebellum
301
seen in which the lesion was isolated demonstrated normal
neurologic follow-up. Involvement of the vermis is usually
associated with a worse prognosis.
59
Obstetric Management
CMV infection usually results in multiple abnormal cerebral findings. Alloimmune thrombocytopenia typically
causes hemorrhages in the cerebral hemispheres. However,
it would seem prudent to exclude both conditions. In continuing pregnancies, there is no indication to modify standard obstetric care.
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severe red blood cell alloimmunization undergoing intrauterine
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Chapter 9
INTRAUTERINE INFECTIONS AFFECTING THE BRAIN
Gustavo Malinger ● Tally Lerman-Sagie
KEY POINTS
1. Depending on geographic factors, cytomegalovirus
(CMV) and toxoplasmosis are the more frequent
intrauterine infections (IUIs).
2. The pattern of brain involvement in CMV-IUI
may range from minimal (small periventricular
cysts, intrathalamic vasculopathy) to severe
damage (brain atrophy, malformations of cortical
development, and hemorrhages).
3. The prognosis is usually poor in the presence of
intracranial findings.
4. Infected fetuses without brain findings are
generally asymptomatic at birth but may develop
sensorineural deafness.
The fetus may become infected with a variety of organisms
through transplacental passage or as a result of an ascending infection. In some patients, the infection may involve
the central nervous system (CNS), causing lesions in different areas and grades of severity ( Table 9–1 ).
Cytomegalovirus (CMV) and Toxoplasma gondii are
the most common pathogens affecting the brain. Other
organisms that may infect the developing fetal brain are
rubella virus,
parvovirus B19,
West Nile virus,
cruzi,
1
varicella zoster virus, 2 herpes simplex virus,
5 , 6
lymphocytic choriomeningitis virus,
8
10
and the nematode filarial.
Treponema pallidum,
9
1 1
Trypanosoma
This chapter reviews
3 , 4
each of these sources of infection.
CYTOMEGALOVIRUS
Definition
Cytomegalovirus (CMV) is a large DNA virus with a wide
infectious clinical spectrum ranging from subclinical to
severe multisystem involvement. CMV is transmitted by
person-to-person contact. Following maternal infection, it
may be transmitted through the placenta to the fetus.
Synonyms
Herpesvirus 5, cytomegalic inclusion disease
Incidence/Prevalence
Following the almost complete disappearance of congenital
rubella after the introduction of widespread immunization
programs, CMV infection has become the most common
infection affecting the developing fetus.
The prevalence of CMV-seropositive pregnant women
or at reproductive age ranges from > 99% in Turkey
to between 43.6% and 57.2% in France
13
and England,
respectively.
A meta-analysis study of 27 culture-based universal
study groups found a birth prevalence of congenital CMV
of 0.64% (95% CI: 0.60–0.69%).
from 954 infants identified with congenital CMV infection,
only 103 (11%) were considered symptomatic.
15
The same study found that
15
A primary
infection during pregnancy carries a significantly higher
risk of fetal transmission than a recurrent infection (32.3%
vs 1.4%).
15
Pathogenesis
Maternal viremia, placental infection, and hematogenous
dissemination to the fetus are the most likely sequence
of events leading to congenital CMV infection.
the viremic phase, the virus circulates and disseminates,
carried by leukocytes. The exact way in which CMV infects
7
the placenta is not clearly understood, but once it reaches
the fetal compartment, hematogenous dissemination
16
ensues.
placental insufficiency has been described as a possible factor in the pathogenesis of fetal disease.
as a teratogen, producing chromosomal injury or altering
modulation of developmental gene expression.
A direct effect on placental development causing
17
CMV may also act
18
Etiology
CMV infection is caused by a large double-stranded
DNA herpesvirus. Geneotypically different CMV strains
have been reported. 19 Preconceptional immunity against
CMV provides only partial protection against intrauterine
1 6
During
12
14
Table 9–1. ULTRASOUND CENTRAL NERVOUS SYSTEM FINDINGS FOLLOWING INTRAUTERINE INFECTIONS
Pathogen CNS involvement Reported in Ventriculomegaly Abnormal PVWM Calcifications Microcephaly Others
304
Chapter 9 Intrauterine Infections Affecting the Brain
CMV Common Fetus, infant Common Common Frequent Frequent MCD, CC, cerebellum,
Toxoplasma Common Fetus, infant Common Rare Common Rare Hydranencephaly
Rubella Common Infant Rare Common Common Common –
Varicella zoster Extremely rare Fetus, infant Rare – Rare Rare Encephalitis, cerebel-
Herpes simplex Extremely rare Fetus, infant Common Common Rare Rare Encephalitis
Parvovirus B19 Extremely rare Fetus, infant Rare – – – Hemorrhage, stroke,
LCMV Common Fetus, infant Common Rare Common – –
West Nile virus Extremely rare Fetus, infant – Rare – – Meningitis, encephalitis
Syphilis Extremely rare Fetus, infant Rare Rare – Rare MCD
Trypanosoma Extremely rare Fetus, infant – – – – Meningoencephalitis
CC, corpus callosum; CMV, cytomegalovirus; LCMV, Lymphocytic choriomeningitis virus; MCD, malformations of cortical development; PVWM, periventricular white matter, including cysts.
