The Sigvard & Marianne Bernadotte Research Foundation for
Children Eye Care was founded in January 1990 by Princess
Marianne Bernadotte and the late Prince Sigvard Bernadotte.
The aim of the Foundation is to support pediatric
ophthalmology research in Sweden, and to create a center for
research and advanced eye care for children at Karolinska
Institutet in Stockholm.
Now, in 2010, the Foundation celebrates its 20th anniversary.
This volume, Advances in Pediatric Ophthalmology
Research, is a part of the celebration, representing an account
of important advances in pediatric ophthalmology in Sweden
and internationally.
Advances in Pediatric
Ophthalmology Research
Reports presented in 2010 at the 20th anniversary of the
Sigvard & Marianne Bernadotte Research
Foundation for Children Eye Care
Edited by Gunnar Lennerstrand and Gustaf Öqvist Seimyr
Advances in Pediatric Ophthalmology Research
Reports presented in 2010 at the 20th anniversary of the
Sigvard & Marianne Bernadotte Research
Foundation for Children Eye Care
Edited by Gunnar Lennerstrand and Gustaf Öqvist Seimyr
The research presented in this publication has been supported by the Sigvard & Marianne
Bernadotte Research Foundation for Children Eye Care
Preface
The Sigvard & Marianne Bernadotte Research Foundation for Children´s Eye Care was
founded in January 1990 by Princess Marianne Bernadotte and the late Prince Sigvard
Bernadotte. The aim of the Foundation is to support pediatric ophthalmology research in
Sweden, and to create a center for research and advanced eye care for children at Karolinska
Institutet in Stockholm.
As the years have passed, the Foundation has become an important contributor to research
funding in pediatric ophthalmology. Scientists from all universities of Sweden have been
supported in their research projects. The Bernadotte Laboratories for pediatric ophthalmology
have been established at St. Erik Eye Hospital in Stockholm. Symposia and other meetings in
pediatric ophthalmology have been funded. A named Honorary Lecture for Prince Sigvard has
been presented at each Nordic Pediatric Ophthalmology Congress since 1994 by a
distinguished researcher of pediatric ophthalmology. A Prize is awarded in the name of
Princess Marianne biannually since 1995 to a prominent researcher in clinical pediatric
ophthalmology.
At its 10th anniversary the Foundation published a résumé of the research it had supported at
that time, included in a short handbook of pediatric ophthalmology for laymen and parents.
Now, in 2010, the Foundation celebrates its 20th anniversary. This volume is a part of the
celebration, representing an account of important advances in pediatric ophthalmology in
Sweden and internationally.
Marianne Bernadotte
Gunnar Lennerstrand
Founder
Chairman
Authors
Ann Hellström, Professor.
Department of Ophthalmology,
University of Gothenburg, Queen Silvia
Children’s Hospital, Gothenburg
Gerd Holmström, Professor.
Department of Clinical Neuroscience.
University of Uppsala, Academic
Hospital, Uppsala
Lena Jacobson, Associate Professor.
Department of Clinical Neuroscience,
Karolinska Institutet, Astrid Lindgren
Children’s Hospital, Stockholm
Peter Jakobsson, Associate Professor.
Department of Ophthalmology,
University of Linköping, University
Hospital, Linköping
Maria Kugelberg, Associate Professor
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Stockholm
Gunnar Lennerstrand, Professor em.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Lene Martin, Associate Professor.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Tony Pansell, Assistant Professor
Department of Clinical Neuroscience,
Karolinska Institutet, Optometry,
Bernadotte Labs, Stockholm
Agneta Rydberg, Associate Professor.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Kristina Teär Fahnehjelm, Associate
Professor.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Jan Ygge, Professor.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Gustaf Öqvist Seimyr, Researcher.
Department of Clinical Neuroscience,
Karolinska Institutet, St. Erik Eye
Hospital, Bernadotte Labs, Stockholm
Contents
Introduction
i
The First 20 Years of the Foundation
1
Gunnar Lennerstrand
Research reviews
I
The Development and Assessment of Vision
2
Agneta Rydberg
II
Development of the Visual Field
3
Lene Martin
III
Eye Development and Refractive Errors
4
Tony Pansell
IV
Ocular Motility Development
5
Jan Ygge
V
Childhood Strabismus
6
Gunnar Lennerstrand
VI
Visual Screening in Children
7
Peter Jakobsson
VII
Pediatric Cataract
Maria Kugelberg
8
VIII
The Impact of Growth and Growth Factors for
9
Vascular and Neural Development in Preterms
Ann Hellström
IX
Prematurity and the Eye
10
Gerd Holmström
X
Visual Function and Ocular Findings in Children with
11
Pre- and Perinatal Brain Damage
Lena Jacobsson
XI
The Eye Mirroring Inherited Metabolic Disorders
12
Kristina Teär Fahnehjelm
XII
Vision for Reading
Gustaf Öqvist Seimyr
13
i
The First 20 Years of the Foundation
Gunnar Lennerstrand
Introduction
The Sigvard & Marianne Bernadotte Research Foundation for Children’s Eye Care was
established in January 1990. The founders were Princess Marianne Bernadotte and the late
Prince Sigvard Bernadotte. Support for the initial idea of this foundation was supplied by the
late artist Sven Inge and by myself. The motto of the foundation is “Vision in the Future”,
recognizing that vision, being low at birth can reach normal levels in adulthood only if proper
visual stimulation is provided during childhood. Retarded visual development will lead to
poor vision throughout life, and early detection of visual dysfunction and early treatment is of
greatest importance in order to restore normal vision.
The by-laws state that the Foundation should promote good visual health in the child
population and support scientific research on vision and eye care of children. A goal of the
Foundation, announced already at the first meeting, is to create an institute for research and
advanced eye care of children at Karolinska Institutet in Stockholm. In the following a
description will be given of how the Foundation has fulfilled these objectives.
The members of the board in 1990 were: Professor, Nobel Laureate 1967, Ragnar Granit;
Princess Marianne Bernadotte; Professor Gunnar Lennerstrand; Managing director Sven
Wallgren; Professor Curt von Euler;Professor Ove Broberger; Dr Theol Bertil Persson; Artist
Sven Inge Höglund.
The start and the development of funds
The first action to bring funds to the foundation was taken by Princess Marianne Bernadotte
in arranging an auction at Bukowskis, the most important auction house in Stockholm. Over
200 works of art were solicited and registered in a catalogue with pictures, and already on
February 13, 1990, the auction took place. The net result was about 1.2 million SEK for the
foundation, a very good start in funding.
Through active work of the board members, contacts with the press and with the help of
promotion material of various kinds, the foundation quite rapidly became known to the public.
Grant applications to other foundations and institutions were relatively successful and
increased the funds. A large donation of 5 million SEK from the Tomteboda School in 1991
constituted a major advance of funds and made it possible for the foundation to start to
support pediatric ophthalmology in 1992 with grants for research and travel. Donations of
varying amounts have been made to the foundation during the years, the most remarkable
being donations at separate occasions, amounting to 50 million SEK, by the late Birgit and
Gösta Törnlöf .
The list of donations of 50 000 SEK or more is as follows:
1994
Stiftelsen Frimurare Barnhuset i Stockholm
Fondation Harari, Paris;
1995
Essilor, Paris
Pharmacia
Sigvard och Marianne Bernadottes Vänförening
1998
Victor J.B. Pastor, Monaco;
1999
Fondation Oussemi, Genève;
2000
Redaktör, med dr h c, Maj Ödman;
2001
Sven-Ivar Marthín, Vilhelmina;
2002
Department of Ophthalmology, Huddinge University Hospital;
2004
Michel Francois-Poncet
Magda & Enrico Bragiotti
Kay & Lyndon L. Olson jr.;
2005
Birgit & Gösta Törnlöf;
2009
Anders Tengbom
In addition to donations, the funds have increased by successful investments in stocks and
other financial instruments, according to a placement strategy worked out in collaboration
with the SE bank, handling the accounts of the foundation. The development of funds is
shown in figure 1. At present the total value of funds is about 65 million SEK.
Development of funds
80 000
70 000
SEK x 1000
60 000
50 000
40 000
30 000
20 000
10 000
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Figure 1. Development of funds of the Foundation since 1991.
Funding of research
Research projects in pediatric ophthalmology have been funded yearly since 1992.
Applications are solicited for presentation before May 1 and the applications are evaluated by
the Scientific committee and presented to the board for decision at the annual meeting in June.
Support has been given in the form of scholarships for travel and for research, grants to
individual researchers or to the Bernadotte laboratories (see below). The amount of support
supplied since 1992 is approximately 10 million SEK, with a marked increase in 2008 and
2009, as shown in figure 2.
In addition to the fields of pediatric ophthalmology represented in the review chapters in this
book, research has been supported also on retinal development, retinal dystrophies, retinal
neovascularisation, visual evoked potentials, fetal alcohol syndrome, congenital glaucoma,
ocular allergy, genetics of eye diseases, and visual handicap in children. The recipients of the
research grants and scholarships are scientists from all of the medical schools in Sweden.
Mainly the younger scientists have been supported and of 77 researchers being funded, 57
were in the beginning of their scientific carrier, most of them Ph.D. students. Of these young
scientists 48 have finished their Ph. D. degree and 3 their Master degree, i.e. about 90% of
them have graduated. The financial support given to them by the foundation would seem very
well invested. A broad basis has been laid for future and expanding research in pediatric
ophthalmology. The other funded scientists have been already established researchers.
The distribution between the Swedish medical schools of the scientists being funded is as
follows: Stockholm 44, Gothenburg 16, Uppsala 8, Lund 3, Linköping 2 and Umeå 1. The
distribution reflects the number of scientists active in pediatric ophthalmology at the different
universities, Karolinska Institutet in Stockholm having the largest number in the country.
Amount of grants awarded
2 000
1 800
1 600
SEK x 1000
1 400
1 200
1 000
800
600
400
200
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Figure 2. The amount of grants awarded by the Foundation since 1992.
The Prince Sigvard honorary lecture
In 1992 the board decided to institute an honorary lecture in the name of Prince Sigvard to
acknowledge the accomplishments of a prominent esearcher in the Nordic countries.
Nominations are done by the board of the Nordic Pediatric Ophthalmology Association and
presented to the board of the foundation for evaluation and decision. The award is presented
at the Nordic Pediatric Ophthalmology meetings and the recipient gives a lecture.
The list of awardees at the different meetings is as follows:
1994
Helsinki – Mette Warburg, Köpenhamn
1996
Copenhagen – Göran Stigmar, Lund
1999
Lugarvatn, Iceland – Hans Fledelius, Köpenhamn
2001
Tromsö – Kerstin Strömland, Göteborg
2003
Uppsala – Heikki Erkillä, Helsingfors;
2005
Åbo – Ruth Riise, Hamar
2007
Helsingör - Olav Haugen, Bergen;
2009
Bergen – Gerd Holmström, Uppsala
The Princess Marianne price
In 1994 the board of the foundation decided to create a price in the name of Princess
Marianne Bernadotte to be presented to a prominent Swedish clinical researcher still in the
active phase of their carrier. Nominations for the price are supplied by the professors of
ophthalmology in Sweden, for dicision by the board of the foundation. The price sum has
been 50 000 SEK. At the price ceremony the awardee presents a price lecture, and the
ceremony finishes with a musical event.
The list of price awardees is as follows:
1995
Kerstin Strömland, Göteborg
1997
Kristina Tornqvist, Lund
1999
Jan Ygge, Stockholm
2002
Lena Jacobson, Stockholm
2004
Gerd Holmström, Uppsala
2006
Ann Hellström, Göteborg
2008
Peter Jakobsson, Linköping
The Bernadotte Laboratories for Pediatric Ophthalmology
The research in pediatric ophthalmology has been strong at the department of ophthalmology
at Karolinska Institutet, particularly from the 1980-ies and onwards. The foundation has
supported this research and the laboratories at the department from the beginning. When the
laboratories were offered a new location at Huddinge University Hospital, they were officially
announced as the Bernadotte Laboratories of Pediatric Ophthalmology and inaugurated by
Prince Sigvard in March of 2000. The laboratories moved to the St. Erik Eye Hospital in
March of 2002. In the laboratories about 20 researchers at different levels are active in studies
of normal and abnormal development of the visual and oculomotor system, strabismus,
dyslexia, pediatric neuro-ophthalmology, ocular manifestations in pediatric diseases, among
others.
Teaching of pediatric ophthalmology for different categories of students and personnel is a
prominent part of activities at the Bernadotte laboratories.
The Laboratories are an important part of the newly created Bernadotte Institute at Karolinska
Institutet for research and advanced eye care of children. This institute is a virtual one,
combining research at the Bernadotte Laboratories with clinical work at St. Erik Eye Hospital
and Astrid Lindgen Hospital for Pediatrics. Support for the institute from the foundation is
directed to the Bernadotte Laboratories and to the hospitals through contracts between the
foundation and the hospitals. The support includes scholarships and salaries for researchers at
the hospitals and the laboratories, and funds for rent and equipment at the laboratories.
Collaboration with other foundations
The Bernadotte Foundation for Children’s Eyecare, Inc. was started 1993 in New York at the
initiative of Princess Marianne Bernadotte and with support from business men and scientists
with a Swedish background. Funds have been collected through auctions of donated art work
and/or charity banquets. Such events have been held in New York 1994, Chicago 1997, Los
Angeles 1999 and Palm Beach 2001, 2003 and 2005. The Foundation has supported three
visiting researchers to the Bernadotte Laboratories in Stockholm, and researchers and doctors
from developing countries to attend internal conferences of pediatric ophthalmology.
An association called The Friends of Sigvard and Marianne Bernadotte was started in 1997.
The members of the association want to support the Bernadotte foundations of Art and of
Pediatric Ophthalmology. The association arranges cultural activities for the members. The
association donates the assets collected each year to the two foundations.
The members of the present board of trustees
Professor, Nobel laureate 1981, Torsten Wiesel (honorary chairman); Princess Dr med h c
Marianne Bernadotte; Professor Gunnar Lennerstrand (chairman); Managing director Sven
Wallgren (vice chairman); Professor Anders Persson (secretary); Director Gunilla Stenberg
Stuckey; Professor Jan Ygge; BM Christina Lagergren; University secretary Ulla-Britt
Schützler- Peterson.
Figure 3. The present board of trustees.
Prince Sigvard and Princess Marianne Bernadotte
Organizers of the charity auction at Bukowskis in February 1990. From left: Attorney Kerstin
Sandels, Princess Marianne, mrs Gun Lennerstrand and professor Gunnar Lennerstrand
From the charity auction at Bukowskis in 1990. Pediatric ophthalmology research
among the art pieces was presented by Gunnar Lennerstrand and Jan Ygge
From the festivities at Waldermarsudde in 1991 when the Foundation received a large
donation from the Tomteboda School, represented by director Gunilla Stenberg Stuckey
Princess Marianne´s Prize presented to professor Lena Jacobson at a
ceremony in the Swedish Medical Association
Exterior and interior of the Bernadotte Laboratories at St. Erik Eye Hospital
Vision and eye motility research being performed using a Tobii eye tracker.
Professor Jan Ygge and test subject
I
The Development and Assessment
of Vision
Agneta Rydberg
Introduction
The normal visual development occurs from birth up to the age of 10-12 years, and requires a
normal visual system. Research during the last decades has emphasized the importance of
adequate visual stimulation during the first months and years of life. It is therefore of great
importance to identify children with subnormal vision early in life to start treatment and
habilitation. A prerequisite is that reliable testing methods are available and can reveal visual
defects as early as possible. The visual acuity testing methods in children can be divided into
3 subgroups according to the types of stimulus used; detection, resolution and recognition
acuity. Different acuity values are usually obtained with the different tests. Contrast
sensitivity measurements can reveal changes and loss of visual function that is not detected
when testing visual acuity. Sweep-VEP could become a valuable test to assess vision in young
children in a clinical setting.
Normal visual development
What can a newborn child see and how does the vision develop? A newborn child can hear
quite well, but the vision is subnormal and has not developed much. A newborn baby can
fixate a light, and from birth up to 4 weeks the baby starts to fixate and follow objects
presented closer than 1 meter. At about 2-3 months the child can fixate and follow an object at
2-3 meters. Eye contact is usually said to be developed at 4-7 weeks, and at 8-12 weeks the
child starts to play with its own fingers in front of the eyes.
The visual acuity, recorded as Snellen decimal acuity, is approximately 0.01-0.05 in a
newborn child, 0.1 at 6-12 months, 0.25 at 2 years, 0.5-0.65 at 3 years, 0.8 at 4 years and 1.0
at 6 years. Not until the age of 10 -12 years the visual acuity is fully developed, approximately
1.3-1.6. However, the acuity values depend to a great extent on the methods used in the
examination and this issue will be discussed in more detail later in this chapter.
