Acta Ophthalmologica 2009

Visual elds and optic disc

morphology in very low
birthweight adolescents
examined with magnetic
resonance imaging of the brain
Kerstin Hellgren,1 Ann Hellstrom2 and Lene Martin1
1

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Department of Ophthalmology, Institute of Clinical Neuroscience, the Sahlgrenska
Academy of Gothenburg University, Gothenburg, Sweden
2

ABSTRACT.
Purpose: We aimed to evaluate visual elds (VFs) and optic disc morphology
in very low birthweight (VLBW) adolescents compared with age- and gendermatched controls, and to relate the ndings to magnetic resonance imaging
(MRI) results.
Methods: Fifty-nine VLBW adolescents and 55 age- and gender-matched controls with normal birthweight were examined. Visual elds were tested using
computerized rarebit perimetry (RB). Optic nerve and retinal vessel morphology were evaluated by digital image analysis of fundus photographs. Brain
MRI was conducted in the VLBW subjects.
Results: Ten of the 57 VLBW subjects (p = 0.022) had subnormal VF results
dened as a mean hit rate below the fth percentile of the controls (i.e.
< 89%). All of these also had signicantly lower mean hit rates (p = 0.039)
in the inferior hemield. Sixteen of 57 (28%) VLBW subjects had white matter damage of immaturity (WMDI) on MRI. Six of 15 subjects with WMDI
(who underwent VF testing) also had subnormal RB results, compared with
four of 39 with normal MRI ndings (p = 0.02). The mean neural retinal rim
area was 9% smaller (p = 0.018) in the VLBW group than in the control
group. The VLBW adolescents had a signicantly higher index for tortuosity
of arterioles than the controls (p < 0.001).
Conclusions: In the present study, 18% of all VLBW adolescents and 40% of
those with WMDI had subnormal RB VF ndings. The VLBW group had
increased arterial tortuosity and a somewhat smaller (9%) mean neural retinal
rim area than the control group. Thus sequels to VLBW appear to persist in
adolescence.
Key words: magnetic resonance tomography optic disc rarebit vascular morphology very
low birthweight visual elds

Acta Ophthalmol. 2009: 87: 843848

2008 The Authors
Journal compilation 2008 Acta Ophthalmol

doi: 10.1111/j.1755-3768.2008.01365.x

Introduction
Children with very low birthweight
(VLBW) ( 1500 g [Platt et al. 2007])
have an increased morbidity of the central nervous and vascular systems, such
as white matter damage of immaturity
(WMDI) (Olsen et al. 1997; KragelohMann 2004). Magnetic resonance
imaging (MRI) of the brain is the
method of choice for diagnosing
WMDI (Flodmark et al. 1989). A relationship between WMDI and optic
nerve hypoplasia (ONH) has been documented (Brodsky & Glasier 1993).
Morphometric studies on fundus photographs from preterm children with
WMDI have demonstrated reduced
neuronal volume, expressed as reduced
optic disc rim area (ORA), and a variant of ONH, manifested as normalsized optic discs with large cups (Jacobson et al. 1997). A previous population-based study of children born
before 29 weeks gestational age demonstrated signicantly smaller ORA
and optic disc area (ODA) in the premature group than in controls born at
term (Hellstrom et al. 2002). In addition, a higher index for tortuosity of
arterioles (ITA), indicating increased
arterial tortuosity in the retina, has
been reported in infants and adolescents born prematurely compared with
controls born at full-term (Hellstrom
et al. 2002; Kistner et al. 2002).

