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TRANSCRIPT
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REGULAR ARTICLE
Lenticulostriated vasculopathy is a high-risk marker for hearing loss in
congenital cytomegalovirus infections
Efraim Bilavsky ([email protected])1,7, Michael Schwarz1,7, Joseph Pardo6,7,
Joseph Attias5, Itzhak Levy3,7, Yishai Haimi-Cohen4,7, Jacob Amir1,7
1Department of Pediatrics C, Schneider Children's Medical Center, Petah Tiqva,
Israel
2Department of Pediatric Radiology, Schneider Children's Medical Center, Petah
Tiqva, Israel
3Infectious Diseases Unit, Schneider Children's Medical Center, Petah Tiqva, Israel
4Day Hospitalization Unit, Schneider Children's Medical Center, Petah Tiqva, Israel
5Institute of Audiology and Clinical Neurophysiology, Schneider Children's Medical
Center, Petah Tiqva, Israel; Department of Communication Sciences & Disorders,
University of Haifa, Haifa 6Department of Gynecology and Obstetrics, Rabin Medical
Center, Beilinson Hospital, Petah Tiqva, Israel
7Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Short title: Lenticulostriated vasculopathy and congenital cytomegalovirus
Correspondence
Efraim Bilavsky, MD, Department of Pediatrics C, Schneider Children’s Medical
Center of Israel, 14 Kaplan Street, Petah Tiqva 49202, Israel. Phone: +972-3-925
3775, Fax: +972-3- 925 3801
E-mail: [email protected]
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Aim: This study investigated the relationship between lenticulostriated vasculopathy
(LSV) and hearing loss in 141 infants with congenital cytomegalovirus (cCMV)
infection.
Methods: We included all infants with cCMV infection who were followed in our
clinic for more than a year with only LSV signs of brain involvement on initial brain
ultrasound. Group one comprised 13 infants with no hearing impairment at birth who
were not treated with gan/valganciclovir during 2006-2009. Group two was 51
infants with LSV and no hearing impairment who had been treated since mid-2009.
Group three was 25 infants born with LSV and hearing loss, who had been treated
from birth. Group four was 52 control infants born during the same period with
asymptomatic cCMV. Hearing tests were performed during the neonatal period and
every four to six months until four-years-of-age.
Results: Hearing deterioration was more extensive in group one (85%) than group
two (0%, p<0.001) and the asymptomatic group (10%, p<0.001) and occurred more
often in group four (10%) than group two (0%, p=0.008).
Conclusion: LSV was common in infants with cCMV infection and may serve as a
sign of central nervous system involvement and further hearing deterioration.
Antiviral treatment may be prudent in such infants.
Keywords brain, congenital infection, cytomegalovirus, hearing loss,
lenticulostriated vasculopathy
3
Key Notes
This study investigated the relationship between lenticulostriated
vasculopathy (LSV) and hearing loss in 141 infants with congenital
cytomegalovirus (cCMV) infections who had been followed up in our clinic for
more than a year.
We found that LSV was common in infants with cCMV and may serve as a
sign of central nervous system involvement and further hearing deterioration.
It may be prudent to provide such infants with antiviral treatment.
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INTRODUCTION
In healthy neonates, the lenticulostriate arteries supplying the basal ganglia and
thalamus are almost indistinct from brain parenchyma on a grey-scale ultrasound
(1). However, bright linear candlestick-like strips (Figure 1), compatible with
thickening of the arterial walls in these regions, suggest lenticulostriated
vasculopathy (LSV) (1,2).
The rate of LSV detected in neonates who have undergone brain ultrasound
studies has been reported to range from 0.4% to 5.8% (1-3). This wide range
probably reflects the study populations, as they included healthy and sick neonates
as well as mature and premature babies (1-3). LSV is also associated with many
congenital or acquired neonatal disorders, including prematurity, fetal alcohol or
drug exposure, congenital heart defects, congenital malformations, hypoxic-
ischaemic conditions and congenital or perinatal infections (1-3).