Development of the visual pathways
The subnormal vision in young children is due to the immaturity of the eye and the whole
visual system-the retina, optic nerve, chiasma, lateral geniculate body, optical radiation, and
visual cortex. At birth the axial length of the human eye is about 17 mm (or 3/4 of adult size),
and by 13 years of age the eye has reached adult size, and an axial length of 23 mm. The
fovea is immature at birth. In the fetal eye cup it appears as an elevation formed by the
ganglion cells. The ganglion cells migrate peripherally during the first 25 weeks of fetal life to
form the foveal pit. The retina and especially the fovea will reach full maturity at about 4
years of age. The main change is in the density and spread of cones in the retina during this
period. The myelination of the optic nerves begins in the lateral geniculate nucleus, reaches
the orbital part of the optic nerve at full term, and continues towards the retina over the
following 2 years. The maturity of the lateral geniculate body and the visual cortex also take
place during the first 4 years of life. Studies of vision in monkeys, with a visual system very
similar to that of the human, have shown that the visual acuity during the first years is much
lower than what could be expected from the structure of the retinal and the neuronal elements.
However, at higher ages it correlates quite well to morphological parameters. The
development of the still higher visual acuity in adulthood is mainly due to the maturity of the
higher visual systems in the brain beyond the visual cortex.
The sensitive period
The plastic period (also called the sensitive period or the critical period) of the visual
development is the time during which the visual acuity is developing and can be modified.
The Nobel laureates of 1981, Professor Torsten Wiesel (honorary president of the Sigvard and
Marianne Bernadotte Research Foundation for Children Eye Care) and professor David
Hubel, already in 1963 established the norms for the sensitive period in cats and monkeys.
The period for cats is up to 16 weeks and in monkeys up to 30 weeks. In the human the
sensitive period proceeds up to 8-10 years of age with the most critical part during the first 23 months.
Abnormal visual development
The normal visual development requires a normal visual system. Different eye diseases such
as congenital cataract, strabismus, refractive errors (especially astigmatism and high
hyperopia), ptosis, lid hemiangioma etc. will prevent clear vision and retard visual
development. Amblyopia (amblyos= lazy, opia= vision) is a common visual sequelae to such
eye disorders. It is defined as a unilateral or bilateral decrease of visual acuity caused by
pattern vision deprivation or abnormal binocular interaction, where no signs of organic
disease can be detected by physical examination of the eye and which in appropriate cases is
reversible be therapeutic measures (see also chapter VI).
Amblyopia can be successfully treated up to approximately the age of 8 years, provided the
obstacle to normal form vision is removed, correct optical correction is provided, and
occlusion of the good eye is introduced to train the amblyopic eye. An alternative treatment to
occlusion is to use cycloplegic eye drops usually atropine in the good eye, a method that has
attracted renewed popularity in the United States, despite the disadvantages with the different
side effects. A contact lens to decrease the vision in the good eye can be used if other methods
fail. Improved vision in amblyopia with pharmacological treatment such as levodopa and
citicoline has also been reported (Leguire et al. 1993, Campos & Fresina 2006).
In congenital cataract the opaque crystalline lens should be surgically removed before the age
of 2 -3 months to reach good visual results (see also Chapter VI).
Methods to assess visual acuity
Visual acuity testing in young children in a clinical setting can be divided into three subtypes
according to the type of stimulus used. In detection acuity the stimulus, usually white balls in
various sizes, should be detected or distinguished from the black background. In resolution
acuity, the stimulus pattern, a black and white grating, should be resolved. In recognition
acuity the stimulus, a letter or symbol should be recognized by the subject and identified by
matching or naming.
The psychologist Fantz already in the 60´s reported that infants will prefer to look at a
patterned stimulus when presented in a homogeneous field of vision. This behavioural method
was called the preferential looking (PL) test. It was further developed by Teller and coworkers
(1986) and brought into clinical practice. The test patterns are black and white gratings of
variable spatial frequencies presented on printed cards, called the Teller Acuity Cards.
We first performed a study in adults to evaluate the method in patients with strabismic
amblyopia. It was shown that grating acuity (resolution acuity) overestimates the acuity
values determined with recognition tests in patients with strabismic amblyopia (Rydberg
1997).
To see how the correlation between the methods were in children, the next study was carried
out in children with manifest strabismus, visual impairment due to organic eye diseases and
children with normal vision. An overestimation of visual acuity was also seen in these groups
of children, when grating acuity was compared with recognition acuity (Fig. 1). Hence,
similar results were obtained in the children and adults.
Figure 1. PL grating acuities plotted against the HVOT linear test in children with normal
vision (circles), visual impairment (triangles) and strabismic amblyopia (squares). Each data
point represents one subject, except for a few representing two subjects. The dashed line
represents the line of equality between the tests. Logarithmic scales are used on both axes
To see whether the PL test could be used as a screening test for amblyopia, the grating acuity
in the amblyopic eyes and the non-amblyopic eyes were compared. In 30% of the subjects
resolution acuity determined with PL was the same in both eyes, and the amblyopia would
consequently have been missed if the PL test had been used in visual assessment (Fig. 2).
Figure 2. PL-grating acuities in the amblyopic eyes, plotted against PL acuities in the nonamblyopic eyes, in the adult patients with strabismic amblyopia (n=28). Each point represents
one patient. The dashed line represents the line of equality between the tests and the solid line
marks the limit for one octave difference between PL-acuity in normal and amblyopic eyes.
Linear scales are used on both axes
There are some Swedish studies on the development of recognition visual acuity using tests
with different kinds of optotypes. Lithander (1997) found a mean visual acuity of 0.48, with
the O-test (single symbols for near), in children 24-29 months old. With the KOLT test for
linear acuity, a visual acuity level of 0.55 was found in children aged 30-35 months, 0.67 in
children of 36-41 months and 0.77 in children 42-48 months old. Rydberg et al. (1998) found
a visual acuity of 0.67 with the LH-line test and 0.6 with the HVOT-test in children 29-41
months old and 0.99 with both tests at 48-83 months (median age 51 months). In a study by
Larsson et al. (2005), 81.6% of the control subjects had a recognition visual acuity of 1.33 or
more at the age of 10 years.
The crowding phenomenon
Crowding also called “separation difficulty” is the inability to discriminate letters and
symbols that are presented closely together, as optotypes in a line. Visual acuity determined
with single optotypes is usually much better than line acuity. Crowding phenomenon is
present to a small extent in normal eyes of young children. and is common in strabismic
amblyopia and also in children with cerebral visual impairment (Pike et al. 1994, Jacobson et
al. 1996).
Different tests assess different types of visual acuity
Different acuity values are often obtained in the same child with the different tests.
For example a child with visual impairment can sometimes detect a small pearl of 0.2 cm at a
distance of 3 meters. The grating acuity (resolution acuity) can be as high as 15 cycles per
degree corresponding to a Snellen visual acuity of 0.5. The recognition acuity with single
letters could be 0.3, whereas the recognition acuity with linear optotypes only is 0.1, due to
crowding. Detection and grating acuity do not correspond to Snellen acuity, and therefore
grating acuity should always be recorded in cycles per degree, and in measuring detection
acuity the size of the object and the distance used should always be recorded. The
discrepancies between the tests have to be kept in mind so that the acuity values are not
misinterpreted.
It is important to have reliable methods to detect subnormal vision at an early age to be able to
start the treatment and habilitation. However, there are still no tests available to get reliable
values when assessing vision in young children. It is not until the age of 3 ½ to 4 when
children can be tested with optotypes (symbols and letters) in a line that reliable responses can
be obtained (Rydberg et al. 1999).
Contrast sensitivity testing
Visual acuity represents only one aspect of visual capacity. Acuity is estimated as the smallest
stimulus that can be detected at a high contrast level. However, most objects in everyday
visual environment are larger than objects used in visual acuity testing and usually appear at a
lower contrast. Contrast is defined as the difference in luminance between adjacent areas in a
stimulus pattern. In determining the Contrast Sensitivity Function (CSF) gratings, symbols or
letters can be used at different spatial frequencies or sizes and at different contrast levels. A
bell shaped CSF curve is obtained with a peak of maximum sensitivity at 3-5 cycles per
degree (Fig 3). The cut-off spatial frequency is the highest spatial frequency that can be
resolved at maximum contrast and also represents the visual acuity value. This value is
normally 30-60 cycles per degree. There are many different tests to assess contrast sensitivity.
Some tests include patterns of different contrast values but only at one spatial frequency.
Other tests use patterns at only one contrast level but with many spatial frequencies (Rydberg
et al.1997). For a description of the whole CSF, different spatial frequencies at different
contrast sensitivity levels should be tested. The normal contrast sensitivity function in young
children is lower than in adults and the function increases with age, as shown in figure 3.
Contrast sensitivity measurements may reveal changes and loss of visual function that is not
detected when testing visual acuity.
Figure 3. CSF for normal adult subjects (thick solid line) and in comparison with CSF for
children at different ages (dashed lines) and older subjects (thin solid lines). (From
Abrahamsson & Sjöstrand 1992)
Sweep- VEP (Visual Evoked Potentials)
An electrophysiological method was introduced for objective assessment of vision in children
by Norcia & Tyler (1985). In this so called sweep-VEP method, the test patterns are
sinusoidal gratings and the visual evoked potentials (VEP) to the pattern stimulation are
recorded with surface electrodes placed on the occipital part of the scalp. The spatial
frequency of the grating changes gradually in a sweep from 32 to 2 cycles per degree. The
pattern is presented in an on-off or a pattern reversal mode, with such a high temporal
frequency that a “steady state” response is obtained. The VEP amplitude is plotted against
spatial frequency of the stimulus, and the visual acuity value can be extrapolated from the
curve.
Sweep-VEP could be a suitable method to assess vision in young children. We have tested
fifty normal subjects age 6 months-50 years (Rydberg et al. 2008). Sweep-VEP gave mostly
reliable results in adults. Good test-retest reliability was obtained in 5 adult patients who were
tested twice. In the younger children the results were more variable and sometimes difficult to
interpret. One possible explanation is poor fixation of the stimulus pattern. If fixation could be
controlled, sweep-VEP could become a valuable test to assess vision in young children in a
clinical setting. More research will be performed in this area in the future.
Conclusions
Reliable visual acuity measurements in children can be obtained at about the age of 3 ½-4
years, when visual acuity can be assessed with a recognition test using letters or symbols in a
line. Detection and resolution acuities overestimates the acuity values and different acuity
values are usually obtained with the different tests. The existing methods for clinical testing of
children under the age of 2 years are limited. Sweep-VEP could become a suitable test to
assess vision in young children.
References
Abrahamson M & Sjöstrand J (1992): Kontrastkänslighet och bländning. Nordisk medicin.
107:316-318.
Campos EC & Fresina M (2006): Medical treatment of amblyopia: present state and
perspectives. Strabismus, 14:71-73.
Jacobson L, Ek U, Fernell E, Flodmark O & Broberger U (1996): Visual impairment in
preterm children wih perivenricular leukomalacia-Visual cognitive and neuro-pediatric
characteristics related to cerebral imaging. Developmental Medicine and Child Neurology,
38:724-735.
Larsson E, Rydberg A & Holmström G (2005): A population-based study of the visual
outcome in 10-year-old preterm and full-term children. Archives of Ophthalmology, 123:82532.
Leguire LE, Walson PD, Rogers GL, Bremer DL & Mc Gregor ML (1993): Longitudinal
study of levodopa/carbidopa for childhood amblyopia. Journal of Pediatric Ophthamology
and Strabismus 30:354-60.
Lithander J (1997): Visual development in healthy eyes from 2 months to four years of age.
Acta Ophthalmologica Scandinavica, 75:275-276.
Norcia AM & Tyler CW (1985): Spatial frequency sweep VEP: visual acuity during the first
year of life. Vision Research, 25:1399-1408.
Pike MG, Holmström G, de Vris LS, Pennock LM, Drew KJ, Sonksen PM & Dubowitz LMS
(1994): Patterns of visual impairment associated with lesions of the preterm infant brain.
Developmental Medicine and Child Neurology, 36:849-862.
Rydberg A (1997): Assessment of visual acuity in adult patients with strabismic amblyopia: A
comparison between preferential looking and different acuity charts. Acta Ophthalmologica
Scandinavica, 75:611-617.
Rydberg A, Han Y & Lennerstrand G (1997): A comparison between different contrast
sensitivity tests for the detection of amblyopia. Strabismus, 5:167-184.
Rydberg A & Ericson B (1998): Evaluation of methods for assessing visual function in
children 1 1/2 years of age with normal and subnormal vision. Journal of Pediatric
Ophthalmology and Strabismus, 35:312-319.
Rydberg A, Ericson B, Lennerstrand G, Jacobson L, Lindstedt E (1999). Assessment of visual
acuity in children aged 1 1/2 - 6 years, with normal vision, visual impairment and strabismus.
Strabismus, 7 (1): 1-24.
Rydberg A, Bengtsson M & Andersson T (2008): Sweep-VEP, a method to assess vision in
children. 32nd Meeting of the European Strabismological Assoociation, Abstract P12:55.
Teller DY, Mc Donald MA, Preston K, Sebris SL & Dobson V (1986): Assessment of visual
acuity in infants and children. The acuity card procedure. Developmental Medicine and Child
Neurology, 28:779-789.
II
Development of the Visual Field
Lene Martin
Introduction
The visual field is defined as the area that can be seen when the eye is directed forward and
steadily fixating, including that which is seen with peripheral vision. The visual field is almost
always tested one eye at the time, and there are several methods and more or less advanced
equipments for visual field testing (also called perimetry). This chapter describes visual field
testing in children and factors influencing the visual field development and the test results.
Methods for testing the visual field in children
A simple, although quite informative way of testing the extent of the visual field is ad modum
Donders, when you use your own hands as stimuli, and your own visual field as reference.
This method is used in adults to detect large constrictions and when no equipment is
available. For quantitative testing of the sensitivity within the visual field, computer assisted
techniques are preferred. Since most of the diseases affecting the visual system first affects in
the central part of the visual field (although not necessarily affecting the area for reading
ability; the fovea), most computerized perimeters test the central 30° area. In children,
however, it is sometimes interesting also to test the extent of the visual field, and then
different manual methods, possible to adapt to the children’s age and ability to co-operate,
have to be used.
In small children, testing the visual field is a challenging task. A number of different methods
have been developed but only a few of them have been adequately evaluated. In very young
children a variant of “preferential -looking” is used, in which the examiner observes if the
infant shifts gaze when a stimulus is presented. In toddlers the so called ball-on-a-stick can be
used. Pre-school children are able to co-operate in a manual Goldmann examination and
school children can perform computerized perimetry (Fig 1).
Figure 1. Different techniques for visual field testing. Goldmann perimetry (Courtesy of
Luisa Mayer) (Left), Computerized perimetry: Rarebit perimetry (Right)
The Normal Visual Field in Children
Measuring the visual field in young children; infants and toddlers, is complicated. Yet, several
studies have provided knowledge about the extent of and sensitivity in the visual field in the
growing child, even if different reports give somewhat varying results. The extent of the
visual field in small children is also depending of the method used; kinetic or static, the size
of the stimulus and, in children at 1-2 years of age, also on the presentation of competing
stimulus in the fixation area.
The effective visual field has been shown to expand between 2 and 4 months of age and the
ability to respond to peripheral objects more distant than the fixation object develops after 3
months. Visual field extent corresponding to adult levels has been reported to be present at 17
and 30 months of age, measured with kinetic and static perimetry, respectively (Dobson et al
1998), see figure 2.
Figure 2. Visual field extent in different ages measured a with 6° stimulus (Goldmann III –
IV). Thin continous blue line = newborn, dashedd blue line = 3.5 months, thick continous
blue line = 7 months, red dash/dot line = 4 years, blue dash/dot line = adult (adapted from
Dobson et al 1998).
Regarding the standard tests, routinely used in adults, it is well known that the child has to
reach an age of 5-7 years before reliable visual field results can be expected. Using the most
common computerized methods the extent and sensitivity values, equal to those from adults,
can be obtained at the age of 10-12 (Martin 2005, Martin & Lundvall 2007; 2009).
Attention
One main reason for the different results in children and adults, especially regarding static and
moving stimuli, may relate to differences in peripheral summation areas or to differences in
attention between infants and adults. The visual field in pre-school children is affected by non
visual factors, such as vigilance and cognitive processes (Tschopp et al 1998). From the age
of 5 to 7, the child is able maintain steady fixation on a target and to respond to a stimulus
presented in the periphery by pressing a button. But in younger children and infants, the
examiner has to rely on the fixation eye movements of the child. However, infants between
approximately 1 and 4 months of age were reported to have difficulty with disengagement, i.e.
looking away from a stimulus, once their attention has been engaged (Hunnius 2007).
The eccentricity to which infants move their gaze to locate a target has been found to increase
rapidly during the first 4 months of age (Harris & MacFarlane, 1974; Lewis & Maurer1992).
Despite this fast early development, several studies report that an adult-like performance is
not attained before the end of infancy or even the school-age years. Other authors have
reported that from the age of approximately 6 months, infants’ performance when shifting
gaze between two stimuli is comparable to that of adults (Atkinson et al, 1992).
Normal visual field development
As has been stated above, there are numerous studies using manual perimetry for examining
the visual field in children and for evaluation of the extent of the visual field. We have been
interested in evaluating new computerized perimetric methods in children for evaluation the
sensitivity of the central visual field, both in healthy children and pediatric patients. Two
methods have been used, both developed in Sweden; the high-pass resolution perimeter (HRP
(Frisén 1993; Martin et al 2008a) and Rarebit perimetry (Frisén 2002; Martin 2005).
Especially the latter was found to be suitable for children of at least 6 year of age. The method
is sensitive to low-degree damage, very patient-friendly, requires short examination time and
is preferred by the children, when compared to other techniques (Martin et al 2004).