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Acta Ophthalmologica 2009

Visual eld (VF) disturbances, especially in the inferior part of the VF,
have been documented in subjects with
WMDI (Jacobson et al. 1996, 2006).
Increased resolution thresholds in the
central part of the VF have been
reported in prematurely born children
(Larsson et al. 2004), but this could
not be conrmed in a recent study by
Lindqvist et al. (2007), which examined VLBW teenagers using Humphrey
perimetry. A correlation between a
small rim : disc ratio (ORA : ODA)
and subnormal rarebit (RB) VF results
has been demonstrated in adolescents
born after intrauterine growth restriction (Martin et al. 2004).
In a previous study (Hellgren et al.
2007), we showed that 30% of VLBW
subjects had abnormal MRI ndings
and that these subjects performed less
well in visual acuity and stereo acuity
testing, and had lower intellectual
capacity and more cognitive visual
problems, compared with both VLBW
subjects without MRI pathology and
with the normal control group.
The aim of the present study was to
evaluate VFs and optic disc morphology in a group of VLBW adolescents
compared with age- and gendermatched controls, and to relate the
ndings to MRI results.

Table 1. Clinical data, showing mean standard deviation (range).

n
Gender, F M
Age at VF examination,
years
Birthweight, g
SDS of birthweight
GA, weeks
BCVA RE
Refraction RE

VLBW subjects

Control subjects

59
26 33
17.0 1.9 (14.720.1)

55
26 29
16.4 1.6 (14.820.1)

1197 200 (6851500)

) 2.61 1.25 to () 4.8 to ) 0.01)
31 2 (2638)
1.25 0.37 (0.062.0)
0.5 2.47 () 10.1 to 6.1)

3550 492 (22304600)

40 1 (3742)
1.37 0.26 (0.82.0)
0.5 1.37 () 3.87 to 4.38)

VLBW = very low birthweight; F = female; M = male; VF = visual eld; SDS = standard
deviation score; GA = gestational age; BCVA = best corrected visual acuity; RE = right eye;
Refraction = spherical equivalent in dioptres.

group with respect to hospital, gender

and maternal parity. Of these, 55
agreed to participate in the current
follow-up study. As the pair-matching
was no longer complete, group comparisons were conducted. Clinical data
for all included subjects are shown in
Table 1.
The study was approved by the
local ethics committee and performed
according to the Helsinki Declaration.
Written
informed
consent
was
obtained from all participants and
their parents prior to enrolment.

Methods
VF testing, using rarebit perimetry

Materials and Methods

The study group has been extensively
described elsewhere (Hellgren et al.
2007). Briey, of the 107 VLBW
infants born live during a 15-month
period in a southeastern region of
Sweden, 86 survived the neonatal period. Of these 86 subjects, 22 did not
accept the invitation to participate in
the current study, and two had moved
abroad. Three subjects were excluded
because of multiple disabilities (one
had Downs syndrome and two had
cerebral palsy and moderate to severe
mental retardation). Thus, 59 VLBW
subjects participated. At 40 postmenstrual weeks, VLBW subjects were
screened for retinopathy of prematurity (ROP) once. Two subjects had
been identied early with visual
impairment caused by ROP. One of
these was blind and had already been
excluded (see above).
In the early neonatal period, a control group of 86 infants was recruited.
These were pair-matched to the study

844

Computerized RB perimetry was used

to evaluate VFs. The technique has
been described in detail previously
and has been shown to be sensitive to
damage of different origins to the
visual pathways (Frisen 2002; Martin
& Wanger 2004; Brusini et al. 2005;
Martin 2005; Gedik et al. 2007). The
software is available free of charge at
http://www.oft.gu.se/webdiagnos.
The principle relies on testing the
retino)cortical detector matrix with
very small bright dots, < 0.5 MAR
(minimum angle of resolution),
presented one or two at a time. The
subjects respond by giving single or
double mouse clicks, depending on the
number of dots they perceive. A total
of 10% of presentations contain one
or no dot and are used for control purposes. These false-positives, expressed
as errors in the presentation of
results, are used as a measure of the
reliability of the test results. Stimuli
are presented in 30 separate test areas
within the 30-degree VF and xation is
encouraged by dynamically changing

the location of the xation mark. As

this retino)cortical matrix is normally
complete, with no gaps between the
receptive elds, a normal person will
have a hit rate of nearly 100%. Loss
of receptive elds gives a lower hit rate
(Frisen 2002). The results are summarized in two measures, the RB mean
hit rate (MHR) and the number of
locations with a hit rate < 90%. In a
previous study of healthy subjects aged
1420 years, the normal MHR was
89)100%, with a median of 97%
(Martin 2005). In the current study,
the MHR in the total VF and the
MHRs in the superior and the inferior
hemields, respectively, were used as
main outcome measures.
Examinations were performed with
habitual correction in right eyes.
Optic disc and retinal vascular
measurements