While congenital cytomegalovirus (cCMV) is the leading cause of congenital
infection, affecting about 1% of all live births worldwide (4), the relationship between
LSV and cCMV remains unclear. Two large studies have reported that congenital
infections, including cCMV, were a rare cause of LSV (5,6). Other smaller reports
have linked cCMV to LSV with, or without, other ultrasonographic findings (7-9).
However, the prevalence of ultrasonographic findings in infants with cCMV, and its
prognostic significance, has not yet been determined.
Our group has also investigated whether LSV, as a single abnormal finding in
neonates with cCMV, was a sign of central nervous system involvement (2).
Because LSV was the only finding on initial examination in nine out of the 18 infants
we studied, we did not start antiviral therapy and all nine of these untreated infants
exhibited hearing deterioration (2). Following these cases, our group began treating
all infants with LSV and cCMV.
5
The aim of this study was to report our experiences when we treated a large
group of infants with cCMV and to determine the relationship between LSV and
hearing loss.
PATIENTS AND METHODS
This was a retrospective study with cohorts that developed over time. The study
was conducted at the Schneider Children’s Medical Center, which is the largest
paediatric hospital in Israel. We reviewed the ultrasonographic and clinical data of all
infants with cCMV infections, due to intrauterine infections, who were followed in our
paediatric clinic between January 2005 and December 2012. Details of the mother’s
pregnancy was also collected. We explored any maternal primary or non-primary
infections, together with the trimester when the infections occurred, as previously
reported (10).
cCMV infection was diagnosed by a positive urine culture, using a shell vial
assay, obtained during the first two-weeks-of life. Additional studies of infants
diagnosed with cCMV immediately after birth included a complete physical
examination, including head circumference, complete blood count, liver and kidney
function tests, funduscopy performed by a paediatric ophthalmologist and brain
ultrasound performed by a paediatric radiologist. Ultrasound over the anterior and
posterior fontanel and asterion was performed using the Philips HDI 5000 and
Philips IU 22 ultrasound imaging platforms (Philips Healthcare, Andover,
Massachusetts, USA) with 8.0-5.0 MHz transducers. The auditory thresholds of all
infants diagnosed with cCMV infection were studied using brainstem evoked
response audiometry (BERA) within four weeks of birth and the audiologists were
unaware of their ultrasound and treatment status.
The auditory tests were performed during natural sleep, without sedation.
Auditory-evoked potentials were recorded in response to rarefaction clicks of 100 µS
duration, presented at a rate of 13 per second through insert earphone transducers
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attached to a plastic tube, providing an acoustic delay of 80ms (E-A-RTONE® 5A;
Aearo Company, Indianapolis, Illinois, USA). The auditory brain response (ABR)
was measured using an active electrode attached to the vertex or forehead and
attached to an electrode at the ipsilateral mastoid. A third ground electrode was
placed on the contralateral mastoid. Amplification band-pass filters were set at 30-
3000 Hz and the analysis period was set at 15.36 ms for two replications of 1,024
sweeps each. Monaural ABRs were recorded in response to air conduction
decreasing the stimulus levels from 90 dB HL up to the thresholds. If air conduction
thresholds were elevated, bone conduction click-stimuli were applied. The auditory
responses were digitised at a sampling rate of 10 kHz, with 12-bit accuracy, using
the Bio-Logic Explorer System (Bio-Logic Systems Corp., Mundelein, Illinois, USA).
Corrected BERA thresholds, embedded as part of the system calibration, were
categorised as normal thresholds (<25 dBHL), mild hearing loss (25 to 44 dBHL),
moderate hearing loss (45 to 69 dBHL) and severe hearing loss (≥70 dBHL).
Only bone-conduction results were reported in cases of air bone gap thresholds.