Figure 3 shows a summary of five of our studies of healthy children of different ages,
evaluating the normal values established with Rarebit perimetry (Martin et al 2004; Martin
2005; Martin & Lundvall 2007; Martin et al et al 2008b; Hellgren et al 2009).
Abnormal visual field development
There are several factors that can disturb the normal development of the visual field. In
several studies we have described the effect of intrauterine incidents, intrauterine growth
restriction, premature birth, treatments for side effects of premature birth (retinopathy of
prematurity) and other hinders for the normal visual development such as ametropia,
strabismus and congenital cataract.
Figure 3. Results from computerized perimetry (Rarebit perimetry), expressed as a
percentage of stimuli seen (hit rate) from age 7 to 20 (healthy subjects). Note the low increase
in hit rate from age 7 to 12 and the somewhat larger variability in examination results in
younger children (Martin & Lundvall, submitted).
Prematurity and co-morbidity
Prematurity influences the visual system in several ways. In a follow-up study of 11-year old
children, born prematurely, we could confirm findings in previous studies, i.e. that children
treated for retinopathy of prematurity have somewhat constricted visual fields compared to
age-matched controls. But we could also show that prematurity per se reduced the sensitivity
in the central visual field (outside the fovea), presumably reflecting a reduced density of
retino-cortical neural channels (Larsson et al 2004). This was true also for children born small
for gestational age due to intrauterine growth restriction (Martin et al 2004).
Approximately one third of the children born prematurely and/or with very low birth weight
have cerebral sequelae, such as white brain matter damage (Olsén et al. 1997). Studies
regarding visual outcome, especially the visual field are sparse, due to the wide-spread
misunderstanding that quantitative perimetry is not possible in these children. However, using
a combination of the manual kinetic Goldmann perimetry for examination of the extent of the
visual field, and one of two computerized techniques for examining the central visual field,
we were able to carefully examine a number of prematurely born teenagers and young adults
with visual dysfunction due to white matter damage of immaturity of pre- or perinatal origin.
They all had subnormal visual field function, although the depth and extension of the defects
differed between subjects. Typically, the inferior field function was more impaired than the
superior. We could also show that, as in adults, the static computerized techniques revealed a
slightly higher frequency of abnormality (Jacobson et al. 2006) compared to Goldmann
perimetry.
In a separate study of adolescents with very low birth weight (<1500 g) we found that the
subjects are at a disadvantage regarding visual outcome compared to subjects with normal
birth weight (Hellgren et al 2007). Almost one fifth of all VLBW children, and 40% of those
with white matter damage, had subnormal visual fields (Hellgren et al. 2009).
Congenital cataract
It is well known that dense cataract, even when surgically treated early in infancy, causes
persistent impairment of visual acuity. Recently we have shown that not only the extent of
the visual field, but also the sensitivity in the 30-degree visual field is affected, although less
pronounced than visual acuity (Martin et al. 2008a). This finding has to be taken into account
when evaluating visual field results in for example in the diagnosis of glaucoma, a frequent
complication after cataract surgery in early infancy.
Glaucoma
Computerized visual field examinations are gold standard in the diagnosis and follow-up of
glaucoma. Nevertheless, not many studies are published using computerized perimetry in
pediatric glaucoma. We have found that the Rarebit perimetry is well suited for glaucoma
management in children (Martin & Lundvall 2007). Recently we could show that the visual
fields remained essentially unchanged during 5 years of follow-up in children and
adolescents, carefully treated for glaucoma (Martin & Lundvall 2009).
Conclusions
Visual fields develop rapidly during early infancy as shown in studies with tests appropriate
for the age of the child. However, conventional perimetric techniques are less suitable for
children below the age of 7 to 12 years. Recent developments in perimetric methods may
improve the ability to detect visual field abnormalities in even younger children.
References
Atkinson J, Hood B, Wattam-Bell J, Braddick O (1992): Changes in infants' ability to switch
visual attention in the first three months of life. Perception. 21(5):643-53
Dobson V, Brown AM, Harvey EM, Narter DB (1998): Visual field extent in children 3.5-30
months of age tested with a double-arc LED perimeter. Vision Res 38:2743-60
Frisén L (1993): High-pass resolution perimetry: a clinical review. Doc Ophthalmol. 83:1–25
Frisén L (2002): New, sensitive window on abnormal spatial vision: rarebit probing. Vision
Res 42:1931-1939
Harris P & MacFarlane A (1974): The growth of the effective visual field from birth to seven
weeks. J Exp Child Psychol. Oct;18(2):340-8
Hellgren K, Hellström A, Jacobson L, Flodmark O, Wadsby M, Martin L (2007): Visual and
cerebral sequelae of very low birth weight in adolescents. Arch Dis Child Fetal Neonatal Ed
92:F259-64
Hellgren K, Hellström A, Martin L (2009): Visual fields and optic disc morphology in very
low birth weight adolescents examined with magnetic resonance imaging of the brain. Acta
Ophthalmol 87:843-8
Hunnius S (2007). The early development of visual attention and its implications for social
and cognitive development.C. von Hofsten & K. Rosander (Eds.) Progress in Brain Research,
Vol. 164. 007 Elsevier B.V.
Jacobson L, Flodmark O, Martin L (2006): Visual field Defects in Prematurely Born Patients
with Periventricular White Matter Damage - a Multiple Case Study Acta Ophthalmol Scand
84:357-362
Larsson E, Martin L, Holmström G (2004): Peripheral and central visual fields in 11-year-old
children who had been born prematurely and at term. J Pediatr Ophthalmol Strabismus 41:3945
Lewis TL, Maurer D (1992): The development of the temporal and nasal visual fields during
infancy. Vision Res. May;32(5):903-11
Martin L, Ley D, Marsal K, Hellström A (2004): Visual function in young adults following
intrauterine growth restriction. J Pediatr Ophthalmol Strabismus 41:212-8
Martin L (2005): Rarebit and frequency-doubling technology perimetry in children and young
adults. Acta Ophthalmol Scand 83:670-677
Martin L & Lundvall Nilsson A (2007): Rarebit Perimetry and Optic Disk Topography in
Paediatric Glaucoma. J Pediatr Ophthalmol Strabismus 44:223-31
Martin L, Magnusson G, Popovic Z, Sjöstrand J (2008a): Resolution visual fields in children
surgically treated for bilateral congenital cataract. Invest Ophthalmol Vis Sci 49:3730-3
Martin L, Aring E, Landgren M, Hellström A, Andersson Grönlund M (2008b): Visual fields
in children with attention-deficit/hyperactivity disorder before and after treatment with
stimulants. Acta Ophthalmol Scand 86:259-64
Martin L & Lundvall A (2010): Rarebit Visual Field Follow-Up in Pediatric Glaucoma
(submitted for publication)
Olsén P, Pääkkö E, Vainionpää L, Pyhtinen J & Järvelin M-R (1997): Magnetic resonance
imaging of periventricular leukomalacia and its clinical correlation in children. Ann Neurol
41:754-61
Tschopp C, Safran AB, Viviani P, Reicherts M, Bullinger A, Mermoud C (1998): Automated
visual field examination in children aged 5-8 years. Part II: Normative values. Vision Res
38:2211-8
III
Eye Development and Refractive
Errors
Tony Pansell
Introduction
The emmetropization process involves monitoring the ocular growth to match the refractive
power of the eye. Myopia occurs when the ocular axial length exceeds the value
corresponding to the refractive power of the eye. This chapter will report the current
understanding of the emmetropization process and present recent findings of myopia research.
Eye development and emmetropization
The ocular refractive status refers to the locus of the optical focus in relation to the retina
during minimal accommodation. In the ideal eye the distance from the cornea to the retina
(i.e. axial length) are in concordance with the total refractive power and the light entering the
eye will form a sharp image on the retina, that is an emmetropic eye. In a hyperopic eye the
light is focused behind the retina which is due to a too low refractive power alternative a too
short axial length. In a myopic eye the light is focused in front of the retina, which can be due
to either a too high refractive power alternative a too long axial length. The axial length of the
eye ball in an adult is approximately 24 mm and to focus the light onto the retina the optical
power has to measure approximately 60 dioptres. The refractive elements of the eye are the
corneal surface, which accounts for approximately 42 diopters of the total refractive power
and the crystalline lens, which accounts for approximately 18 diopters. In a newborn full term
child the axial length is shorter (~17 mm) and the refractive power higher (~85 dioptres). The
cornea counts for ~50 diopters and the crystalline lens 35 diopters. The eye bulb reaches
almost full axial length at 3 years of age but the ocular growth does not cease until 14-15
years of age. The eye thus only grows approximately 1 mm from 3 years of age to early
teenage. When growing, the relation between ocular axial length and ocular refractive power
has to be adjusted simultaneously to maintain a well working optical system. This mechanism
is referred to as the emmetropization process.
Emmetropization regulates the shape of the refractive media, by detecting the refractive error
of the eye at rest and initiating ocular changes to minimize the refractive error. In
experimentally induced focusing errors by means of positive or negative lenses, the net result
of the initiated ocular changes was that the eyes become approximately emmetropic with the
lenses in place (Schaeffel et al. 1988). When the lenses were removed, the eyes showed a
refractive error in the opposite direction, hyperopic after imposed myopia and myopic after
imposed hyperopia. After removing form deprivation filters in chick eyes, the myopia quickly
decreased to negligible levels, provided that optical correction was not introduced and that the
treatment was initiated at a sufficiently early age (Wallman & Adams 1987).
When inducing monocular deprivation in animals the occluded eye ball became longer than
normal. The difference in length was over 1 mm and the sclera of the on the posterior wall of
the occluded eye was thinner. This effect was found to be largest on younger animals (Wiesel
& Raviola 1977). Even a modest degree of constant form-deprivation using partially
occluding filters would trigger an axial length growth inducing myopia. The denser the filter
is the larger the myopia became (Smith & Hung 2000). The fovea is not essential for normal
refractive development as foveal ablations has no apparent effect on emmetropization.
However, the peripheral retina, in isolation, can regulate emmetropizing responses and
produce anomalous refractive errors (Smith et al. 2007). Hyperopia is more common than
myopia in early infancy, and most individuals undergo emmetropization to a refractive state
of low hyperopia rather than precise emmetropia (Irving et al. 1996). A few are born myopic
and this has to be reversed before reaching young adulthood because the eye ball can grow,
but it can not shrink.
Current research in myopia
While hyperopia is considered relatively harmless, myopia is clearly linked to eye health
hazards. Myopia is considered to be the leading cause of visual impairment (World Health
Organization, 2000). Immense effort is put into understanding the underlying mechanisms of
myopia progression and the biological, neurophysiological and environmental bases for
myopia development. The goal is to find predictors to show who will develop myopia and to
begin prophylactic treatment in them to minimize or hinder its progression.
The prevalence of myopia is increasing globally and myopia has reached epidemic
proportions in parts of East Asia with up to 70% to 90% of 17- to 18-year-olds in the region
affected (Lin et al., 2001; Saw et al., 2005; Zhao et al., 2000). A Swedish prevalence study in
12-13 year old school children from 2000 showed myopia in 49.7% (Villarreal et al. 2000).
Previous prevalence studies in Scandinavia revealed considerably lower values for myopia. In
Denmark, 1983, Fledelius reported a prevalence of 30% myopia in individuals 16 years of age
and older (Fledelius 1983). In Finland, 1980, Laatikainen found a prevalence of 29% in the
14- to 15-year-olds (Laatikainen & Erkkilä 1980).
During the last decade the understanding in the mechanisms of myopia development have
increased through ocular biometry, i.e. measurements of the intraocular parameters affecting
the refractive state of the eye. From the CLEERE multicentre study in US it seems clear that
both early-onset myopia (childhood) and late-onset myopia (15-18 y) typically involve
excessive enlargement of the eye where the axial length is prolonged in the absence of
compensatory lens changes (see table 1 below for details).
Table 1. Summary of the main findings of the Collaborative Longitudinal Evaluation of
Ethnicity and Refractive Error (CLEERE) study, a US multicentre 6-year study on normal
ocular growth in 2583 children aged 6-14 years (Zadnik et al., 2003)
Parameter
Aged 6 years
Aged 14 years
Spherical equivalent refractive error (D)
+0.85 ± 0.86
-0.28 ± 2.48
Corneal power (D)
43.67 ± 1.48
43.37 ± 2.48
Anterior chamber depth (mm)
3.54 ± 0.25
3.66 ± 0.29
Vitreous chamber depth (mm)
15.50 ± 0.61
16.44 ± 1.19
Crystalline lens power (D)
24.23 ± 2.16
22.38 ± 2.09
Myopic eyes are larger in all three dimensions (i.e. equatorial, anterior-posterior, and vertical
axes). Twin and family studies indicate a genetic predisposition to myopia (Goss & Wickham
1995) and a parental history of myopia is well known to be a high risk factor for developing
myopia. The prevalence with two myopic parents is 30% to 40%, whereas it is reduced to
20% to 25% in children with one myopic parent, and to >10% with no myopic parent (Mutti
et al. 1996). Anterior and vitreous chamber depths are larger as the risk (the number of
myopic parents) of myopia increases.
Although the eye growth ceases at around 15 years of age, between 8 and 15 % of the myopes
develop their myopia between 15 and 18 years of age (i.e. late-onset myopia) with slow
progression to levels rarely exceeding 2 D. The environmental risk factors most often cited
include education, urbanization and near work but the nature of their interaction with genetic
factors remains unclear (Saw 2003). Late-onset myopia has been attributed to near work,
especially when the work has a high level of cognitive demand. The influence of electronic
displays on myopia progression is still not clear and a better understanding of the interaction
of accommodation and the oculomotor system to these displays need to be consolidated,
especially as a new generation of 3D displays is forthcoming. Interestingly, sustained
accommodation has been shown to reduce intraocular pressure by up to 2.4 mm/Hg and there
is recent evidence for a relationship between IOP and myopia in a Japanese population.
Refractive errors in prematurely born children
Low birth weight is one factor influencing the refractive development. Premature infants are
more prone to develop myopia from an early age and myopia development can continue up to
2 years of age. The incidence of myopia in preterm infants ranges from 1% to 16% and the
children may remain myopic later on in childhood and adolescence. Retinopathy of
prematurity (ROP) is a disease affecting prematurely born infants due to an immature eye and
incomplete development of the retinal blood vessels. The incidence of ROP among
prematurely born infants is approximately 40% (Holmström et al. 1993). If mild ROP is
present the incidence of myopia increases to 17% to 50%. The more severe the ROP is the
higher the incidence of myopia became. Some populations show up to 100% incidence of
myopia in the advance stages of the disease. The biometric components found to contribute to
the refractive error in prematurely born children include a shallower anterior chamber and a
shorter axial length (15 mm), increased lens power (45 D) and increased corneal refractive
power (54 D). The mechanism of myopia development thus seems different from that in full
term children. The available treatment options for ROP are cryo therapy and laser treatment
and it is very difficult to differentiate the effects of the disease and the effect of the treatment
on myopia. Treated infants have a higher incidence of myopia than non-treated infants. At the
same time, the more advanced stages of ROP are more likely to need more treatment.
Research on myopia prevention
Today the best single predictor for developing myopia is cycloplegic refraction. Children with
hyperopia of 0.75 D or less at a mean age of 8.6 years have been shown to have a sensitivity
of 86.7 % and specificity of 73.3 % for developing myopia (Zadnik et al.1999). The question
is how refractive errors should be treated while the eye still is growing. There is unfortunately
no straightforward answer on that question. The clinical tradition recommends undercorrecting myopia and fully correcting hyperopia in children before entering puberty. The
philosophy is to reduce the accommodative demand in order to not induce transient myopia
and in the long run manifest myopia. One theory of myopia progression is based on the
observation that myopic children have a higher lag of accommodation than non-myopic
children. The hyperopic retinal blur that results from a high lag of accommodation during near
work is hypothesized to cause an increased rate of axial length growth. However, several
studies could not find any change in axial growth when prescribing near reading addition,
which minimizes or eliminates the lag of accommodation. The CLEERE study suggests that
high accommodative lag is a by-product of myopia, rather than the causative factor.
Pharmacological treatment by Pirenzepine, a muscarinic receptor antagonist, shows promising
results in reducing the myopia progression. In a recent US study a significant 0.27 D
reduction in myopia progression was found after the first year of treatment and a 0.41 D
overall reduction after the second year (Siatkowski et al. 2004). Development of new
pharmacological agents for controlling scleral growth is today a topic for discussion. This is
an exciting and hopefully promising treatment option for the future.
Several challenges for myopia research society still exist. The current treatment options are
more based on a clinical experience than scientifically proven evidence. The majority of
myopia research performed is based on animal studies. Human research is required to fully
understand the interaction of genetic and environmental risk factors for developing myopia.
Further, better tools for measuring near work exposure are required in order to fully
understand the effect of near work on myopia.
Conclusions
A clear optical image is of main importance for a normal ocular development. The
emmetropization process regulates ocular growth and is based on defocus of the peripheral
image on the retina. Neural mechanisms involving the fovea or the visual cortex do not seem
to be take part in the process. Myopia due to excessive axial length of the eye has increased
globally and has become a major concern with regard to ocular health. Great efforts have been
made in trying to understand the mechanisms of ocular growth and how to retard myopia
progression.