Digital fundus photographs were

obtained using ve different Topcon
cameras at ve different settings. Only
correctly focused photographs from
right eyes with the optic disc centred
were accepted for analysis.
Optic disc parameters were evaluated by marking the end-points of the
long and short diameters of the optic
disc and cup, assuming an elliptical
shape (Williams 1987). In order to
compensate for differences in magnication caused by camera and eye
optics, the centre of the macula was
marked. The distance between the
macula and the disc centre is reported
to be quite constant among adults
(Mok & Lee 2002). This distance
between the macula and the optic disc
centre was used as a reference measure (Wakakura & Alvarez 1987; Williams 1987; Williams & Wilkingson

Acta Ophthalmologica 2009

1992) when converting pixel units to

metric distance (Bartling et al. 2008).
The evaluations were made by two
independent observers, with practically identical results (r = 0.93). The
optic disc cup (ODC), ODA, ORA
and the ORA : ODA ratio were used
as outcome measures.
The morphology of the retinal vessels was measured by one of the
authors (AH) and the ITA and
number of vascular branching points
were calculated using digital analysis
(Stromland et al. 1995). Measurements
were made by tracing each vessel (path
length) from its origin on the optic disc
to a reference circle with a radius of
3.0 mm from the geometric centre of
the optic disc. The ITA was calculated
from the length index (i.e. the path
length of the vessel divided by the linear distance from the vessel origin to
the reference circle). Vessels were also
traced from their branching point to
the reference circle, and the total number of branching points (i.e. the number of retinal vessels within this area)
was calculated. Different magnications in the four cameras used caused
the analyses to result in relative, rather
than absolute, values. The clinicians
who made the measurements had no
knowledge of the identities and diagnoses of the study subjects.

Results
Fifty VLBW subjects and 46 controls
performed all examinations. The distribution of participants in the different examinations is shown in Fig. 1.
Visual eld results

Fifty-seven VLBW subjects and 52

controls underwent VF examinations.
The median number of errors was one
in both the VLBW and control
groups. Ten subjects had four or more
errors (four in the VLBW group and
six in the control group). There was
no signicant difference in RB MHR
between those with few or none
errors, and those with four to seven
errors. Rarebit results are summarized
in Table 2 and Fig. 2. The results
from the control group did not differ
signicantly from those previously
described (Martin 2005). There was
no signicant difference in RB MHR
between the groups, but the difference

Magnetic resonance imaging

Brain MRI was conducted in the

VLBW subjects, but not in controls, as
the control group in a previous similar
study had shown no pathology (Olsen
et al. 1997). The WMDI ndings were
classied by one experienced neuroradiologist as representing normal or
mild (loss of < 25% of periventricular
white matter or only gliosis), moderate
(loss of > 25% but < 50% of periventricular white matter) or severe
(loss of > 50% of periventricular
white matter) levels of abnormality.