BERA was performed on all children aged two-years-of-age or under during the
neonatal period and every four to six months until the age of four. A behavioural
hearing test was performed on all children over the age of two, every four to six
months, until they were four-years-old. Behavioural audiometry included visual
reinforcement audiometry in children between two to three-years-of-age and
conditioned play audiometry or conventional audiometry for children aged four or
older. Behavioural audiological responses were measured using calibrated GSI-61
audiometers and speakers (Grason Stadler, Inc, Madison, Wisconsin, USA) in a
double-walled sound-attenuated room (Industrial Acoustics Co Ltd, Winchester,
Hampshire, UK). In addition, standard tympanometry was performed using an
electroacoustic admittance instrument (AZ26 Middle Ear Analyzer, Interacoustic,
Assens, Denmark). A high-frequency (1 kHz) probe tone was used.
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If middle ear dysfunction was suspected, patients underwent a detailed otologic
inspection. All auditory thresholds tests were administered by certified and skilled
audiologists and were considered as reliable thresholds.
An infant was diagnosed with symptomatic cCMV infection if any of the following
conditions were present: 1) microcephaly, head circumference <3%, 2) hearing
impairment detected by the BERA test; 3) chorioretinitis and 4) abnormal findings on
brain ultrasound including calcifications, periventricular hyperechosity, ventricular
dilatation and pseudocysts. LSV was not considered a sign of central nervous
system involvement in our clinic until mid-2009. However, since then, LSV has also
been considered a sign of symptomatic cCMV infection and a basis for starting
antiviral treatment.
During the study period, all infants with symptomatic cCMV infection were
treated with one of two protocols. The first protocol was intravenous ganciclovir 5mg
per kilogram (mg/kg) for six weeks followed by oral valganciclovir (Valcyte,
Hoffmann-La Roche Ltd, Basel, Switzerland) given as two daily doses of 17 mg/kg
for another six weeks and then one daily dose until one-year-of-age. The second
protocol was two daily doses of oral valganciclovir of 17 mg/kg for 12 weeks and
then one daily dose until one-year-of-age, as previously described (11). Infants with
an asymptomatic infection at birth were followed up with BERA or a behavioural
hearing test every four to six months until the age of four.
For the purpose of this study, hearing deterioration was defined as an increase
of ≥10 dB in the auditory threshold in one or two ears during two consecutive BERA
assessments or two behavioural tests resulting in a change in hearing category,
such as from normal to mild, mild to moderate or moderate to severe hearing loss.
Statistical analysis
Data from each infant were entered into an electronic database and analysed
using SPSS 17.0 (SPSS Inc., Chicago, Illinois USA) Continuous variables, such as
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age, are given as means and standard deviations. Categorical variables, such as
severity of hearing deterioration, were compared using a standard chi-square test. A
p value of 0.05 or lower was a priori defined as statistically significant.
The study was approved by the Institutional Helsinki Committee.
RESULTS
During the study period, 210 infants -158 symptomatic and 52 asymptomatic - were
diagnosed with cCMV in our clinic and then followed for more than a year (Figure 2).
Of the 158 symptomatic infants, 139 (88%) displayed abnormal brain findings on
initial brain ultrasound and LSV was the leading ultrasonographic finding, diagnosed
in 114 (82%) of these cases. When we looked at the 114 infants with LSV, we
observed other ultrasonographic signs of cCMV in 25 (21.9%) infants and LSV was
the only finding in 89 (78.1%) of the cases.
As seen in Figure 2, these 89 infants comprised three of our study groups.
Group one was made up of 13 infants with solitary LSV on brain ultrasound, who
had normal hearing at birth and were not treated with antiviral therapy during 2006
to 2009. Group two consisted of 51 infants who displayed solitary LSV on brain
ultrasound and had normal hearing at birth, which had been treated with
gan/valganciclovir since mid-2009. Group three comprised 25 infants with solitary
LSV on brain ultrasound, who had abnormal hearing at birth and had been treated
with gan/valganciclovir since 2006. The 89 infants excluded the 52 asymptomatic
infants in group four, who served as controls. A small number of these infants were
also included in our previous study (2).