References
Fledelius HC (1983): Is myopia getting more frequent? A cross-sectional study of 14-16
Danes aged 16 years+. Acta Ophthalmologica 61: 545-559.
Goss DA & Wickham MG (1995): Retinal-image mediated ocular growth as a mechanism for
juvenile onset myopia and for emmetropization. A literature review. Documenta
Ophthalmologica Advances in Ophthalmology 90: 341-375.
Holmström G, el Azazi M, Jacobson L &Lennerstrand G (1993): A population based,
prospective study of the development of ROP in prematurely born children in the Stockholm
area of Sweden. British Journal of Ophthalmol 77: 417-423
Irving EL, Sivak JG, Curry TA & Callender MG (1996): Chick eye optics: zero to fourteen
days. J Comperative Physiololgy and Sensory Neural Behaviour Physiology 179: 185-194.
Laatikainen L & Erkkilä H (1980): Refractive errors and other ocular findings in school
children. Acta Ophthalmologica Scandinavica 58: 129-136.
Lin LL, Shih YF, Hsiao CK, Chen CJ, Lee LA & Hung PT (2001): Epidemiologic study of
the prevalence and severity of myopia among schoolchildren in Taiwan in 2000. Journal of
the Formosan Medical Association 100: 684-691.
Mutti DO, Zadnik K & Adams AJ (1996): Myopia: The nature versus nurture debate goes on.
Investative Ophthalmology & Visual Sciences 37: 952-957.
Saw SM (2003): A synopsis of the prevalence rates and environmental risk factors for myopia
Clinical & Experimental Optometry 86: 289-294.
Saw SM, Tong L, Chua WH, Chia KS, Koh D, Tan DT & Katz J (2005): Incidence and
progression of myopia in Singaporean school children. Investigative Ophthalmology & Visual
Science 46: 51-57.
Schaeffel F, Glasser A & Howland HC (1988): Accommodation, refractive error and eye
growth in chickens. Vision Research 28: 639-657.
Siatkowski RM, Cotter S, Miller JM, Scher CA, Crockett RS & Novack GD (2004): Safety
and efficacy of 2% pirenzepine ophthalmic gel in children with myopia: a 1-year, multicenter,
double-masked, placebo-controlled parallel study. Archives of Ophthalmology 122: 1667-74.
Smith EL & Hung LF (2000): Form-deprivation myopia in monkeys is a graded phenomenon.
Vision Research 40: 371-381.
Smith EL, Ramamirtham R, Qiao-Grider Y, Hung LF, Huang J, Kee CS, Coats D & Paysse E
(2007): Effects of foveal ablation on emmetropization and form-deprivation myopia.
Investigative Ophthalmology & Visual Science 48: 3914-3922.
Villarreal MG, Ohlsson J, Abrahamsson M, Sjöstrom A & Sjöstrand J (2000): Myopisation:
the refractive tendency in teenagers. Prevalence of myopia among young teenagers in
Sweden. Acta Ophthalmologica Scandinavica 78: 177-181.
Wallman J & Adams JI (1987): Developmental aspects of experimental myopia in chicks:
susceptibility, recovery and relation to emmetropization. Vision Research 27: 1139-1163.
Wiesel TN, Raviola E (1977): Myopia and eye enlargement after neonatal lid fusion in
monkeys. Nature 266: 66-68.
World Health Organization (2000): Elimination of Avoidable Visual Disability due to
Refractive Errors (WHO/PBL/0079) Geneva: World Health Organization; Vision 2020
Zadnik K, Manny RE, Yu JA, Mitchell GL, Cotter SA, Quiralte JC, Shipp M, Friedman NE,
Kleinstein RN, Walker TW, Jones LA, Moeschberger ML & Mutti DO (2003): Ocular
component data in schoolchildren as a function of age and gender. Optometry and Vision
Science 80: 226-236.
Zadnik K, Mutti DO, Friedman NE, Qualley PA, Jones LA, Qui P, Kim HS, Hsu JC &
Moeschberger ML (1999): Ocular predictors of the onset of juvenile myopia. Investigative
Ophthalmology & Visual Science 40: 1936-1943.
Zhao J, Pan X, Sui R, Munoz SR, Sperduto RD & Ellwein LB (2000): Refractive Error Study
in Children: results from Shunyi District, China. American Journal of Ophthalmology 129:
427-435.
IV
Ocular Motility Development
Jan Ygge
Introduction
Ocular motility, i.e. the ability to move the eyes is very important for humans to have a good
visual function. Our eyes are equipped with a fovea, i.e. the area of the retina with the highest
visual acuity. Since this fovea represents only about a degree of the visual field we only have
a high visual acuity in a very limited part of the visual field. Therefore we need to move the
eyes in order to keep the visual surroundings updated. To do so it is required that the eyes are
able to i) keep a steady fixation on a stationary target of visual interest, ii) keep a steady
fixation although the target is moving, iii) move the eyes precisely to different parts of the
visual field and iv) have a well developed eye alignment and avoid double vision.
Eye movements of different types are required for these specific functions, and they are
controlled by different areas of the brain and the brain stem. The separate types normally
mature during different stages of child development. Therefore studies of the development of
the eye movement types can bring information about the maturity of the specific brain region
from which it is generated and also help in diagnosing and following diseases in the brain and
brainstem.
Visual Fixation
Visual fixation is the ability to hold the eyes stable on a stationary target both when the head
and body are stationary as well as when in motion. This is crucial for the good visual function
since as stated above the visual acuity is highest within only a very small part of the visual
field. A stable fixation is usually interrupted by several involuntary eye movements such as
micro tremor, visual drift, and micro saccades and blinks (Fig. 1).
Figure 1. Ten seconds recording of a ten year old child fixating a stationary target on a
computer screen. Note the presence of micro saccades, drifts and tremor
It was recently shown that the ability to keep a steady fixation on a stationary target matures
with age and that this ability does not reach adult values until in the teens (Fig. 2).
A stable fixation is also required when the head and body are moving. Since humans are in
motion most of the time we need an effective reflex to obtain a stable view of the visual
surroundings. Two reflexes, both initiated in the balance organ in the inner ear serve this
function. The VOR, i.e. the vestibulo-ocular reflex originates in the semicircular canals of the
vestibular apparatus in the inner ear. The semicircular canals detect rotational forces in all
directions. The signals from them help keep the eyes on a target by inducing eye movements
that compensate for body and/or head movements. This ability develops early in childhood
and a well functioning VOR can be seen already at a few days of age.
Figure 2. Histograms showing increased fixational stability by lesser number of intruding
saccades during fixation. Note also that the number of blinks during fixation is almost similar
between the different age groups. Group A1 represent children 4-7 years, A2 6-9 years, A3 912 years and A4 12-15 years.
When the human body rotates with larger amplitude the VOR cannot compensate fully for the
rotation since the amplitude response of the reflex is limited. Instead the OKN, i.e. the
optokinetic reflex keeps the eyes on a target when the body is rotating or the visual scene is
moving with larger amplitude. An example is when being on a train and looking out of the
window. The image of the world outside is moving and in order to get a detailed view of a
target, the eyes have to follow it. When the eyes reach a certain deviation and viewing
sideways becomes inconvenient, the eyes move rapidly towards the straight ahead position to
fixate on a new target and then follow it. In doing so fixation and good vision is maintained
on targets of interest, although the surrounding is moving. The sequence of following eye
movements and rapid re-fixations is the OKN. The same reflex is effective when we view the
surroundings sitting on a rotating chair. The OKN is quite a primitive reflex and it develops
early. However, during the first months of life directional asymmetries have been observed.
When testing the monocular OKN, the temporal-nasal directed OKN is seen to be developed
earlier than the nasal-temporal OKN. Normal OKN is not developed until about a year of age.
In subjects with early childhood strabismus this directional asymmetry is known to persist
throughout life.
Saccadic system
As stated above, the area of a good visual acuity is corresponding to only about a degree of
the visual field and in order to view a larger visual scene we need to move our eyes to fixate
different parts of interest. These eye movements, called saccades, are used both spontaneously
as well as voluntary in all our daily activities. When reading for example, the line of sight is
not moved continuously over the text but instead in small jumps, saccades, between different
parts of fixation in the text. The amplitude of saccadic movements and the duration of the
fixation periods depend on the complexity of the text and the reading comprehension. It is
known that the more difficult the text, the shorter are the saccadic jumps between points of
fixation. It is also known that the beginner reader makes smaller saccades and longer fixations
on the different words before acquiring an adult reading performance (Fig. 3).
Figure 3. Increased fixational stability by more central fixation with increasing age. For
explanation of procedure see text. Same age groups as fig 2.
The saccadic system has to be trained to mature. There are two fundamental differences
between mature saccadic performance and saccades performed by a child. Firstly, it is known
that the latency to initiate a saccade is about 200 msec in the adult whereas in the child the
latency can be much longer. The saccadic latency in a preschool child is usually about 400
msec, i.e. twice the adult value (Fig. 4). The system matures with age and adult values for
saccadic latencies will be reached at about the age of school start or even later. The other
difference between a child and an adult regarding saccadic development is that the child
usually makes multi-step saccades. Since the saccadic system is still immature, the ability of a
child to adequately calculate the exact amplitude of a saccade is not yet developed. Thus the
child will make several saccadic steps when trying to reach a target within the visual scene
(Fig. 4). Also this function matures with age (and training) and adult values are probably
reached by the early teens. Children with neurological disease such as Ataxia teleangiectasia
will never reach adult values and they show also in the teens extremely long saccadic
latencies.
Figure 4. Reading eye movements in a normal 10 year old child (left) and a Dyslexic 10 year
old (right). Same time scale in both figures. Note that the normal child performs better reading
eye movements with two lines completed during the recording while the Dyslexic child
during the same time has almost only completed reading of one line of text due to longer
fixations and shorter reading saccades.
Smooth pursuit eye movements
In order to keep a moving target in a visual scene on the foveal area representing best vision,
we need to track the target. The eye movements that serve this function are the smooth pursuit
movements. The ability to exactly track the moving object requires practice to get well
calibrated. This ability to perform adequate smooth pursuit movements develops with the
maturation of the fovea and visual acuity, since a good vision is needed to be able to see the
target and to track it. During the period of fovea development and subnormal visual acuity,
small children often exhibit a cogwheel tracking, i.e. a tracking consisting of with small
saccades instead of a smooth pursuit movement. This type of tracking is represented by a very
low so called smooth pursuit gain, i.e. the ratio between eye position and target position is
below normal. The smooth pursuit gain in adults usually is close to 1.0, meaning that the eye
is tracking the target almost perfectly. The pursuit gain in children can be as low as 0.6, which
means that the eyes are directed exactly at the target only 60% of the time trying to track it.
The adult smooth pursuit gain is probably reached at early teenage.
Vergence eye movements
The vergence eye movements are used for tracking targets in depth and for keeping the eyes
aligned. Vergence eye movements depend on the maturation of the fovea and visual acuity
function as does the smooth pursuit movements. The first months of life when the fovea starts
to mature and the visual acuity increases, is also the time when accommodation begins to
function and the vergence eye movements start to develop. A full convergence response to a
near target can be seen already in a 2 months old baby (figure 5).
Figure 5. Vergence in a two-month old child.
However, the other vergence functions are not fully developed at this early age. Deviations of
eye position can be seen in infants both in the horizontal and the vertical directions. Even if
vergence positions stabilize during the first couple of years, they are probably not mature until
the early teens (Fig. 6).
Figure 6. Histograms showing the increased fixational stability in terms of horisontal and
vertical vergence positional SD with increasing age. Both the horizontal as well as the vertical
vergence stability increases.
Conclusions
The different eye movement systems mature at different times of child development. Some
systems parallel the maturation of the visual acuity function as the smooth pursuit system and
the vergence eye movements. On the other hand, some eye movement systems seem to be
independent of the visual maturation such as the VOR and OKN, and they are functioning
already soon after birth. It is therefore important when examining a child to take all the
different eye movements systems into consideration and after a thorough clinical investigation
draw conclusions if the child has a normal eye movement development or not. Several
neurological, metabolic and endocrine inborn diseases include eye movement abnormalities,
which must be separated from the normal development. With a careful investigation of the
eye movement ability in the child such diseases can sometimes be excluded or verified.
References
Aring E, Grönlund MA, Hellström A & Ygge J. (2007): Visual fixation development in
children. Graefes Arch Clin Exp Ophthalmol. 11:1659-1665.
Leigh J & Zee DS (2006): Neurology of Eye movements, fourth edition, Oxford University
Press, Oxford.
Riise R, Ygge J, Lindman C, Stray-Pedersen A, Bek T, Rødningen OK & Heiberg A. (2007):
Ocular findings in Norwegian patients with ataxia-telangiectasia: a 5 year prospective cohort
study. Acta Ophthalmol Scand 85:557-562.
V
Childhood Strabismus
Gunnar Lennerstrand
Introduction
Strabismus is a condition in which the two eyes are not parallel but one is deviated with
respect to the other, horizontally and/or vertically. The cause of childhood strabismus is
generally unknown, although weakness of one or several of the eye muscles may be present as
will be shown in the case presentation below. The most common type of strabismus, without
any obvious dysfunction of the eye muscles, is called concomitant strabismus, implying that
the angle or size of the strabismus is more or less constant, irrespective of the direction of
gaze. This is in distinction to strabismus due to muscle weakness, called incomitant
strabismus where the angle varies with the direction of gaze.
Manifest concomitant strabismus is quite a common disease, affecting about 2 % of the
population. In this type of strabismus the eyes are constantly deviated in relation to each
other. Latent concomitant strabismus is even more common and seen in more than half the
population. In latent strabismus the eyes stay straight most of the time due to activation of the
eye muscles over the visual system to keep the eye aligned in binocular single vision.
After the presentation of a case of complicated strabismus, the effects of strabismus on the
visual functions will be described, and the connections between strabismus and eye muscle
function and eye proprioception explored.
Case report
The following case report exemplifies recent advances in the management of a difficult case
of incomitant strabismus. An infant boy presented with horizontal convergent strabismus of a
very large angle, as a part of a so called Möbius syndrome, a congenital disorder, involving
weakness of both the outer (lateral) eye muscles and of many of the facial muscles (Fig. 1,
left). Ordinary surgery for convergent strabismus failed due to the complete absence of
function of both lateral eye muscles. In order to restore some ability to deviate the eyes to the
sides and obtain an acceptable eye position, the tendons of the upper and lower vertical eye
muscles were transposed to the insertion of the non-functioning lateral eye muscles. A
weakening was also done of the inner (medial) horizontal eye muscles of both eyes by
injection of Botulinum toxin into the medial muscles. This combination of surgical and
pharmacological procedures resulted in fairly straight eyes (Fig. 1, right), a limited range of
horizontal movements and almost normal vertical eye motility. Vision was normal in both
eyes due to alternate fixation and well performed occlusion therapy during the first years of
life (see Chapter I). Binocular vision was abnormal as a result of the early onset strabismus.
Figure 1. (Left) Boy 18 months old with Möbius´syndrome, prominent convergent strabismus
and slight vertical strabismus. (Right) Same boy at 9 years of age after strabismus surgery
supplemented with Botulinum toxin. Much improved appearance, although some vertical
strabismus remains.
Visual functions
In manifest strabismus where one of the eyes is constantly out of line, the child will
experience double vision. In childhood the visual system is very flexible and double vision
may be quite easily compensated and shifted into single vision by suppressing the image of
one eye at a time. However, suppression may impair the visual development of the eye that is
out of line most of the time, i.e. the image of the object fixated is falling outside the fovea
centralis. In order to prevent reduced vision of the deviated eye treatment is instituted. It
consists of occlusion of the better eye with a patch for a period each day. In most cases
glasses are also prescribed, producing sharp images on the retina of the two eyes and
supplementing the occlusion therapy. The therapy has to be started at an early age, and
continued and supervised up to about age 10-12, during the so called plastic period of visual
development (see also Chapter I). Suppression leads to disrupted binocular vision, the main
part being loss of stereopsis, but this is a visual handicap of very limited consequences for the
individual with strabismus. Reduced vision due to strabismus is uncommon in our country as
a result of the extensive scheme for visual screening of young children and early treatment of
children with impaired vision in one or both eyes (see also Chapter VI). Thus, we now know
very much of the visual dysfunctions that are a result of manifest strabismus and we have
reliable means to detect and treat them.
Motor functions
Some types of convergent strabismus are connected with refractive errors of the child´s eye,
the most common being hyperopia (far-sightedness). In order to see clearly without glasses,
the hyperopic eye has to accommodate and the motor activity of the ciliary (focusing) muscle
inside the eye produces an impulse to converge the eyes, which may result in a manifest
convergent strabismus. This type of strabismus may be cured by proper glasses to compensate
the hyperopia.
In concomitant strabismus there exist only small abnormalities of eye muscle function. The
eye muscles that move the eyes and control the gaze positions are known to be very fast and
strong with respect to their size, and also very fatigue resistant. Fast movements are used in
repositioning the eyes and delicate but long-lasting muscle activity is needed in steady
fixation with both eyes directed to the same point in space. The muscle components for steady
fixation have been shown to develop earlier than those for swift eye movements, showing that
steady control of the eye position is needed for proper development of visual acuity and
binocular functions. Function of the muscle components can be adjusted in proportion to
visual activity, and in strabismic eye muscles the components for steady control do not
develop to a full extent when the need for steady control in binocular vision is reduced. In
some of the divergent types of strabismus the eyes have to converge constantly in order to
overcome an inherent outward deviation and subsequently the medial eye muscles become
stronger in order to keep the eyes straight.