Fig. 1. Diagram showing the distribution of

very low birthweight participants in various
examinations.
RB = rarebit
perimetry;
MRI = magnetic resonance imaging.

between the superior and inferior

hemields was larger in the VLBW
subjects (p = 0.02, MannWhitney
U-test) (Table 2). Ten of the 57
VLBW subjects (p = 0.022, Fishers
exact test) had subnormal VF results
dened as an MHR below the fth
percentile of the controls (i.e. < 89%;
Fig. 2), and all of these also had a signicantly lower MHR (p = 0.039,
MannWhitney U-test) in the inferior
hemield. For an example, see Fig. 3.
Optic disc and retinal vascular
measurements

Fundus photographs from 53 VLBW

subjects and 49 controls were digitally
analysed. One VLBW subject refused
cycloplegic eyedrops and was not photographed. Images from six controls
and ve VLBW subjects were either
missing or of insufcient quality.
Table 3 shows the optic disc parameters in VLBW subjects and controls,
respectively. The ODA was equal in
the two groups, but the OCA was signicantly larger (p = 0.013, unpaired
t-test) in the VLBW group and, consequently, the ORA (p = 0.018) and
ORA : ODA ratio (p = 0.012) were
smaller. The coefcient of variation in
ORA in the control group was 22%,
similar to previously reported data
(Nguyen et al. 2004). The difference in
mean ORA between the VLBW subjects and the control group corresponds to 9% (1.77 0.36 mm2 and
1.95 0.43 mm2, respectively).
No correlations were found between
optic disc parameters and RB results.
There was a signicant difference
in ITA (p < 0.001, MannWhitney
U-test) between the groups, but not in
the number of vessel branching points
(p = 0.57). For an example, see Fig. 4.
Magnetic resonance imaging

Fifty-seven VLBW subjects underwent

MRI. Seventeen subjects had abnormal

Statistics

Unpaired t-test with Welch correction,

MannWhitney U-test, Spearmans
rank correlation and Fishers exact
test were used for statistical analysis.
A stratied MannWhitney test
(strata = setting) was employed for
branching point measurements as a
result of different magnications in
the fundus photographs.

Table 2. Rarebit visual eld tests, showing median (range).

RB hit rate %
Superior hemield
Inferior hemield
Diff SI

VLBW subjects
(n = 57)

Control subjects
(n = 52)

Signicance of
difference (p)

96 (44100)
95.5 (46100)
96.5 (42.5100)
0 ()47 to 47)

96.5 (88100)
96.5 (85100)
97 (86100)
) 1 ()22 to 10)

0.18
0.69
0.092
0.020

VLBW = very low birthweight; RB =- rarebit; Diff SI, superior hemieldinferior hemield.

845

Acta Ophthalmologica 2009

Fifty-ve of the VLBW subjects

who underwent MRI examinations
also performed RB perimetry. Six of
15 subjects with WMDI and four of
39 without MRI pathology had subnormal RB VF results (i.e. < 89%;
p = 0.020, Fishers exact test).
There was no difference in VFs,
optic disc parameters, arteriolar tortuosity or MRI ndings between genders.

Discussion

Fig. 2. Rarebit mean hit rate (%) in the examined groups. Box = interquartile range; whiskers = 1.5 interquartile range; bold line inside box = median; small ring = outlier;
* = extreme values. RB = rarebit; VLBW = very low birthweight.

Fig. 3. Rarebit visual elds from a very low birthweight subject (to the left) and a control subject (to the right). Note the difference between the superior and the inferior hemield in the
very low birth weight subject.

Table 3. Optic disc parameters in the two examined groups, showing mean standard deviation (range).

ODA
OCA
ORA
RADA
ITA

VLBW subjects (n = 53)

Control subjects (n = 49)

Signicance of difference
(p) Unpaired t-test

2.04
0.28
1.77
0.87
1.1

2.13
0.18
1.95
0.92
1.08

0.32
0.013
0.018
0.012
<0.001

0.44
0.23
0.36
0.09
0.07

(1.053.15)
(00.88)
(1.052.87)
(0.631.0)
(0.711.21)

0.41
0.18
0.43
0.08
0.26

(1.323.19)
(00.71)
(1.223.19)
(0.691.0)
(1.041.15)

VLBW = very low birthweight; ODA = optic disc area, mm2; OCA = optic cup area, mm2;
ORA = optic rim area, mm2; RADA = ORA : ODA; ITA = index for tortuosity of arterioles.