As seen in Table 1, a maternal primary infection with CMV was diagnosed in
130/141 cases (92.2%), with no significant difference between the study groups.
Non-primary maternal infections were diagnosed in eight (5.7%) cases. In three
cases (2.1%), the maternal primary/non-primary infection could not be determined.
Maternal infections were observed in 44 (31.2%) cases during the first trimester and
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in 75 (53.2%) of the cases in the second trimester. They occurred more often in
groups one and two during the first trimester than in group four (p=0.044 and
p=0.02, respectively). Groups one and two showed no significant differences
between any of the other study parameters, including no manifestations in the
central nervous system (Table 1).
Hearing deterioration was observed in 16 (13.8%) of the 116 infants with normal
hearing at birth: 11 in group one (84.6%), five in group four (9.6%) and none in
group two. Hearing deterioration was significantly higher in group one than in group
two (p<0.001) and group four (p<0.001) and also in group four than group two
(p=0.008).
The main side effect of the treatment in the 76 infants in groups two and three
was neutropenia, defined as an absolute neutrophil count (ANC) of ≤1000/mm3, with
22 (28.9%) experiencing a total of 30 episodes of neutropenia. None had severe
neutropenia (ANC<500mm3). Episodes of neutropenia were only observed during
the first three months of treatment, mainly during the first six weeks in infants who
started intravenous antiviral treatment. No treatment changes were required, just
repeated blood counts.
DISCUSSION
This study reports the incidence and importance of LSV, which was the most
common abnormal finding in infants with cCMV. LSV was observed in 54.3% of
infants with cCMV and occurred in 72.2% of our symptomatic infants and 82% of
infants with abnormal brain ultrasound. It was also the sole reason to start antiviral
treatment in 32.3% of our cases. This relatively high incidence of brain involvement
may reflect the fact that, unlike in many other reports in the literature, our series
included mostly infants whose mothers had a primary infection during pregnancy.
Nevertheless, where solitary LSV was not an indication for antiviral treatment, most
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of these infants had hearing deterioration, significantly more than in the
asymptomatic group (85% versus 9.6%, p<0.001).
Did this study discover a new sign of central nervous system involvement and a
high-risk marker for further hearing deterioration in infants with cCMV?
We believe that four aspects relating to LSV and cCMV should be clarified
before answering this question:
1. What is the true incidence of LSV in otherwise healthy term neonates? This
question is important to make sure that we don’t over-diagnose infants with
cCMV and solitary LSV as symptomatic.
2. Why hasn’t LSV been acknowledged in the past as a sign of brain involvement
in infants with cCMV?
3. What is the natural history of infants with cCMV and solitary LSV who are not
being treated?
4. What is the safety profile of the suggested antiviral treatment and what are its
complications?
In order to answer the first question, a literature search on the incidence of LSV
was conducted. Our search for large-scale studies reporting on the incidence of LSV
in infants who had undergone brain ultrasound is summarised in Table 2. The rate of
LSV detected in infants who had undergone brain ultrasound ranged from 0.4% to
5.8% (1,3,5,12-15). However, all of these studies collected data on infants with an
underlying medical condition and healthcare staff had a reason for conducting an
ultrasound, usually prematurity and its related complications. Therefore, significant
medical conditions were identified in most cases. The percentage of infants without
a major underlying medical problem was reported to be 0% in four out of the six
studies and 0.08% and 0.2% in the other two studies (1,3,5,12-15). Moreover, the
rate of cCMV in this population ranged from 0% to 0.5%. Thus, our conclusion is
that, while the incidence of LSV might have been as high as 5.8% in a selected
population of premature or sick neonates who had undergone brain ultrasound, its
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true incidence in previously healthy full-term newborns was much lower. Therefore,
the answer to our first question does not appear in studies assessing the incidence
of LSV in sick infants. However, it can be found in studies that assessed the rate of
brain abnormalities, including LSV in normal full-term neonates.