Control of eye position is mediated also by connective tissue structures outside the eye
muscles proper. These structures can control the muscle tendon directions and therefore
influence the actions of the muscle on position and movements the eye globe. The connective
tissue structures are under influence of the eye muscles themselves, possibly independent of
the main eye muscle activity. This would imply that eye position and eye movements are
controlled by two muscle systems, one directly acting on the eye globe and the other
indirectly by adjusting the sideway forces on the muscle tendon. The control of the connective
components around the tendon could be of importance for high precision eye movement
activities in e. g. prolonged fixations for near, but the clinical significance of this motor
system and how it works in strabismus has to be further investigated.
Eye muscle proprioception
The disturbances that strabismus exerts on vision are treated with glasses and occlusion as
described in Chapter I. There is as yet no effective treatment for binocular dysfunction. Even
if the eyes seem properly aligned by surgery at an early age, and weak binocularity may be
restored, the stereoscopic vision will always remain abnormal.
Eye muscle surgery is the common mode of treatment and it is generally performed at an age
when the child can cooperate in mea in creating an acceptable eye position and facial
appearance, so important for the self-esteem and social interaction of the child. Surgery also
often creates conditions for some binocular vision although abnormal.
In addition to surgery, treatment with eye muscle injection of Botulinum toxin A has been
recently introduced. Such injection can reduce small angle strabismus without surgery and has
been used in childhood strabismus of both manifest and latent types. In may be useful also in
the treatment incomitant strabismus as shown in the Case report.
Treatment of strabismus
The disturbances that strabismus exerts on vision are treated with glasses and occlusion as
described in Chapter I. There is as yet no effective treatment for binocular dysfunction. Even
if the eyes seem properly aligned by surgery at an early age, and weak binocularity may be
restored, the stereoscopic vision will always remain abnormal.
Eye muscle surgery is the common mode of treatment .It is generally performed at an age
when the child can cooperate in the measurements needed for surgery. The aim of surgery is
to create an acceptable eye position and facial appearance, so important for the self-esteem
and social interaction of the child. Surgery also often creates conditions for some binocular
vision although abnormal.
In addition to surgery, treatment with eye muscle injection of Botulinum toxin A has been
recently introduced. Such injection can reduce small angle strabismus without surgery and has
been used in childhood strabismus of both manifest and latent types. In may be useful also in
the treatment incomitant strabismus as shown in the Case report.
Conclusions
Concomitant childhood strabismus is a common eye disorder and about 2% of the population
is affected by the manifest type and at least 50% by the latent type. The cause of strabismus is
most likely a deficiency in the visual system leading to a misalignment of the eyes. Manifest
strabismus is accompanied by reduced vision, sometimes manifested as monocularly reduced
visual acuity and always as reduced binocular vision. Latent strabismus may cause visual
discomfort and headache due to eye muscle fatigue in keeping the eye aligned. The ocular
motor dysfunction is considered secondary to the primary visual deficits. In order to gain
further understanding of the underlying basic mechanisms of strabismus more studies are
needed of the visual and ocular motor development.
References
Lennerstrand G, Tian S & Han Y. (2000).: Functional properties of eye muscles: motor and
sensory adaptation in strabismus. In Lennerstrand G & Ygge J (eds) Advances in Strabismus
Research: Basic and Clinical Aspects”, Wenner-Gren International Series, vol. 78, Portland
Press, London, pp 3-15.
Lennerstrand G (2007): Strabismus and eye muscle function. A review. Acta Ophthalmol
Scand, 85: 711 – 723
Lennerstrand G, Bolzani R, Schiavi C, Tian S & Benassi M (2009): Isometric force
development in human horizontal eye muscles and pulleys during saccadic eye movements.
Acta Ophthalmologica, 87: 837 – 842.
VI
Visual Screening in Children
Peter Jakobsson
Introduction
Screening for ocular disease and visual dysfunction in children has been conducted at
different levels and to varying extent in different countries of the world. There are two main
periods in a child’s life that are of special interest. In the neonatal period detection of organic
disease such as congenital cataract and retinopathy of prematurity (ROP) is important.
Screening for congenital cataract is a type of mass screening, where every child is examined,
while examination for ROP is a selective screening of a special high-risk group of premature
babies. For many of the congenital ocular conditions there may be no treatment available as
such, but an early detection is nonetheless essential since early visual rehabilitation plays an
important role in the child’s visual development. In the developed countries the incidence of
severe visual handicap has been quite constant at about 3 in 10 000 inhabitants for several
decades (Riise 1993). For other conditions such as cataract and ROP there are successful
treatments and for the individual this could mean the difference of being socially blind or
seeing as an adult.
The other period in a child’s life at the age of 2-4 years involves finding less serious
conditions, mainly amblyopia. Amblyopia is preferably diagnosed by testing monocular
visual acuity.
Amblyopia
Amblyopia is defined as a reduction in visual acuity due to abnormal visual development,
usually caused by a defocused retinal image where a refractive error leads to under-stimulated
neurons in the visual cortex or by inhibition of the connections to the neurons in the visual
cortex of one eye caused by anisometropia or strabismus. It is the most common cause of
reduced vision in the population below the age of 50 years and the prevalence is about 3%
(Hauffman 1974). Amblyopia can be treated successfully if detected at an early age, i.e. in the
preschool years. Strabismus is usually detected and diagnosed in the first years of life at home
or at the Child Health Care Centers, while amblyopia caused by refractive errors and anisometropia more commonly is detected with testing of monocular visual acuity at the Child
Health Care Centers.
The disability caused by having amblyopia in one eye has been disputed (Snowdon &
Stewart-Brown 1997). In a study by Packwood et al. (1999) a significant number of
amblyopic patients complained that the amblyopia interfered with school (52%) and work
(48%). Although there is argument about the significance of having amblyopia in one eye
there is little argument about the fact that a patient is seriously handicapped when losing
vision in the non-amblyopic eye. Amblyopia was the main cause of decreased visual acuity in
one eye in at least 1.72% of the patients at visual rehabilitations centres (Jakobsson et al.
2002). This means that approximately 1.2% of the people with amblyopia ≤0.3 will eventually
become visually handicapped due to lesions in the better eye. This visual handicap could have
been avoided by screening and treatment in childhood.
Screening in the world
The most extensive programs of ocular and visual surveillance and with good attendance from
the parents and children seem to be those performed in Scandinavia and Holland and in some
provinces in Canada (Köhler & Stigmar 1973, 1978; Nörskov 1984; Lantau et al. 1991;
Lantau 1992; MacPherson et al. 1991). The attendance rate at the Child Health Care Centres
is reported to be 95% or more in Sweden and Holland for the children below 1 year of age,
but lower in the other countries. In the studies from Denmark, where population studies have
been performed before and after the introduction of screening programs for children, the
prevalence particularly of deep amblyopia (visual acuity <0.1) has been reduced markedly,
from 1.5% before screening to <0.01% when screening was introduced and amblyopia
treatment was started at an early age (Vinding et al. 1991, Jensen & Goldschmidt, 1986).
Screening in Sweden
Screening for visual disorders was introduced in Sweden in the 1960-ies and a national
program was established in the 1970-ies. Nordlöw and Joachimson (1966) and Köhler and
Stigmar (1973, 1978) showed convincingly that amblyopia and other types of visual disorders
could be efficiently detected by monocular testing of visual acuity, performed by the nurses at
the Child Health Care Centers in all children when they were 4 years of age. This system has
now been in use for almost 40 years.
All children are examined within the Child Health Care system at the age of 1–3 days, 6–12
weeks, 6, 18 and 36 months. These examinations are done by visual inspection and
behavioural testing. The children with clear or suspected visual and ocular abnormalities are
referred to (paediatric) ophthalmologists. All children are tested for monocular visual acuity
at the age of 4 years (and also at 5.5 years in some areas), at the Child Health Care Centres,
and in school at 7 years and 10 years of age. Visual acuity (VA) is tested on charts with
optotypes in rows.
A more extensive study was performed in three different populations of 10-years old children
(Kvarnström et al. 1998, Kvarnström et al. 2001), in order to determine the efficiency of the
system of screening at the Child Health Care Centers. Some of the results of this study will be
presented in the following:
The attendance rate was more than 99%. The sensitivity was 92 % and specificity was 97%,
both very high. The numbers of false negative and false positive cases were small.
Figure 1 show the total number of patients who are referred to the Eye Clinic at different ages.
As expected there is a predominant peak at the age of 4 and less predominant peaks in the first
year of life, and at 5 and 7 years. After the age of 8, the patients are mostly referred to
opticians. These children are not included in this diagram.
Number of children
160
140
120
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10
11
Age (years)
Figure 1. Age at referral to the eye clinic (Jakobsson et al. 1996).
Figure 2 shows a more detailed view of when refractive errors are detected. The first vision
test is done at 4 years and as can be seen the main part of the ametropes are detected here. The
ametropes detected earlier than this are mainly those with known hereditary factors. Quite a
few of the ametropias are also diagnosed after the age of 4, which is seen in the figure. The
graph does not display the children who are referred to the optician. This means, for instance,
that children older than 8 years who are developing myopia do not show up in this diagram.
70
Ametropia
Number of children
60
Anisometropia
50
40
30
20
10
0
0
1
2
3
4
5
6
Age (years)
7
8
9
10
11
Figure 2. Age at detection of refractive errors (Jakobsson et al. 1996).
In the first year of life many cases of strabismus are diagnosed (Figure 3). Among these are
the children with infantile esotropia and those with known heredity. Between 1 and 4 years
additional cases of strabismus are discovered. Many children with strabismus are detected at 4
years of age, and one third of them have microtropia. After the age of 4, very few cases of
strabismus are detected, which is also a sign of the efficiency of the screening system at the
earlier ages.
Number of children
25
20
Strabismus
Strabismus + ametropia
15
10
5
0
0
1
2
3
4
5
6
Age (years)
7
8
9
10
11
Figure 3. Age at detection of strabismus (Jakobsson et al. 1996).
How efficient has the screening system in combination with early treatment been at reducing
the prevalence of amblyopia? This is illustrated in Table 1 where a comparison has been made
between the prevalence of amblyopia prior to the screening system (Lennerstrand 2000) and
after (Kvarnström et al. 1998). The table shows that the benefits of screening and amblyopia
treatment are most pronounced for the lower visual acuities. The number of persons with
visual acuity ≤ 0.3 is reduced 10-fold while the number of persons with visual acuity ≤ 0,1 is
reduced almost 20-fold.
Table 1. The prevalence of persons with different degrees of amblyopia before (Lennerstrand
et al. 2000) and after screening (Kvarnström et al. 1998).
Visual acuity
≤ 0,1
≤ 0,3
≤ 0,5
≤ 0,7
Lennerstrand et al. 2000
1.15%
2.00%
2.84%
3.77%
Kvarnström et al 1998
0,06%
0,19%
0.90%
1.70%
At which age should the child be tested?
Since amblyopia should be detected as early as possible Kvarnström and Jakobsson (2005)
tested if visual acuity could be examined at the age of 3 years instead of 4. Three-year-old
children co-operate well in visual acuity testing. However, the examination time is a little
longer and the testability rate is about 10% lower than at 4 years. However, the positive
predictive value was 58% for the 3-year-olds as compared to 75% for the 4-year-olds. This
puts an extra load on the eye clinics and it is therefore doubtful whether visual acuity testing
at 3 years is worthwhile.
Conclusions
Screening for visual disorders in combination with treatment has proven to be an efficient
way of reducing visual impairment and amblyopia. Visual acuity testing in 4-year-old
children has a high sensitivity and specificity. The prevalence of amblyopia with visual acuity
below 0.5 is very low compared to the prevalence without visual screening. Together with
additional measures in Child Health Care system to detect ocular disorders, the rate of serious
amblyopia has been substantially reduced.
References
Hauffman M (1974): Reduction of visual acuity in a Swedish population. Ph. D. Thesis,
Karolinska Institutet.
Jakobsson P., Kvarnström G. and Lennerstrand G. (1996) Amblyopia in Sweden.
Transactions of the 23rd European Strabismological Association Meeting 23, 25-30.
Jakobsson P, Kvarnström G, Abrahamsson M, Bjernbrink-Hörnblad E & Sunnqvist B (2002):
The frequency of amblyopia among visually impaired persons. Acta Ophthalmologica Scand
80: 44-46.
Jensen H & Goldschmidt E (1986): Visual acuity in Danish school children. Acta
Ophthalmologica 64: 187- 191.
Kvarnström G, Jakobsson P & Lennerstrand G (1998): Screening for visual and ocular
disorders in children, evaluation of the system in Sweden. Acta Paediatr 8: 1173 – 1179.
Kvarnström G, Jakobsson P & Lennerstrand G (2001): Visual screening in Sweden: An
ophthalmological evaluation. Acta Ophthalmologica Scand 79: 240-244.
Kvarnström G & Jakobsson P (2005): Is vision screening in 3-year-old children feasible?
Comparison between the Lea Symbol chart and the HVOT (LM) chart. Acta Ophthalmol
Scand 83: 76-80.
Köhler L & Stigmar G (1973): Vision screening of four-year-old children. Acta Paediatr
Scand 62: 17-27.
Köhler L & Stigmar G (1978): Visual disorders in 7-year-old children with and without
previous vision screening. Acta Paediatr Scand 67: 373-377.
Lantau K, Loewre-Sieger DH & Wenniger-Prick LJJM. (1991): Early detection of visual
disorders in young children in health care centers- implementation into the Netherlands - age:
0-4 years. In: "Advances in amblyopia and strabismus", Transactions of the 7th International
Orthoptic Congress, pp 357.
Lantau K (1992): Early visual screening at age 1, 9, 18 and 30 months with the VOV-method:
instruction of the method by orthoptists to all community doctors in the Netherlands. In:
Kaufmann H (ed) Transactions of the 20th Meeting of the European Strabismological
Association, Brussels. pp 339-341.
Lennerstrand G, Hauffmann M, Jakobsson P, Kvarnström G & Lindeberg A (2000):
Prevalence of amblyopia in Sweden 1970 and 1992. In: Spiritus M (ed) Transactions of the
26th European Strabismological Association Meeting, Brussels. 26: 3-6.
MacPherson H, Braunstein J & La Roche GR (1991): Utilizing basic screening principles in
the design and evaluation of vision screening programs. Am Orthoptic J 41: 110- 121.
Nordlöw W & Joachimsson S (1966): The incidence and results of treatment of reduced
visual acuity due to refractive errors in four year old children in a Swedish population. Acta
Ophthalmol (Copenh) 44: 152-163.
Nörskov K (1984): Screening for amblyopia in pre-school children in Denmark. In:
Transaction of the 14th meeting of the European Strabismological Association, Jenkodan
Tryk AS, Copenhagen, pp 327.
Packwood E, Cruz O, Rychwalski P & Keech R (1999): The psychosocial effects of
amblyopia study. J AAPOS 3: 15-17.
Riise R (1993) Nordic registers of visually impaired children. Scand J Soc Med. 21: 66 - 68.
Snowdon SK & Stewart-Brown SL (1997): Preschool vision screening. Health Technol
Assess 1997 1: 1-75.
Vinding T, Gregersen E, Jensen A and Rindziunski E (1991): Prevalence of amblyopia in old
people without previous screening and treatment. An evaluation of the present prophylactic
procedures among children in Denmark. Acta Ophthalmol 69: 796 - 798.
VII
Pediatric Cataract
Maria Kugelberg
Introduction
A study in Sweden showed the incidence of all congenital cataract cases to be 36/100,000
(Abrahamsson et al. 1999). In addition, a few hundred children develop juvenile cataract each
year in Sweden. Congenital cataract is considered to be the most common cause of treatable
blindness in children. It is present at birth and may be unnoticed until the visual function is
affected or a whitish pupil is seen. If the babies do not have surgery quickly they develop
irreversible amblyopia. Pediatric cataract surgery is nowadays an increasingly safe procedure,
although there are some complications to the surgery. Visual axis opacification is the most
common complication, which threatens the vision again and can lead to amblyopia if not
managed. Secondary glaucoma is the most feared complication and can lead to blindness and
a cosmetically disturbing eye. Developmental cataract, which is not dense at birth, is more
common and could be operated on much later. This would lead to fewer complications and a
better outcome.
Congenital cataract
Congenital cataract is hereditary in approximately one third of the cases. It is often inherited
autosomal dominant but can also be inherited autosomal recessive or X-linked. In
approximately one third of the cases other diseases can be found. Metabolic disorders, such as
galactosaemia and hypocalcaemia are rare causes. Intrauterine infections such as rubella,
toxoplasmosis, herpes, varicella and syphilis can cause congenital cataract. Genetic
syndromes such as trisomy 21 or Turner’s syndrome and a variety of neurological disorders
are often associated with congenital cataract. Other ocular anomalies such as iris coloboma,
aniridia, microphthalmia, retinopathy of prematurity, or persistent foetal vasculature (PFV)
are often combined with cataract. In the rest of the patients, the congenital cataract is
idiopathic. In unilateral cases, the cause is most often idiopathic and in a clinically healthy
child, or if the cataract is inherited, there is no need for an extensive pre-operative evaluation.