MRI ndings; 16 had WMDI (28%)

and one had a malformation. Thirteen
were classied as having mild, one as
having moderate and two as having
severe WMDI.
Fifty-two of the VLBW subjects
who underwent MRI also underwent
fundus photography. No signicant
difference was found in optic disc

846

variables
or
arterial
tortuosity
between VLBW subjects with and
without abnormal MRI ndings. The
three subjects with moderate to severe
WMDI had less arterial tortuosity
and fewer retinal vessel branching
points, and two of them also had
smaller rim areas compared with those
with mild WMDI.

To our knowledge, this is the rst

population-based study to relate VFs
and optic nerve morphology to brain
MRI ndings in VLBW adolescents.
More VLBW subjects with abnormal
MRI ndings had subnormal VFs
compared with those with normal
MRI results. A signicant difference
in ORA was observed between the
VLBW and control groups, but this
nding was unrelated to MRI ndings. The main VF abnormality was
reduced sensitivity in the inferior
hemield, possibly indicating that the
upper part of the optic radiations is
more affected by WMDI than the
lower parts that subserve the superior
VF and whose course through the
temporal lobe seem to make them less
vulnerable to damage by periventricular leukomalacia (Edmond & Foroozan 2006).
Lindqvist et al. (2007), using Humphrey perimetry, and OConnor et al.
(2004), using the Damato Campimeter, found no differences in VF results
in similar studies on similar subjects.
However, as OConnor et al. (2004)
commented, they may have missed
subtle defects because of low sensitivity of the technique. By contrast,
Larsson et al. (2004) found signicant
differences using high-pass resolution
perimetry. Martin et al. (2004) found
VF restrictions using RB perimetry,
but not using frequency-doubling
technology perimetry, in adolescents
born after intrauterine growth restriction. This might indicate that RB is
more sensitive in detecting subtle
restrictions in VF perception than
other perimetry techniques.
Subnormal VF results were related
to WMDI. In previous studies periventricular leukomalacia, which is a
variant of WMDI, has been documented as a cause of VF restrictions
(Jacobson et al. 1996, 2006). In these
studies the inferior part of the VF was

Acta Ophthalmologica 2009

Fig. 4. Fundus photographs from a very low birthweight subject (to the left) and a control subject (to the right). Note the increased arterial tortuosity and larger optic cup in the very low
birthweight subject. The optic discs are of similar size.

more affected than the superior, as in

the current study.
Visual eld defects have been documented in 1-year-old children with
severe WMDI (Cioni et al. 1997). In
the current study, the three adolescents with moderate to severe WMDI
had pathological VF results, as did a
further seven VLBW subjects with
mild or no WMDI. This is probably
explained by the use of more sensitive
techniques in the current study and
different selection criteria.
The VLBW subjects had slightly
reduced neural ORA, but normal
ODA, which might indicate a reduced
number of axons. The nding is in
accordance with a report by Jacobson
et al. (1997) of large ODC in normalsized optic discs and with ndings
from
Brodsky
(2001),
showing
pseudoglaucomatous cuppings in subjects born preterm with WMDI. As
far as we know, the presumed mechanism of optic disc cupping in WMDI
in children born preterm concerns a
decrease in the neuroretinal rim area
which is assumed to reect a decrease
in the number of axons in the optic
nerve caused by retrograde transsynaptic degeneration across the lateral
geniculate nucleus. This is secondary
to the ischaemic brain lesion (i.e.
WMDI). The brain lesion is acquired
in late pregnancy (the third trimester;
Krageloh-Mann 2004) when the surrounding structures of the optic disc
have become more rigid, and an adaptation to the smaller number of ganglion cells in the optic disc is unlikely.
Consequently, the reduced nerve tissue
may result in a normal-sized optic disc
with enlarged cupping (Hellstrom