Our search of the literature yielded five large studies comprising more than
4,000 healthy full-term infants (16-20) and brain ultrasound showed that none of
these had LSV. The incidental finding of LSV in otherwise full-term healthy infants
was rare. Our conclusion is that if the incidence of cCMV is about 1% of all live
births, then the chance of misdiagnosis, or over diagnosis, due to a brain ultrasound
showing solitary findings of accidental LSV that indicate symptomatic cCMV, is
minimal.
In our study, LSV was found to be the most common abnormal finding in infants
with cCMV. Therefore, the next question is why hasn’t it been reported by many
other centres as a sign of brain involvement? Firstly, our group of Israeli infants
might not have fully represented the regular epidemiology of cCMV, due to the high
level of maternal screening for CMV infection during pregnancy leading to the
identification of a primary maternal infection. Secondly, the routine evaluation of
infants with cCMV differs in many countries, which may influence how often LSV is
detected.
Our routine evaluation only included brain ultrasound, while many other centres
worldwide use cranial computed tomographic (CT) scans or magnetic resonance
imaging (MRI), which are unable to identify LSV. Cranial CT was used in the past to
identify symptomatic cCMV infections and proved to be a good predictor of adverse
neurodevelopmental outcomes (21). However, cranial CT scans have major
drawbacks in neonates, mainly due to radiation exposure and the need for sedation.
On the other hand, there are many advantages to performing MRI scans on infants
with cCMV. They are safe and can identify white matter lesions or gyral
abnormalities, which are relatively common in infants with cCMV. However, the
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need for sedation, and the high costs of MRI scans, limits their use in this population
(22,23).
Therefore, brain ultrasound has replaced cranial CT as an evaluation tool in
many centres in recent years (22,23). A study by Ancora et al showed good
correlation between ultrasound abnormalities and predicting neurodevelopmental
outcomes in this population (23). The use of brain ultrasound in infants with cCMV is
increasing and this will further underline the prevalence and importance of LSV.
The answer to the third question, relating to the natural history of infants with
cCMV and solitary LSV who were not treated, is found in the results section of this
study. Hearing deterioration developed in almost 85% of our study infants with
cCMV and solitary LSV who did not receive antiviral treatment. This was significantly
higher than in children who were asymptomatic at birth, as hearing deterioration
occurred in 9.6% of those cases. This observation is significant because it
demonstrates that infants with cCMV and solitary LSV are a specific high-risk group
when it comes to hearing deterioration. Thus, if antiviral treatment is not initiated, as
in other cases of symptomatic cCMV, a close follow-up of hearing studies is
warranted.
The safety profile of antiviral treatment in infants with a cCMV infection has
previously been evaluated. In the classic report by Kimberlin et al, who assessed
infants treated intravenously with ganciclovir for six weeks, the main side effect was
neutropenia (24). While 63% of the treated infants had grade three or four
neutropenia, almost half required a ganciclovir dose adjustment and the drug had to
be permanently discontinued in 13.7% of cases (24). However, oral valganciclovir
has been commercially available in recent years. The fact that valganciclovir can be
given at home, combined with its high bioavailability, has led to a change in many
treatment protocols worldwide.
Many institutions have changed their treatment policy to a combination of
intravenous ganciclovir followed by oral valganciclovir or just valganciclovir
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(4,10,25,26). The safety profile of valganciclovir is superior to ganciclovir and long-
term treatment has been found to be well tolerated (4,10,25,26).
In our study, 28.9% of infants developed neutropenia, with episodes only
observed during the first three months of treatment, mainly during the first six weeks
of life in infants who started intravenous antiviral treatment. While our reported
cases required no change of treatment, we believe that the response to our fourth
question is also in favour of treatment.