5-20% of childhood blindness worldwide is caused by cataracts.
There are different types of cataract; nuclear, lamellar, sutural, polar, lenticonus, membranous
and those associated with PFV. The size, density, laterality of the cataract and the presence of
associated ocular abnormalities decide how strong the indication is for surgery. The more
central and the more posteriorly located, the more visually significant the cataract will be.
Since there are more complications after early surgery as discussed below, it is important to
wait if the cataract is not visually significant.
In cases with dense congenital cataract the cataract surgery must be performed early to
prevent irreversible amblyopia and nystagmus. At the same time the risk of secondary
glaucoma increases in these very small children, the earlier the surgery is performed. It is
therefore very important to find ways to reduce the risk for secondary glaucoma. Also, the
visual axis opacification formation is much more pronounced in the youngest children.
Secondary glaucoma
The earlier the surgery is performed, the greater the risk of secondary glaucoma. The risk also
seems to be greater in small eyes, as in microphthalmus with persistent fetal vessels. It is yet
not clear what causes the secondary glaucoma. However, an IOL seems to decrease the risk.
Arsani et al (Asrani et al. 2000) found a much higher rate of glaucoma following cataract
surgery in patients who were left aphakic (14/124 patients), than if they were implanted with
an IOL (1/377 patients). They also reviewed the literature and found no reported case of openangle glaucoma in the over one thousand pseudophakic patients from the studies. In one of
our studies, no eye out of 31 children implanted with a small acrylic SA30AL IOL at 2-28
months of age developed secondary glaucoma (Kugelberg et al. 2006). In a rabbit study we
performed with 20 three week old rabbits, no eye implanted with an AcrySof SA30AT IOL
developed secondary glaucoma, but three aphakic eyes did during the follow-up time.
However, in other animal studies with different IOLs the frequency of secondary glaucoma
was similar in aphakic and pseudophakic eyes. It might also be due to the increased
inflammatory response in young children and infants, compared to older children.
Treatment of postoperative aphakia
Implantation of an IOL is now a common and accepted management of the postoperative
aphakia even in the smallest children. For the very small eye of an infant most of the
commercially available IOLs are too large. The myopic shift that occurs in the child’s
growing eye is also a great concern. Lately, after surgery for unilateral cataract, many
surgeons implant an IOL also in infants. However, for optical correction in bilateral cases
with congenital cataract, contact lenses are probably still most often used in the Western
World. Contact lenses can cause infection, are sometimes hard to handle, tedious for the
family and expensive. Compliance is often also poor regarding the use of contact lenses.
Therefore it would be of great interest if it were possible to develop an IOL that fits the small
eye. We have performed some studies evaluating different smaller lenses in a rabbit model
and in small children. They seem well tolerated by the small eye.
Visual axis opacification
Visual axis opacification or after-cataract occurs when lens epithelial cells (LECs) migrate
and proliferate from the anterior capsule and the equator of the lens capsule, onto the posterior
capsule. The visual axis is then obscured, and vision blurred again. Children develop more
and faster visual axis opacification than adults. This opacification, or posterior capsule
opacification as it is called in adults, can be removed in a second procedure in adults, using
Neodymium: YAG (Nd:YAG) laser. An opening is then created in the posterior capsule, and
the vision is clear again. In most cases, visual axis opacification in children can not be
removed with only Nd:YAG laser, because the LECs will continue to grow on the anterior
vitreous surface. The opacification has preferably to be removed in a second surgical
procedure with anterior vitrectomy, often via the pars plana. However, in the very small
children the LECs can grow also on the posterior surface of the IOL, even after a vitrectomy
is performed.
To diminish visual axis opacification in children, most cataract surgeons perform posterior
capsulorhexis at surgery. It is also debated whether or not to do an anterior vitrectomy at
primary surgery. It could be performed through the pars plana, or through the anterior
chamber after the posterior capsulorhexis and implantation of an IOL. When the anterior
vitreous has been removed, the LECs most often cannot grow on the remaining vitreous. It
seems that anterior vitrectomy is necessary at least in children below 5 years, to avoid rapid
visual axis opacification.
Another surgical technique that has been studied is a so called optic capture, i.e. the IOL is
pushed through the posterior capsulorhexis, while the haptics remain in the bag. However, the
technique does not seem to fully prevent the formation of visual axis opacification, and it has
been described that the anterior vitreous face became semi-opaque and that the LECs can
grow also on the anterior surface of the IOL. However, optic capture might be a suitable
technique in some instances, since it provides a good centration of the IOL, which is
necessary in cases after trauma or an incomplete rhexis.
Removal of residual LECs during the primary surgery is a key factor in avoiding posterior
capsule opacification. Several chemicals have been suggested in experimental settings to
remove or destroy residual LECs, but it has to be kept in mind that the substances may be
toxic to other ocular structures. Research is directed towards finding a device or substance
that can selectively remove the LECs. There are always complications associated with
touching the vitreous and breaking the posterior lens capsule. If this can be avoided, it would
be highly advantageous. This however, generates the need for a lens capsule with no
remaining LECs. Perhaps a sealed-capsule irrigation could be an option at least in pediatric
patients.
Perfect Capsule
The sealed-capsule irrigation device, Perfect Capsule, invented by Anthony Maloof (Agarwal
et al. 2003), consists of a silicone plate, 0.7 mm thick, 7 mm in outer diameter, and 5 mm in
inner diameter. It has an inflow tube, an outflow tube, and a tube for creation of a vacuum.
The device can be folded and introduced through a normal small incision. After the lens
extraction, the device is placed over the anterior capsulorhexis, and a vacuum is created with a
syringe. This produces a sealed system between the capsular bag and the device. The capsule
can be irrigated with a substance through the inflow tube, and the substance does not come in
contact with the other intraocular structures. The substance is washed out with balanced salt
solution (BSS), the vacuum is released, and the device is withdrawn. An IOL then can be
placed in the bag.
Human studies have reported the safety of the device in adults undergoing cataract surgery. In
that study, the sealed system was irrigated with distilled deionized water, which did not
prevent posterior capsule opacification development. Earlier in vitro studies had shown that
the LECs succumbed from osmotic lysis when they were exposed to distilled deionized water.
However, this evidently did not work in vivo.
We evaluated the Perfect Capsule in a young rabbit model. Our experiments showed that 5fluorouracil 50 mg/ml was the most effective substance evaluated to prevent visual axis
opacification (Abdelwahab et al. 2008) (Fig. 1 D). We also investigated a substance called
thapsigargin, which has proven effective in in vitro studies of human LECs, but the substance
was not effective in our model (Fig. 1).
Tg
BSS
5-FU 25
mg/ml
5-FU 50
mg/ml
Figure 1. Rabbit eyes that have undergone clear lens extraction and irrigation with different
substances in the sealed-capsule irrigation device Perfect Capsule. Conditions six weeks
postoperativly. (Top left) Eye irrigated with thapsigargin. The eye shows synechia and visual
axis opacification. (Top right) Eye irrigated with BSS; synechia and visual axis opacification
is seen. (Bottom left) Eye irrigated with 5-fluorouracil 25 mg/ml. Some synechia is seen.
(Bottom right) Eye irrigated with 5-fluorouracil 50 mg/ml. A clear visual axis and no synechia
(Abdelwahab et al. 2008).
The safety of 5-FU 50 mg/ml as an irrigation substance with the Perfect Capsule device was
investigated, no damage was seen in the corneal endothelium, trabecular meshwork, and
central and peripheral retina. We did not detect any damage when looking at the posterior
capsule with transmission electron microscopy.
Conclusions
In conclusion, pediatric cataract is still much more problematic than cataract in adults.
However, nowadays, IOLs are implanted at a younger age, less secondary glaucoma is then
seen, and methods are invented to diminish the visual axis opacification. Hopefully, the
research can continue and provide even more information to aid the children in the future.
References
Abdelwahab MT, Kugelberg M & Zetterstrom C (2008): Irrigation with thapsigargin and
various concentrations of 5-fluorouracil in a sealed-capsule irrigation device in young rabbit
eyes to prevent after-cataract. Eye (Lond) 22: 1508-13.
Abrahamsson M, Magnusson G, Sjostrom A, Popovic Z & Sjostrand J (1999): The
occurrence of congenital cataract in western Sweden. Acta Ophthalmol Scand 77: 578-80.
Agarwal A, Agarwal S & Maloof A (2003): Sealed-capsule irrigation device. J Cataract
Refract Surg 29: 2274-6.
Asrani S, Freedman S, Hasselblad V, et al. (2000): Does primary intraocular lens implantation
prevent "aphakic" glaucoma in children? J Aapos 4: 33-9.
Kugelberg M, Kugelberg U, Bobrova N, Tronina S & Zetterstrom C (2006): Implantation of
single-piece foldable acrylic IOLs in small children in the Ukraine. Acta Ophthalmol Scand
84: 380-3.
VIII
The Impact of Growth and Growth
Factors for Vascular and Neural
Development in Preterms
Ann Hellström
Introduction
Despite significant improvement in neonatal intensive care the number of preterm children
with severe visual impairment is increasing. Retinopathy of prematurity (ROP) is a major
cause of blindness in children in the developed and developing world, despite current
treatment of late-stage ROP. Approximately 40% of perinatal blindness can be attributed to
ROP. A recent Swedish study demonstrated that one third of the boys born below 25 weeks of
gestational age became visually impaired or blind due to ROP and /or cerebral dysfunction
(Jacobson et al. 2009).
Angiogenesis is a complex process involving changes in many metabolic pathways. Our
research group has found a strong association between the circulating growth factor Insulinlike growth factor 1 (IGF-I), postnatal growth and development of vascular and neural
elements in preterm infants. Ours and others findings on this topic will be presented in detail
below.
IGF-I and foetal growth
IGF-I is a polypeptide, which resembles insulin in its molecular structure. In humans IGF-I is
primarily produced by hepatocytes in the liver and the production is regulated by pituitary
growth hormone. IGF-I exists extra-cellular and is bound to and controlled by six insulin-like
growth factor binding proteins. Seventy-five percent of the IGF-I is bound to insulin-like
growth factor binding protein 3 (IGFBP-3) together with an acid labile subunit (ALS). The
insulin-like growth factor binding proteins can either inhibit, or potentiate cellular IGF-I
responses, and influence distribution and elimination of IGF-I. The cellular actions of IGF-I
are mediated through binding of IGF-I to the IGF-I receptor, which is located on the surface
of different cell types in all tissues. IGF-I can also bind to the insulin receptor, but at a much
lower affinity than insulin.
IGF-I is of major importance for foetal growth and is synthesized by all foetal tissues early in
gestation, and the placenta is actively involved in regulating circulatory foetal levels of IGF-I.
Concentrations of foetal IGF-I are closely related to placental transfer of nutrients. The
disruption of placental nutrient supply as well as amniotic supply at birth is followed by a
rapid decline in levels of IGF-I. During pregnancy thyroxine plays a more important role than
pituitary growth hormone in the regulation of foetal IGF-I, but after birth IGF-I is regulated
by pituitary growth hormone.
IGF-I is related to nutrition, birth weight and gestational age (Hellström et al. 2003) .
Nutrition is an important environmental factor influencing IGF-I levels. At very preterm birth
the IGF-I levels of the newborn decrease abruptly, and do not reach normal intrauterine values
for several weeks/months (Engström et al. 2005), in contrast to term infants who restore their
serum levels of IGF-I in a few days. A recent study found a dramatic decrease in the
circulating serum levels of IGF-I and its major binding protein, IGFBP-3 in very preterm
infants and that inflammation at birth with increased cord levels of pro-inflammatory
cytokines was associated with a decrease in IGF-I (Hansen-Pupp et al. 2007). The important
role of nutrition for the foetal IGF-I levels was demonstrated in an animal study of foetuses of
pregnant rats, who were fasted during the last days of gestation, and the serum IGF-I levels
were 30 % lower than in the control foetuses (Davenport et al 1990).
IGF-I and brain development
IGF-I acts directly on the brain and promotes differentiation, proliferation and maturation of
progenitors of neural stem cells, and has anti-apoptotic properties (Ye & D´Ercole 2006).
Oligodendrocyte maturation is crucial for myelination as mentioned above, and several
studies on mice and other rodents have shown an important role of IGF-I in differentiation of
oligodendrocyte progenitor cells (Ye & D´Ercole 2006). In vitro, IGF-I has been found to
promote remyelination and cerebellar Purkinje cell development. In addition, a relationship
has recently been shown in preterm infants between cerebellar volume and serum IGF-I
(unpublished data).
IGF-I may also play an important role in the stimulation of postnatal brain growth. Overexpression of IGF-I in mice stimulated the brain growth and ameliorated the brain growth
even in the face of under-nutrition, and IGF-I protected myelination in cases with undernutritional insults. A relationship between low circulating levels of IGF-I, the development of
ROP, and poor development of head circumference in preterm infants has also been
documented (Löfqvist et al. 2006). IGF-I is essential for the development of normal
vascularisation of the human retina as mentioned above (Hellström et al. 2001, Hellström et
al. 2002), and promotes the angiogenesis in the brain (Lopez-Lopez et al. 2004). In the study
by Lopez-Lopez and co-workers (2004) systemic injections of IGF-I in adult mice increased
the brain vessel density.
A gender difference in IGF-I levels, where boys had lower levels than girls, has been shown
in preterm (GA < 32 weeks) infants (Engström et al. 2005).
IGF-I and retinal development in prematurity
Ocular growth is influenced by IGF-I and treatment with IGF-I increases the ocular axial eye
length in patients with short axial lengths due to growth hormone insensitivity (Laron
syndrome).
In infants born prematurely the retina is not fully vascularised. The more premature the child,
the larger is the avascular area. The sudden loss of nutrition and growth factors necessary for
normal growth at preterm birth causes the vascular growth that would normally occur in utero
to slow down or cease. In addition, the relative hyperoxia of the extra-uterine milieu together
with supplemental oxygen cause a regression of already developed retinal vessel. IGF-I is
necessary for normal development of retinal blood vessels (Hellström et al. 2002).
Preterm birth is associated with a rapid fall in IGF-I, and the baby often suffers from
immaturity, poor nutrition, acidosis, hypothyroxemia and sepsis which all may further reduce
the IGF-I levels. When the neural elements of the retina mature and need more oxygen, poor
vascularisation leads to hypoxia and production of vascular endothelial growth factor
(VEGF). If sufficient IGF-I is not available VEGF is accumulated, as a minimum level of
IGF-I is required for VEGF to induce vessel growth. When the IGF-I levels slowly increase
when the infant matures, and IGF-I reaches the minimum level for VEGF to promote vessel
growth, an excessive and uncontrolled neovascularisation may take place, see figure 1. The
serum levels of IGF-I during the first weeks of life in the babies are inversely correlated with
the severity of ROP (Hellström et al. 2003).
In an experimental study on neonatal mice it was recently shown that exogenous administered
IGF-I attenuated retinopathy and improved weight gain as well as maturation
(Vanhaesenbrouck et al. 2009).
Hök Wikstrand et al (2009) recently demonstrated that preterm children had reduced neuronal
rim area of the optic disc and that this finding was associated with both low birth weight and
poor early postnatal growth. This indicates that early weight gain is important for neural
development of the visual system in preterm children. The same authors also found in preterm
infants that poor visual acuity and visual perception was correlated with poor early weight
gain and that the infants with hyperopia at school age had low neonatal serum IGF-1 levels
(Hök et al. 2010).
Figure 1. Schematic representation of IGF-I/VEGF control of blood vessel development in
ROP. (A) In utero, VEGF is found at the growing front of vessels. IGF-I is sufficient to allow
vessel growth. (B) With premature birth, IGF-I is not maintained at in utero levels, and
vascular growth ceases. (C) As the premature infant matures, the developing but nonvascularized retina becomes hypoxic. VEGF increases in retina and vitreous. With
maturation, IGF-I level slowly increases. (D) When the IGF-I level increases, with high
VEGF levels in the vitreous, endothelial cell survival and proliferation driven by VEGF may
proceed. NV ensues at the demarcation line, extending into the vitreous, leading to retinal
detachment and blindness can occur. (Hellström et al 2001).
Program to predict severe ROP
An association between poor postnatal growth and later development of ROP has earlier been
reported (Wallace et al. 2000).
Hellström and co-workers have recently developed a web-based program to predict which
children are at risk of developing the most severe form of ROP. This program named
WINROP combines in a highly novel way the use of neonatal data (weight) and biomarkers
(serum IGF-I levels) with statistical monitoring (Löfqvist et al. 2006). Löfqvist and coworkers (2006) have verified the program's ability to provide early and accurate identification
of children with the greatest risk of developing the disease ROP in a new follow-up study of
extremely preterm children (Löfqvist et al. 2009).
A further development and significant simplification of this program has resulted in
monitoring of the children's postnatal weight gain only in order to predict the development of
severe ROP. This simplified approach was recently published and confirmed that WINROP
correctly identified the very premature children at high risk of developing severe ROP
(approx. 15%) and also correctly excluded those children who did not develop the disease
(approximately 75%) (Löfqvist et al. 2009).
