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REGULAR ARTICLE

Lenticulostriated vasculopathy is a high-risk marker for hearing loss in

congenital cytomegalovirus infections

Efraim Bilavsky (yoji@netvision.net.il)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: yoji@netvision.net.il

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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

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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.

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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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Acknowledgements

The authors thank Mrs Phyllis Curchack Kornspan for her editorial services

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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.