hemorrhage
lum, MCD
MCD
Chapter 9 Intrauterine Infections Affecting the Brain
Figure 9–1. Cytomegalovirus (CMV) inclusion body in the white
matter at 24 postmenstrual weeks. (Courtesy of Dr. Deborah Kidron,
Kfar Saba, Israel.)
transmission of the virus, as reinfection with a different
strain of CMV may lead to intrauterine transmission and
symptomatic congenital infection.
2 0
Pathology
Intrauterine CMV infection frequently affects the fetal
brain; the motif of this predilection is not clear, and
the cellular targets not well defined. The presence of
intracellular inclusion bodies in the brain ( Figure 9–1 )
is considered diagnostic of CMV infection, but there
are almost no histologic data regarding the type of cells
affected.
21
From human and animal cell line cultures,
it seems that neural stem cells in the fetal brain are
the predominant cell type affected during development
by CMV. Cheeran et al
2 1
proposed possible mechanisms
of CMV developmental disruption, including direct damage followed by reduction in the number of neural stem
cells or intermediate progenitors; alterations in stem cell
migration and fate of cell differentiation; infection of
astroglia, causing disruption of their normal supportive
functions; and alterations in the microenvironment of
the developing brain due to cytokines and soluble factors
generated by resident glial cells.
These combined factors may produce not only malformative pathologies of different severity, including microcephaly and malformations of cortical development
22
( Figure 9–2 ), but also direct injury to the brain, resulting
in ventriculomegaly, calcifications, brain atrophy, cyst formation, or hemorrhage.
22 , 23
Associated Anomalies
Fetal CMV infection may affect other systems and organs.
Reported gastrointestinal findings include hyperechogenic intestines,
splenomegaly,
rience, a frequent early sign of infection is hyperechogenic
intestines. It is rarely observed as an isolated finding, and
it is usually transient.
Rarely, fetal CMV infection may involve the heart
and cause cardiomegaly,
24 – 26
bowel dilation,
24 , 26 , 28 , 29
and liver calcifications.
29
endocardial fibroelastosis with
2 7
hepatomegaly and/or
25
In our expe-
Figure 9–2. Polymicrogyria in a fetus at 31 postmenstrual weeks with
CMV infection. Low field magnification. Note the transition from an
almost normal six-layer cortex to the zone with polymicrogyria. Similar
foci of polymicrogyria were found in other locations. (Courtesy of
Dr. Letizia Schreiber, Holon, Israel.)
hypoplastic left heart,
restriction, hydrops, and oligohydramnios are frequently
24 – 26 , 29
present;
however, hydrops and oligohydramnios may
29
and cardiomyopathy.
24
Growth
be transient and resolve following the acute stages of the
fetal disease. Placental thickness is significantly increased
in infected fetuses.
29 , 30
When a diagnosis is reached during pregnancy,
multiple organ involvement may be present in as much as
42% of the patients.
2 9
Risk of Recurrence
Although uncommon recurrent maternal CMV infection
may produce fetal disease, this may be due to reactivation of the disease or more probably to infection by a
different strain.
fetuses the infection may be mild or even subclinical,
but according to our personal experience and also to
isolated cases reports, this assumption may not necessarily be true.
found six fetuses with sonographic findings characteristic of CMV infection whose mothers were known to
be CMV seropositive before or at the beginning of the
index pregnancy; five out of six fetuses had severe brain
involvement.
Well-documented cases of the consecutive occurrence of fetal CMV infection in the same woman are
extremely rare. Stagno et al
pregnant women who delivered affected siblings. The
interval between the pregnancies was 17 and 14 months,
respectively, and in both cases, the younger children were
asymptomatic.
It is important to remember that, in these cases,
the differential diagnosis includes the possibility of
fetal disease due to a different infective agent and the
autosomal recessive Aicardi-Goutières (pseudo-TORCH
20
It is usually recognized that in these
31 – 34
During a 3-year period, Zalel et al
35
described in 1973 two
305
34
306
Chapter 9 Intrauterine Infections Affecting the Brain
Normal
AB C
A
B
Figure 9–3. Transvaginal parasagittal planes. ( A ) Normal fetus at 24 postmenstrual weeks. The echogenicity of the brain parenchyma is similar
throughout the whole surface. (B–F) Five fetuses with proven CMV at different gestational ages showing a clearly demarcated hyperechogenic periventricular zone ( arrows ). Not all of the affected fetuses have ventriculomegaly. Note the presence of punctuate calcifications ( B, F ), periventricular cysts
( D, E ), and intraventricular adhesions ( E, F ).