In addition, we have successfully validated WINROP in cooperation with the
neonatal/ophthalmology wards at Brigham and Women in Boston (Wu et al. 2010) and at the
Departments of Ophthalmology and Pediatrics, Hospital de Clínicas de Porto Alegre, Federal
University of Rio Grande do Sul, Brazil (Hård et al. 2010).
WINROP provides a tool to identify infants at risk for sight threatening ROP. We believe that
additional NICU data from developing countries will help in modifying the algorithm for
these populations. The close association between poor neonatal weight development and ROP
indicates that optimizing growth may be one way to reduce ROP.
Conclusions
In summary, for decades neonatal intensive care has focused on survival of the most immature
babies. The time has now come to find ways to optimize weight development and normalize
growth of vital structures such as vessels and neurons.
References
Davenport ML, D'Ercole AJ, Underwood LE (1990): Effect of maternal fasting on fetal
growth, serum insulin-like growth factors (IGFs), and tissue IGF messenger ribonucleic acids.
Endocrinology, 126: 2062-7.
Engström E, Niklasson A, Albertsson Wikland K, Ewald U, Hellström A (2005): The role of
maternal factors, postnatal nutrition, weight gain and gender in regulation of serum IGF-I
among preterm infants. Pediatric Research, 57: 605-10.
Hansen-Pupp I, Hellström-Westas L, Cilio CM, Andersson S, Fellman V, Ley D (2007):
Inflammation at birth and the insulin-like growth factor system in very preterm infants. Acta
Paediatr, 96: 830-6.
Hellström A, Carlsson B, Niklasson A, Boguszewski M, De Lacerda L, Savage M, Svensson
E, Smith LE, Weinberger D, Albertsson-Wikland K, Laron Z (2002): Insulin-like growth
factor I is critical for normal vascularisation of the human retina. Journal of Clinical
Endocrinology and Metabolism, 87: 3413-3416.
Hellström A, Engström E, Hård A-L, Albertsson-Wikland K, Carlsson B, Niklasson A,
Löfqvist C, Svensson E, Holm S, Ewald U, Holmström G, Smith LE (2003): Postnatal serum
insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other
complications of premature birth. Pediatrics, 112: 1016-1020.
Hellström A, Hard AL, Engström E, Niklasson A, Andersson E, Smith L, Lofqvist C (2009):
Early weight gain predicts retinopathy in preterm infants A new simple and efficient approach
to screening. Pediatrics, 123: 638-45.
Hellström A, Peruzzi C, Ju M, Engström E, Hård A-L, Lui J-L, Albertsson-Wikland K,
Carlsson B, Niklasson A, Sjödell L, LeRoith D, Senger D, Smith LE (2001): Insulin-like
growth factor-I is critical to retinopathy of prematurity. Proceedings of the National Academy
of Science, 98: 5804-5808.
Hård AL, Löfqvist C, Borges JFF, Soibelmann Procianoy R, Smith L, Hellström A (2010):
The new screening algorithm named WINROP predicts proliferative retinopathy in a
Brazilian population of preterm infants. Arch Ophthalmol, in press.
Hök Wikstrand M, Hård A-L, Niklasson A and Hellström A (2009): Birth weight deviation
and early postnatal growth are related to optic nerve morphology at school age in very
preterm children. Pediatr Res, 67: 325-9.
Hök Wikstrand M, Hård A-L, Niklasson A and Hellström A (2010): Postnatal growth
variables are related to morphologic and functional ophthalmologic outcome in children born
preterm. Acta Ped, 99: 658-64.
Jacobson L, Hård A-L, Hammarén H, Hellström A (2009): Visual outcome in children born
less than 25 gestational weeks. Acta Ped, 98:261-5.
Lopez-Lopez C, LeRoith D, Torres-Aleman I (2004): Insulin-like growth factor I is required
for vessel remodeling in the adult brain. Proc Natl Acad Sci, 101: 9833-8.
Löfqvist C, Engström E, Sigurdsson J, Hård A-L, Niklasson A, Ewald U, Holmström G,
Smith LE, Hellström A (2006): Postnatal head growth deficit in premature infants parallels
retinopathy of prematurity and Insulin-like growth factor-I deficit. Pediatrics, 117: 1930-1938.
Löfqvist C, Andersson E, Sigurdsson J, Engström E, Hård AL, Niklasson A, Smith LE,
Hellström A (2007): Longitudinal postnatal weight and insulin-like growth factor I
measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol, 124: 1711-8.
Erratum in: Arch Ophthalmol, 125: 426.
Löfqvist C, Hansen-Pupp I, Andersson E, Holm K, Smith L, Ley D, Hellström A (2009):
Validation of a new ROP screening method monitoring longitudinal postnatal weight and
IGF-I. Arch Ophthalmol, 127: 622-7.
Vanhaesebrouck S, Daniëls H, Moons L, Vanhole C, Carmeliet P, De Zegher F (2009):
Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation
by IGF-I administration. Pediatr Res, 65: 307-10
Wallace DK, Kylstra JA, Phillips SJ, Hall JG (2000): Poor postnatal weight gain: a risk factor
for severe retinopathy of prematurity. J AAPOS, 4: 343-7.
Wu C, Vanderveen D, Hellstrom A, Löfqvist C, Smith L (2010). Longitudinal postnatal
weight measurements for the prediction of retinopathy of prematurity. Arch Ophthalmol, in
press.
Ye P, D'Ercole AJ (2006): Insulin-like growth factor actions during development of neural
stem cells and progenitors in the central nervous system. J Neurosci Res, 83: 1-6.
IX
Prematurity and the Eye
Gerd Homlström
Introduction
Prematurely born children have an increased risk to develop visual and eye problems
compared to children born at term. In the neonatal period they may develop retinal disease,
while later there is a risk of various visual dysfunctions.
Retinopathy of Prematurity (ROP)
Retinal disease in prematurely born infants was first decscibed by Terry in the beginning of
the 1940ies and was given the name Retrolental fibroplasia (RLF). In the middle of the
1980ies the disease was given a new name, Retinopathy of prematurity (ROP), and a new
classification by an international committee. ROP was divided into five stages, where stage 5
represents a total retinal detachment and a blind eye. Recently, a revised classification has
been presented (ICROP 2005), describing aggressive and rapidly progressing ROP in the most
immature infants. Without adequate treatment this type of ROP most often leads to
progression to stage 5 ROP and blindness. ROP stages 2 and 3 and Aggressive ROP are
illustrated in Figure 1.
Early stages of ROP (ROP 1 and 2) often regress spontaneously, while more severe stages
need treatment to prevent retinal detachment. In the 1970ies, treatment of the peripheral retina
with so-called cryo therapy was introduced, to destroy the anoxic part of the eye that was
stimulating the deleterious production of growth factors and vascular proliferations. In the
1990’s laser treatment has become the method of choice. Laser therapy is also a destructive
method, but more beneficial for the eye. Given at a correct time, it is successful in most cases
of ROP. If retinal detachment occurs, so-called vitrectomy may be performed. In the most
advanced cases with total retinal detachment (ROP stage 5), the chance of useful visual
function is, however, negligible regardless of surgical method.
A.
B.
C.
D.
Figure 1. Normal fundus, including retina, optic disc and vessels (A). ROP stage 2, including
ridge at the border between vascularised and non-vascularized retina (B). ROP stage 3,
including vascular proliferations (C). Aggressive posterior ROP (D). (ICROP 2005)
Incidence of ROP
The incidence of ROP is related to the quality of neonatal care. In poor countries almost no
ROP occurs since prematurely-born infants rarely survive. In middle-income countries with
an increasing survival, there is a new epidemic of ROP leading to severe visual impairments
and blindness. In Sweden several population-based studies on the incidence of ROP have
been performed during the last decades. Twenty years ago we reported an ROP incidence of
40% in infants with a birth weight of 1500 grams or less born in the Stockholm County during
the years of 1988 to 1990 (Holmström et al 1993). A new study in exactly the same
geographical area 10 years later, revealed a similar incidence but a change in the distribution
of ROP. The more ”mature” infants had a reduced incidence of ROP, while the most
immature babies, previously not surviving, had the highest risk of ROP and particularly
severe ROP, see figure 2. (Larsson et al 2002).
Figure 2. Probality of ROP in relation to gestational age at birth (weeks) in two consecutive
studies on ROP (1988 to 1990 and 1998 to 2000, respectively) in the Stockholm area of
Sweden (Larsson et al 2002).
During the last decade, improvements in neonatal care have resulted in a new population of
extremely immature babies with a high risk of various complications. A recent study
enclosing all infants in Sweden born before 27 weeks of gestations from 1 April 2004 to 31st
March 2007, revealed that 70% of the infants survived up to one year of age (EXPRESS
Group 2009). Major morbidities , i.e. intraventricular haemorrhage, broncopulmanry
dysplasia and / or ROP, were found in 45 % of these infants. The ophthalmic data were
separately collected and analysed. We recently reported that 73% of this population developed
ROP; mild ROP in 38 % and severe ROP in 35 % (Austeng et al 2009). Treatment was
performed in 20% of the infants. The most immature infants had the highest risk to develop
ROP and to reach treatment criteria, and they also developed ROP earlier and were treated
earlier than those born at a slightly higher gestational age (Austeng et al 2009).
Screening for ROP
ROP is one of the few causes of childhood blindness, which in most cases can be prevented.
Screening for ROP with repeated eye examinations in the neonatal period is therefore of
utmost importance for detection of severe ROP and for initiation of treatment at a correct
time. Since the incidence of ROP is related to the neonatal care and socio-economic situation
of the country, guidelines for screening have to be adapted to the country per se.
In Sweden, the first national guidelines were suggested after the population-based study in
1988-1990 (Holmström et al 1993). ROP screening was recommended to include all infants
born before 33 weeks of gestation and to start at 5 to 6 weeks of life and continue with one to
two weeks interval up to term or until regression of ROP. In case of progressing ROP, the
intervals between examinations were reduced and treatment was performed if indicated.
Based on the results of the incidence study in the Stockholm area during 1998 to 2000,
modification of screening recommendations with reduction of inclusion criteria to infants
born before the 32nd week of gestation were proposed (Larsson & Holmström 2002).
Analyses of the natural history of ROP in infants with a gestational age of less than 27 weeks
at birth have revealed new information on the importance of time and retinal location of ROP
at onset of the disease (Austeng et al 2010). These findings will probably lead to
modifications of the screening guidelines in the group of extremely preterm infants.
To further improve the quality of ROP screening, a national web based register for ROP, the
so-called SWEDROP, has been developed (www.swedrop.se). The register was started in late
2006, has a steering group of six regional responsible ophthalmologists and today has a cover
of around 80% of the prematurely-born infants in the country. In the near future we hope to
have reliable data to further modify and improve the screening guidelines, leading to
improved outcome for the infants.
Other ophthalmological sequels in prematurity
Retinopathy of prematurity (ROP) is a neonatal complication of the eye. Long-term follow-up
studies in childhood and adolescence, however, have revealed various visual dysfunctions in
prematurely-born children. Population-based studies on children of 10 years age in Denmark,
United Kingdom and New Zealand have reported increased risks to develop refractive errors,
strabismus, visual field defects, contrast sensitivity defects, and visual perceptual deficits.
Children from the population-based study in Stockholm during 1988 to 1990 have been
followed up repeatedly up to 10 years age (Holmström et al 1998, 1999). At that age, an
extensive ophthalmological follow-up was performed together with a similar group of
children born at term in the same geographical area. The visual acuity was found to be
reasonable in a majority of the preterm children and only 2 % had a visual impairment (≤ 0.3),
while a significant proportion had a subnormal visual acuity (Larsson et al 2005). Contrast
sensitivity was slightly, but significantly, reduced (Larsson et al 2006), strabismus was much
commoner (Holmström et al 2006), visual fields were slightly reduced (Larsson et al 2004)
and refractive errors (Larsson 2003, Holmström et al 2005, Larsson et al 2006) were much
more common in the preterm children compared to those born at term. The various
ophthalmologic sequels were most common in children with previous severe ROP and with
neurological problems, but also the children without such complications had an increased risk
to develop ophthalmic problems. Finally, our studies revealed a significant correlation
between visual dysfunction at 10 years and various school problems (Holmström & Larsson
2008).
Ophthalmological follow-up in prematurely-born children
As illustrated above, prematurely-born children indeed have an increased risk to develop
various ophthalmological problems and dysfunctions. Major sequelae are well-known, while
more subtle dysfunctions recently have been reported to affect the quality of life of these
children. Hence, the question arises if these children ought to be offered a long-term followup, and in that case, which children and when and by whom. There is no consensus in the
literature, but some authors suggest frequent follow-up of all prematurely-born children
during childhood, some suggest follow-up of all children with ROP, while some propose
follow-up of only those with severe ROP and neurological sequealae. The Stockholm children
born in 1988 to 1990 had been followed up repeatedly up to 10 years, giving us the possibility
to evaluate risk factors which could predict visual dysfunction at 10 years. Multiple regression
analyses revealed that, apart from children who had been treated for ROP and children with
neurological sequelae, also those with significant refractive errors (anisometropia and
astigmatism) at 2.5 years, had an increased risk to develop visual dysfunction, according to
our definition, at 10 years of age (Holmström&Larsson 2008). Based on our findings, we
recommend that children who have been treated for ROP and children with obvious
neurological lesions have a regular ophthalmic follow-up. Regarding the children with
untreated ROP and without ROP, we propose that at least one follow-up is offered at around
2.5 years when the refraction is stabilized and amblyopia, with or without strabismus, is still
treatable. This examination can preferably be performed by an orthoptist with a possibility to
refer to a paediatric ophthalmologist, when indicated.
Conclusions
Prematurely-born infants and children are a risk group for various visual and
ophthalmological problems. Screening programmes to detect and treat these children are
necessary, but will continuously need to be modified parallel to new achieved knowledge. An
upcoming 6.5-year follow-up of the Swedish cohort of 500 extremely preterm infants born
before 27 weeks of gestation will hopefully provide us with new knowledge of the visual
function in this group of children.
References
Austeng D, Källen K, Ewald U, Jakobsson P & Holmström G (2009). Incidence of
retinopathy of prematurity in infants born before 27 weeks' gestation in Sweden. Arch
Ophthalmol, 127:1315-9.
Austeng D, Källen K, Ewald U, Wallin A & Holmström G (2009). Treatment of ROP in a
population of extremely preterm infants born before the 27th week of gestation in Sweden. Br
J Ophtalmol, Nov 30, Epub ahead of print.
Austeng D, Källn K, Hellström A, Tornqvist K & Holmström G (2010): Natural history of
ROP in a population of extremely preterm infants born before the 27th week of gestation in
Sweden. Arch Ophthalmol, In press.
EXPRESS group (2009): One-year survival of extremely preterm infants after active perinatal
care in Sweden. JAMA, 301: 2225-2233.
Holmström G, el Azazi M, Jacobson L & Lennerstrand G (1993): A population based,
prospective study of the development of ROP in the Stockholm area of Sweden. Br J
Ophthalmol, 77: 417-23.
Holmström G, el Azazi M & Kugelberg U (1998): Ophthalmological follow-up of preterm
infants - a population-based study of the refraction and its development. Br J Ophthalmology,
82: 1265-71.
Holmström G, el Azazi M, Kugelberg U. Ophthalmological follow-up of preterm infants - a
population-based study of visual acuity and strabismus (1999). Br J Ophthalmology, 83: 14351.
Holmstrom GE & Larsson EK (2005): Development of spherical equivalent refraction in
prematurely born children during the first 10 years of life: a population-based study. Arch
Ophthalmol, 123: 1404-11.
Holmström G, Rydberg A & Larsson E (2006): Strabismus and its development in 10-yearold prematurely-born children – a population-based study: J Pediatr Ophthalmol Strabismus,
43:346-52.
Holmström G & Larsson E (2008): Longterm follow-up of visual functions in prematurelyborn children – a prospective population-based study up to 10 years of age. JAAPOS, 12:157162.
International Commitee for the Classification of Retinopathy of Prematurity (ICROP) (2005).
The International Classification of retinopathy of prematurity Revisited. Arch Ophthalmol,
123: 991-999.
Larsson E, Carle-Petrelius B, Cernerud G, Ots L, Wallin A & Holmström G (2002): Incidence
of ROP in two consecutive population-based studies. Br J Ophthalmology, 86: 1122-26.
Larsson E & Holmström G (2002): Screening for ROP – evaluation and modification of
guidelines. Br J Ophthalmology, 86: 1399-1402.
Larsson E, Rydberg A & Holmström G (2003): A population-based study of the refractive
outcome in 10-year-old preterm and full-term children. Arch Ophthalmol, 121: 1430-1436
Larsson E, Martin L & Holmström G (2004): Peripheral and central visual fields in 11 year
old children who had been born prematurely and at term. Pediatric Ophthalmol Strab, 41: 3945
Larsson EK, Rydberg AC & Holmstrom GE (2005): A population-based study on the visual
outcome in 10-year-old preterm and full-term children. Arch Ophthalmol, 123: 825-32.
Larsson E, Rydberg A & Holmstrom G (2006): Contrast sensitivity in 10 year old preterm and
full term children: a population-based study. Br J Ophthalmol, 90: 87-90.