1999). In the current study this variant of ONH was not correlated to
WMDI, but to VLBW per se. This
might be explained by the MRI technique used in the current study. A
recently developed technique using
diffusion image MRI and volume
measurements has documented the
presence of more subtle brain damage
than we were able to show. Consequently, our study group may include
VLBW subjects with ischaemic brain
damage that is not apparent with the
technique used here. An enlarged cup
size may represent the result of
destruction of nerve bres secondary
to increased intraocular pressure
(IOP). However, as no relationship
between increased IOP and prematurity had been found (Spierer et al.
1994) at the time we planned the current study, IOP measurements were
not included. Further observations
similar to those reported by Spierer
et al. (1994) were published recently
(Ng et al. 2008). Another group examined a sample of preterm children
with periventricular leukomalacia who
were found to have large cups and
WMDI, but in whom IOP was normal
(Jacobson et al. 1997). As no relationship between optic disc parameters
and VF results were found in the current study, the risk for glaucoma was
judged to be low. Yet, in retrospect,
our failure to include IOP measurements in the current study may reect
a study weakness.
The VLBW adolescents had a signicantly higher ITA compared with
the controls, but this was not correlated to WMDI. This nding may represent a response to a diminished need

of vascular support in a pronounced

reduction of neuronal tissue. On the
contrary, the three VLBW subjects
with moderate to severe WMDI had
less arterial tortuosity and fewer vessel
branching points than the VLBW
subjects with mild or no WMDI.
In the neonatal period arterial tortuosity in a preterm child is a sign of
severe ROP plus disease. Increased
arterial tortuosity has previously been
reported in children born prematurely
children, independently of ROP.
Hypoxia (i.e. perinatal distress) has
been suggested to be the cause of
muscle relaxation of the arterioles,
resulting in elongation and abnormal
tortuosity (Bracher 1982). The astrocytes supporting the retinal vessels are
vulnerable to hypoxia and a reduction
in the number of astrocytes may cause
increased tortuosity (Chan-Ling &
Stone 1992). Hence increased tortuosity of retinal arterioles may be a sign
of perinatal hypoxia and indicate the
presence of associated hypoxic brain
damage. It may also be associated
with increased systemic blood pressure
later in life (Kistner et al. 2002).
The number of retinal vascular
branching points was not reduced in
the VLBW group, which is inconsistent
with reported ndings in adolescents
born after intrauterine growth retardation (Hellstrom et al. 2004). However,
in the current study the participants
were born with VLBW, and the majority of them were not born small for
gestational age or at a very low gestational age; hence there was no indication of intrauterine growth retardation.

Conclusions
In the present study, 18% of the
VLBW adolescents had subnormal
RB VFs and 28% had WMDI. Six of
the latter had subnormal RB VF
results. The VLBW group had somewhat smaller (9%) mean ORA than
the control group. Thus sequels of
VLBW appear to persist into adolescence.

Acknowledgements
This report is part of a multidisciplinary, prospective, follow-up study of
very low birthweight children and
controls in southeast Sweden. The
examination at 15 years of age was
planned and performed by a working

847

Acta Ophthalmologica 2009

group which included the authors of

this paper and Orvar Finnstrom, Ingemar Leijon, Per-Olof Gaddlin, Stefan
Samuelsson, Marie Wadsby, Chen
Wang, Eva Aring, Jan Ygge, Lena
Jacobson and Olof Flodmark.
This research was funded by grants
from the Health Research Council in
the Southeast of Sweden (FORSS), the
County of Jonkoping and Ostergotland, St Eriks Eye Hospital (St Erik
Eye Hospital Research Foundation),
Samariten Foundation, Solstickan
Foundation and the Sigvard and Marianne Bernadotte Research Foundation
for Pediatric Ophthalmology.

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Received on October 26th, 2007.

Accepted on May 29th, 2008.
Correspondence:
Kerstin Hellgren
Department of Clinical Neuroscience
Ophthalmology and Vision
Karolinska Institutet
St Eriks Eye Hospital
S-112 82 Stockholm
Sweden
Tel: +46 86 723 665
Fax: +46 86 723 330
Email: kerstin.hellgren@ste.ki.se