The main limitations of our study were the retrospective methodology and
relatively small number of infants in the untreated group. However, in mid-2009 we
felt the need to change the paradigm of our treatment policy. It is important that
other centres worldwide share their data on infants with LSV who have been treated
or not treated to determine the most appropriate approach to this specific, yet
common, group of infants.
CONCLUSION
In conclusion, the results of this study indicate that LSV is a relatively common
finding in infants with symptomatic cCMV, a sign of central nervous system
involvement and further hearing deterioration. Larger prospective studies are
needed to further characterise this specific group of infants and illustrate the
importance of LSV in infants with cCMV.
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Abbreviations
ABR Auditory brain response
BERA Brainstem evoked response audiometry
cCMV Congenital cytomegalovirus
CT Cranial computed tomographic scan
LSV Lenticulostriated vasculopathy
MRI Magnetic resonance imaging
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Table 1 Clinical data on the infants with cCMV in the four study groups
Group Solitary LSV without
treatment (group one)
Solitary LSV with
treatment (group
two)
Solitary LSV with
abnormal BERA with
treatment (group
three)
Asymptomatic
(group four)
Number 13 51 25 52
Male/female n (%) 9/4 (69/31) 29/22 (57/43) 15/10 (60/40) 26/26 (50/50)
Maternal infection Primary n (%) 12 (92%) 48 (94%) 21 (84%) 49 (94%)
Non-primary 1 (8%) 2 (4%) 3 (12%) 2 (4%)
Unknown 0 (0%) 1 (2%) 1 (4%) 1 (2%)
Time of maternal
infection during
pregnancy
Periconceptual or first
trimester n (%)
3 (23.1%) 20 (39.2%) 8 (15.7%) 13 (25%)
Second trimester n (%) 6 (46.2%) 24 (47.1%) 12 (23.5%) 33 (63.4%)
Unknown n (%) 4 (30.8%) 7 (13.7%) 5 (20%) 6 (11.5%)
Non central nervous
system
manifestations
Splenomegaly 1 (7.7%) 6 (11.8%) 8 (32%) 4 (7.7%)
Thrombocytopenia 2 (15.4%) 2 (3.9%) 3 (12%) 2 (3.8%)
Hepatitis 1 (7.7%) 1 (2%) 2 (8%) 0 (0%)
Purpura 0 (0%) 0 (0%) 1 (4%) 0 (0%)
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Table 2 Previous large studies of infants with LSV
Name (Ref.) Year published Number of infants Infants with LSV
n (%)
Infants without an underlying major
diagnosis n (%)
Infants with cCMV
n (%)
Hughes et al (11) 1991 1324 25 (1.9%) 0 (0%) 4 (0.3%)
Weber et al (12) 1992 3600 15 (0.4%) 3 (0.08%) 2 (0.06%)
Cabañas et al (13) 1993 1893 37 (2%) 3 (0.2%) 1 (0.05%)
Wang et al (1) 1995 586 34 (5.8%) 0 (0%) 3 (0.5%)
Coley et al (14) 2000 1500 63 (4.2%) 0 (0%) 4 (0.3%)
Makhoul et al (3) 2003 857 21 (2.5%) 0 (0%) 1 (0.1%)
De Jong et al (5) 2010 2088 80 (4%) not reported 0 (0%)
Total - 11,848 275 (2.3%) 6/9760=0.06%* 15 (0.13%)
*Data was extracted from articles reporting other major diagnoses
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Figure Legends
Figure 1: LSV in infant with cCMV - ultrasound sagittal view through the
anterior fontanel showing LSV in an infant with cCMV. Arrows - branching
echogenic linear structures in the thalamus (right - grey-scale, left - colour
Doppler).
Figure 2: Findings of LSV in infants with cCMV and a follow-up period of more
than one year.