F
E
D
C
DE F
[toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus) syndrome.
24w
25w
36
Intracranial calcifications involving the brain paren-
chyma, thalami, basal ganglia, and cerebellum can be dem-
21w
22w
30w27w
onstrated in at least some cases, starting from the second
Sonographic Diagnosis
Fetal CNS signs of congenital CMV infection were first
described in the 1980s
in newborns.
38
grades of severity, calcifications, and microcephaly are the
more frequent presenting signs, abnormal periventricular
echogenicity with or without cysts is consistently present
in severely affected fetuses.
CMV may produce a very wide spectrum of brain
pathologies according to the period of brain development
in which the infection starts and probably also to the
virulence of the virus or the immunological status of the
mother and fetus. The general understanding is that early
infection produces a more severe and generalized pattern of disease, whereas late infection produces a milder
39
disease.
Increased periventricular echogenicity is best depicted
by transvaginal sonography ( Figures 9–3 and 9–4 ).
Characteristically, it involves the whole periventricular
zone of both hemispheres, and it is well demarcated from
the remaining brain parenchyma. Cysts and calcifications
may be found within the zones of increased echogenicity.
Cyst formation may be the result of parenchymal necrosis
or liquefaction of small zones of hemorrhage; we have
observed that in some cases the cyst walls, when adjacent,
undergo lysis, and a larger porencephalic cyst is formed
( Figure 9–5 ). The presence of abnormal periventricular
findings may be depicted in some, but not all, patients
during a routine transabdominal examination using axial
planes ( Figure 9–6 ).
37
and are similar to those reported
Although ventriculomegaly of different
trimester. The calcifications may be punctuate or coarse;
regional, isolated, diffuse, or in clusters (see Figures 9–3
and 9–4 ). Coarse echogenicities adjacent to the lateral
ventricles may represent an end stage of periventriculitis.
The differential diagnosis of intracranial calcifications
includes other infectious agents, intracranial teratomas,
tuberous sclerosis, Sturge-Weber syndrome, AicardiGoutières syndrome, and sagittal or transverse sinus
thrombosis.
36 , 41 – 46
Microcephaly is consistently observed but may not be
obvious during the second trimester or even the early third
trimester; in many cases, microcephaly is accompanied by
brain atrophy ( Figure 9–7 ). Migration and organization
disorders ranging from focal sulcal anomalies to generalized lesions
40 , 47
(see Figures 9–4 and 9–7 ) are usually found
in fetuses with severe involvement.
Congenital CMV may affect the white matter; this pattern of disease has been described in children and adults
but may also be depicted during fetal life, usually late in
the third trimester ( Figure 9–8 ). Callosal dysgenesis may
be the result of this type of insult.
Estroff and colleagues
22 , 40
49
reported the presence of
branching linear echogenic areas in the thalami of a
fetus with CMV. This entity is frequent in the neonatal
period and was initially considered a characteristic sign of
infection.
40
nonspecific sign, as it has also been described in children
50 , 51
The current approach is that it represents a
with asphyxia, chromosomal anomalies , metabolic diseases,
maternal heroin abuse, and in the recipient in twin-to-twin
transfusion syndome.
3 8
Single or ramified linear echo
densities, produced by hyalinization or mineralization of
48
Chapter 9 Intrauterine Infections Affecting the Brain
307
Normal
A
25w 20w 22w
BC
25w
26w 29w
DEF
Figure 9–4. Transvaginal coronal planes. (A) Normal transthalamic section at 25 postmenstrual weeks. The thalami are slightly more echogenic than
the brain. (B–F) Increased periventricular echogenicity with clear demarcation from the remainder of the brain ( arrows ) in five fetuses with CMV at
different gestational weeks. Transfrontal plane ( D ), transcaudate plane ( B, F ), transthalamic plane ( C ), and transoccipital plane ( E ). Coarse calcifications
and abnormal sulcation with early development of numerous shallow sulci are present in the fetus at 29 weeks of gestation ( F ).
24.5w
26.0w
AB
Figure 9–5. Transvaginal parasagittal planes. Periventricular occipital cysts ( A ) at 24.5 postmenstrual weeks converting into a larger porencephalic
occipital cyst or intraventricular adhesion ( B ) 2 weeks later. (From Malinger G, Lerman-Sagie T. Fetal cytomegalovirus infection: The brain as a window
in the establishment of prognosis. In: Ramenghi A, Evrard P, Mercuri E, eds. Mariani Foundation Paediatric Neurology. Perinatal brain damage: From
Pathogenesis to Neuroprotection. Vol 19. Montrouge: Editions John Libbey Eurotext; 2008;49–54, with permission.)
308
Chapter 9 Intrauterine Infections Affecting the Brain
24w
AB
Figure 9–6. Transabdominal axial planes at the level of the lateral ventricles. (A–B) Images of fetuses with known CMV infection and periventricular
hyperechogenicity show that it is clearly differentiated from the surrounding brain ( arrows ). Both fetuses (A) at 24 weeks, (B) at 26 weeks, presented
with porencephalic occipital cysts ( arrowheads ) but without ventriculomegaly.
the perforating striatal arteries, are better visualized in the
parasagittal plane ( Figure 9–9 ). Striatal arteries originate
from the middle cerebral arteries and irrigate the germinal
matrix and when normal are not depicted.
Although extremely uncommon, isolated cases of
cerebral
52 , 53
and cerebellar
reported. The cerebellum may also be involved demonstrating calcifications, cysts,
54
hemorrhages have been
22 , 40
or a reduction in size.
examinations. In 13 fetuses in which US only depicted
extracerebral findings, MRI detected brain lesions in 46%.
MRI confirmed the presence of cerebral signs found by US
in the remaining 14 fetuses and in some of them added new
information that was not depicted by US.
23
leagues
studied by targeted US and MRI 49 fetuses with
proven CMV infection and compared the results to the postnatal US or post mortem examinations; the best positive pre-
26w
5 5
Benoist and col-
dictive value (88.9%) was obtained when both US and MRI
Magnetic Resonance Imaging Diagnosis
Two recent retrospective studies have compared fetal ultrasound (US) and magnetic resonance imaging (MRI) findings in patients with CMV. Picone and colleagues
38 fetuses in which CMV polymerase chain reaction (PCR)
was positive in the amniotic fluid.
5 5
MRI failed to show
any sign of brain infection in 11 fetuses with normal US
55
studied
showed abnormal findings, and the best negative predictive
value (93.5%) was obtained when the US was normal.
We have seen five CMV PCR-positive fetuses in whom
there was a discrepancy between the US and MRI findings.
The US was normal, whereas the MRI raised the suspicion
of white matter abnormalities. Three children were delivered and were developing normally at ages 2 to 4 years;
two pregnancies were terminated, and the autopsies were
3
2
AB C
Figure 9–7. Orthogonal views of a fetus with CMV at 24 weeks, 2 days; the head circumference (HC) was 20 cm (<–2 SDs [standard deviations]).
Axial ( A ), coronal ( B ), and sagittal ( C ) views. Note the enlarged subarachnoidal space ( 1 ), the underdeveloped sylvian fissure ( 2 ), and the presence of an
abnormal sulcus in the frontal lobe ( 3 ). The small coronal figure provides an image for comparison of a normal fetus at 22 weeks of pregnancy.
2
1
1
1
Chapter 9 Intrauterine Infections Affecting the Brain
309
4
2
1
A
Figure 9–8.
and was referred because of ventriculomegaly ( 1 ) at a routine ultrasound (US) examination. Bilateral large intraventricular cysts ( 2 ) and small periventricular pseudocysts ( 3 ) are depicted. The sulci and gyri are not observed due to white matter involvement ( 4 ).
CMV in a fetus at 35 postmenstrual weeks; (A) axial, (B) coronal, (C) sagittal. The mother was CMV seropositive during the first trimester
4
2
1
BC
negative for brain CMV; but in one patient microglial nodules consistent with an inflammatory reaction were found.
Garel 56 reported that in all patients with a normal US the
MRI was also normal.
Neurosonography and MRI perform equally in the
demonstration of morphological anomalies ( Figures 9–10
and 9–11 ).
4
3
the available tests, and the lack of proven intrauterine
treatments, universal screening for CMV infection is
not an integral part of prenatal care. In these patients,
second- or third-trimester US examinations are the only
opportunity to raise the suspicion of fetal disease. The
presence of any of the extracerebral findings described
previously should prompt the performance of serological
4
2
tests and a detailed brain examination for CMV signs.
Implications for Sonographic Screening,
Including Earliest Recognition
Due to the low prevalence of symptomatic congenital
CMV infection, the low sensitivity and specificity of
Before 20 weeks, the only described sign of fetal infection
is intestinal hyperechogenicity; later on the presence of
hepatosplenomegaly, ascites, or cardiomegaly should be
considered suspicious. During routine second-trimester
examinations, the presence of ventriculomegaly or
Figure 9–9. Linear striatal vasculopathy ( arrows ) at 35 postmenstrual weeks in an otherwise apparently normal fetus with positive polymerase chain
reaction (PCR) CMV amniotic fluid.