Larsson EK & Holmström GE (2006): Development of astigmatism and anisometropia in
preterm children during the first 10 years of life. Arch Ophthalmol, 124: 1608-14.
X
Visual Function and Ocular Findings
in Children with Pre- and Perinatal
Brain Damage
Lena Jacobson
Introduction
Children with visual impairment due to damage to the retro-geniculate visual pathways
constitute an increasing group among visually impaired children in the Western world. The
developing visual system may be affected by malformations arising early in gestation, by
white matter damage of immaturity (WMDI) both in utero and as a sequel to premature birth,
and by asphyxia as well as by cortical-subcortical damage due to perinatal cerebral infarcts in
children born at term. Infections and trauma in the neonatal period may also affect the visual
system. Much of the brain is devoted to vision. Damage causes visual problems ranging from
profound impairment to cognitive visual problems only.
Visual and ocular outcome after pre- or perinatal brain damage depends on localisation and
extension of the lesion, but also on at what stage the developing system was injured. Plasticity
of the brain may modify the functional outcome when the visual system is injured early in
gestation Thus, reorganisation of the visual system by bypassing the lesion in the ipsilateral
hemisphere or maybe by inter-hemispheric reorganisation may take place in the immature
brain. In addition, retrograde trans-synaptic degeneration may affect the appearance of the
optic disc in retro-geniculate lesions occurring during the pregnancy or in the neonatal period
in children born preterm.
Brain imaging techniques
Examination of the newborn infant brain with ultrasound (US) may detect lesions engaging
the posterior visual pathways, but US is an insensitive method to find minor injuries. Later
during infancy and childhood magnetic resonance imaging (MRI) is the most sensitive
imaging modality to detect permanent lesions to the posterior visual system. The paediatric
neuroradiologist thus plays an important part in the identification of children with cerebral
visual impairment. White matter lesions may be further understood and mapped out with
diffusion tensor imaging techniques.
Visual dysfunctions
The manifestations of this kind of visual impairment include subnormal visual acuity and
crowding, affected visual field function and associated disorders of higher visual processing.
The principal cognitive visual pathways comprise the dorsal and the ventral streams. The
dorsal stream runs between the occipital lobes, which process incoming visual data, the
posterior parietal lobes, which process the whole visual scene and give attention to component
parts, the motor cortex, which facilitates movement through the visual scene and the frontal
cortex, which directs attention to chosen parts of the visual scene. The ventral stream runs
between the occipital lobes and the temporal lobes, which enable recognition of people and
objects facilitating route finding and serve visual memory. In addition, impaired control of the
eye movements and disordered focusing may further complicate the effective use of vision.
These problems can occur in any combination and severity. Visual function may improve
over time.
Cerebral palsy, learning disabilities and behaviour and attention problems are other wellknown consequences of pre- and perinatal brain damage. Concomitant cerebral visual
impairment is common but often remains undetected, and therefore is not taken into account
when designing habilitation programs for the individual child. Early brain damage may
however cause only visual problems, and often manifests itself as early-onset strabismus. In
these cases, the paediatric ophthalmologist is responsible for identification of children with
cerebral visual impairment, for assessment of visual function, and for initiating habilitation.
The habilitation of these children demands a multi-disciplinary team including paediatric
ophthalmologist, orthoptist, neuropsychologist, paediatric neurologist, occupational therapist,
physiotherapist, low vision teacher and remedial teacher.
Our research team at Karolinska Institutet has in collaboration with researchers from
Gothenburg during the years 1996-2009 contributed to the bank of new knowledge of visual
and ocular outcome in children with pre- and perinatal brain damage.
Prematurely born children with WMDI
Crowding and cognitive visual problems in children with WMDI
In a study of prematurely born children with visual impairment due to WMDI, we described
subnormal visual acuity and crowding (Jacobson et al 1996). Using standard
neuropsychological tests we described visuo-spatial deficiencies in this group with problems
judging depth and movement, with simultaneous perception, with face recognition and with
orientation. Other groups described similar findings; among them Dutton et al. 1996.
Nystagmus, eye motility disorders, strabismus in children with WMDI
Nystagmus was previously reported to be absent in children with cerebral visual impairment.
In fact, the presence or absence of nystagmus was thought to reveal whether the cause of
visual impairment in a child was of ocular or cerebral origin. In the 1990ies we studied
fixation with infrared technique in a group of prematurely born children with cerebral visual
impairment due to WMDI and reported latent or manifest nystagmus in a majority of these
children (Jacobson et al. 1998). However, children with the most severe WMDI, with cerebral
palsy and visual impairment presented an ocular motor apraxia with complete disruption of
ocular motor organization, including absence of fixation and they had no nystagmus. Children
with less extensive WMDI, representing the other end of the clinical spectrum, all exhibited
nystagmus. Thus, nystagmus may be seen in children with cerebral visual impairment and the
presence of nystagmus may depend on the extent, and maybe, on the timing of the insult
which may affect input to the visual integrating circuits.
Defective smooth pursuit movements and inability to perform visually guided saccadic
movements in children with WMDI were found by us and by Cioni et al (1997) and Lanzi et
al (1998). Strabismus as a consequence of WMDI was reported by Scher et al (1989) and also
by us. The frequent finding of early-onset strabismus associated to WMDI may be the
consequence of a deficient afferent pathway caused by axonal interruption in the optic
radiation.
Optic disc appearance in children with WMDI
Brodsky and Glasier (1993) found a link between optic nerve hypoplasia and WMDI, but did
not confirm their observations by fundus photography. We performed digital analysis of the
fundus photographs of children with WMDI and found that the time at which the primary
lesion of the optic radiation occurred was of importance for the appearance of the optic disc
(Jacobson et al. 1997, Jacobson et al. 2003). Early WMDI, sometimes of prenatal origin,
before gestational week 28 was associated with small discs. Normal-sized optic discs with
large cupping and consequently a reduced neuro-retinal rim area was the consequence of later
lesions, occurring after 28 weeks of gestation. In this developmental phase, the supportive
structures of the optic nerve have become established and probably do not adapt to the smaller
number of nerve fibers. The reduced rim area, either expressed as a small disc or as a large
cup in a normal-sized disc is probably the result of retrograde trans-synaptic degeneration of
optic nerve axons caused by the primary bilateral lesions in the optic radiation. Thus, optic
disc appearance together with the pattern of cerebral morphology depicted by MRI may give
information about the timing of the lesion.
Visual field defects in children with WMDI
Interruption of axons in the optic radiation may explain restriction of visual field (VF).
Variable restriction of the fields may also be attributable to problems with simultaneous
attention. Thus the functional VF may vary depending on the amount of visual stimuli present
and on the degree of attention paid to the fixation target. We assessed VF function in a group
of children with WMDI (Jacobson et al. 2006). All subjects had subnormal VF function,
although the depth and extension of the defects differed between subjects. The lower VF was
often more affected than the upper, which could be interpreted as a bilateral homonymous
lower quadrant dysopia due to the bilateral lesions in the upper part of the optic radiation. The
VF abnormalities could be demonstrated by both manual and computerized perimetry.
Case report
This case illustrates visual outcome associated to WMDI (Jacobson & Dutton 2000). A boy
was born prematurely at 32 full gestational weeks, with asphyxia at birth and he was early
diagnosed with cerebral palsy (spastic diplegia). His verbal development was normal.Visual
function is characterized by normal visual acuity (RE=LE 1.0) inferior altitudinal visual field
defects (Fig. 1), strabismus, nystagmus, defect saccades and smooth pursuit movements and
severe dorsal and ventral stream dysfunction. Thus, he is not able to judge depth by vision, he
cannot find his way around and he cannot recognise even family members if he meets them
unexpectedly. He is a slow reader, and often gets lost in the text. He has developed a battery
of compensating strategies based on hearing, tactile information and memory.
The optic discs are of normal size with large cupping (Fig. 2); the intraocular pressure is
normal. GDx of the fundus (Fig. 3) documents loss of ganglion cell axons above the optic disc
secondary to the brain lesions. MRI of the brain (Fig. 4 and 5) illustrates bilateral
periventricular WMDI. With fiber tractography of the optic radiation (Fig. 6) connecting
fibres are only detectable in the lower part of optic radiation on both sides which corresponds
well with the finding of an inferior bilateral homonymous quadrant anopia.
Figure 1. Altitudinal inferior visual field defects (bilateral inferior homonymous quadrant
anopias) due to bilateral WMDI affecting the upper parts of the optic radiations.
Figure 2. Large cupping of normal-sized optic discs; a consequence of retrograde transsynaptic degeneration from interruption of axons in the optic radiation occurring after 28
gestational weeks.
Figure 3. GDx fundus images illustrating loss of nerve fibres layer above the optic discs, due
to retrograde trans-synaptic degeneration from the lesions in the upper part of both optic
radiations, corresponding to the visual field defects
Figure 4. This MRI at the level of the
posterior horns and trigonum shows the
occipital horns to be dilated due to reduced
periventricular white matter volume and
consequent loss of axons in motor and
visual pathways. Note how cortex abuts the
ventricular wall giving trigonum of the
ventricles a slight irregular shape. Also
note increased signal in remaining white
matter adjacent to the frontal horns and
extending deep into white matter in both
frontal lobes. (Courtesy of Olof Flodmark,
Dept of Neuroradiology, Karolinska
University Hospital)
Figure 5. This image is at a level just at
the top of the lateral ventricles. Increase
signal beyond the borders of the lateral
ventricles in the parietal and frontal lobes
represent gliosis in damaged white matter.
(Courtesy of Olof Flodmark, Dept of
Neuroradiology, Karolinska University
Hospital)
Figure 6. Fiber tractography of the optic radiation (OR). It is difficult to accurately track the
OR with tensor-based tracking. Here, instead tractography between LGN and primary visual
cortex is performed with probabilistic tractography in a crossing-fiber model. The results
show a normal periventricular extent of OR in a healthy volunteer (Left). In our case (Right)
connecting fibers are only detectable in the lower part of OR. The degree of connectivity is
also lower (i.e. lower probability that initiated fibers in LGN reach the target area in primary
visual cortex), and more so on his left than on his right .side. This finding corresponds well
with loss of nerve fibres in the upper part of the fundi and with an inferior bilateral
homonymous quadrant anopia. (Courtesy of Annika Kits and Finn Lennartsson, Dept of
Neuroradiology, Karolinska University Hospital)
Visual field outcome in children with unilateral cerebral palsy
The frequency of VF defects in different groups of children with cerebral palsy has been
estimated to 20-25%. However, in most studies only confrontation techniques have been used.
We have recently assessed VF function in a group of children with unilateral cerebral palsy
(CP) with confrontation technique and with Goldmann perimetry. The type and extension of
brain lesion was documented with cerebral imaging. 62% had subnormal VF function, and
the VFs were severely restricted in 21%. The underlying brain lesions were malformation,
WMDI and cortico-subcortical lesions. VF function could be correlated to the pattern of brain
damage in cortico-subcortical lesions and in extensive lesions due to malformation or WMDI.
Total homonymous hemianopia was common in the cortico-subcortical group but rarely found
in children with malformation or WMDI. Five children had malformation or WMDI engaging
parts of the brain that usually contain the posterior visual system, but they had normal VF
function.
Thus, the VF function may be preserved by plasticity of the immature brain in children with
malformation and WMDI. Severely restricted VF function was more often associated with
brain damage occurring later in the developing brain. All children with severely restricted
VFs were identified with confrontation technique. Goldmann perimetry was a suitable method
to identify also relative VF defects in this age group of children with unilateral CP (Jacobson
et al. 2010).
Conclusions
Visual impairment due to pre-and perinatal brain damage has become the most common cause
of visual disturbance among children in the Western world; a consequence of increased
survival of very immature and very sick infants. The resulting visual dysfunction depends on
localisation and extension of the lesion involving the visual brain, but also on at what stage of
maturity the brain was damaged. As there is considerable plasticity of the developing visual
system, the outcome may be difficult to predict by routine imaging of the brain.
Assessments of acuities, visual field function, fixation, eye motility and of cognitive visual
function constitute the basis for implementation of developmental programmes designed for
these children.
References
Brodsky M & Glasier (1993): Optic nerve hypoplasia: clinical significance of associated
central nervous system abnormalities on magnetic resonance imaging. Arch Ophthalmol 111:
66-74.
Cioni G, Fazzi B, C et al. (1997): Cerebral visual impairment in preterm infants with
periventricular leukomalacia. Pediatr Neurol 17: 331-8.
Dutton G, Ballantyne J, Boyd G et al. (1996): Cortical visual dysfunction in children. Eye
(London) 10: 302-9.
Jacobson L & Dutton G (2000): Periventricular leukomalacia: an important cause of visual
and ocular motility dysfunction in children. Surv Ophthalmol 45: 1-13.
Jacobson L. Ek U, Fernell Eet al. (1996): Visual impairment in preterm children with
periventricular leukomalacia – visual, cognitive and neuropaediatric characteristics related to
cerebral imaging. Dev Med Child Neurol 38: 724-36.
Jacobson L, Flodmark O & Martin L. (2006): Visual field defects in prematurely born patients
with white matter damage of immaturity; a multiple case study. Acta Ophthalmol Scand 84:
357-62
Jacobson L, Hellström A & Flodmark O (1997): Large cups in normal-sized optic discs. A
variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch
Ophthalmol 115: 1263-9
Jacobson L, Hård AL, Svensson E, et al. (2003): Optic disc morphology may reveal timing of
insult in children with periventricular leukomalacia and/or periventricular haemorrhage. Br J
Ophthalmol 87: 1345-9
Jacobson L, Rydberg A, Eliasson AC et al. submitted manuscript. Visual field function at
school age in children with spastic unilateral cerebral palsy, related to different patterns of
brain damage
Jacobson L, Ygge J & Flodmark O (1998): Nystagmus in periventricular leucomalacia. Br J
Ophthalmology 82: 1026-32.
Lanzi G, Fazzi E, Uggetti CD, et al. (1998): Cerebral visual impairment in periventricular
leukomalacia. Neuroped 29: 145-50.
Sher M, Dobson V, Carpenter N, et al. (1989): Visual and neurological outcome of infants
with periventricular leukomalacia. Dev Med Child Neurol 31: 353-65.
XI
The Eye Mirroring Inherited
Metabolic Disorders
Kristina Teär Fahnehjelm
Introduction
A few decades ago many children with inborn errors of metabolism died early. Today, with
better diagnostic procedures and more efficient treatment they often reach adulthood.
However, somatic or ocular complications are common as long-term sequels. Early diagnosis
does not make already existing ocular complications vanish but often, although not always,
treatment can stop progression. It is therefore important for the paediatric ophthalmologist to
be acquainted with the pathogenesis of metabolic disorders and to get a good knowledge of
how, why and when the eyes are affected. Although the individual inherited inborn errors of
metabolism are rare diseases, taken as a group, they affect approximately 1 child per 2500. In
the following a few common inherited metabolic disorders with severe ocular complications
are presented.
Mucopolysaccharidosis I (MPS I) Hurler
Mucopolysaccharidoses are lysosomal storage diseases, due to deficiencies of different
enzymes, where MPS I - Hurler is the most common. It is a life-threatening disease where
corneal clouding can be one of the first presenting signs and thus also a diagnostic clue. The
world wide incidence of MPS I has been reported to be 1/100 000 newborns. More than 90
mutations in the gene coding for the lysosomal enzyme α-L-iduronidase are known to cause
deficiency or absence of the enzyme. This abnormality leads to intra- and extracellular
accumulation of the glucosaminoglucans (GAG), causing cell death, tissue damage and
disturbance of normal tissue growth as well as excessive excretion of GAG in the urine. The
children, who usually grow normally until six months of age, will manifest severe skeletal
deformations, short stature, scoliosis, coarsening of facial features, large heads,
communicating hydrocephalus, mental retardation, hepatosplenomegaly, and cardiac
complications. Death, in untreated children, usually occurs during the first decade of life
(Wraith 2005). Ocular characteristics apart from corneal clouding (Figure 1) include
protruding wide set eyes, atypical eyebrows, retinal dystrophies, glaucoma, chronic
papilloedema and optic atrophy. Also posterior visual pathway pathology or visual cortical
abnormalities have been reported due to accumulation of storage material in the white matter
of the CNS.
Early allogeneic stem cell transplantation (SCT), where a HLA matched graft is given to a
conditioned patient, has been used as a treatment since the early 1980-ies. SCT has been
shown to reduce the accumulation of GAG in visceral organs and to increase survival and
stabilising long-term neuro-cognitive functions. Today SCT is offered to children below two
years of age with a normal intellectual development (Wraith 2005) but SCT performed even
earlier, at 12 months of age, is preferable. With regard to eye symptoms, various degrees of
improvement of the corneal clouding after SCT have been reported. However, despite early
improvement of retinal conditions with SCT, it has been suggested that retinal dysfunction
will still progress (Gullingsrud et al. 1998).
As life expectancy increases in children with MPS I-H, it becomes more important to detect
remaining ocular complications and additional SCT related complications, such dry eye
syndrome and cataract. In a Swedish study corneal opacities diminished in four children with
MPS I (one of them shown in Figure 2), after SCT before 2 years of age (Fahnehjelm et al.
2006). Although early SCT thus seems to be beneficial, no objective grading of the corneal
opacities was made and the number of patients was limited. In accordance with previous
studies, no patient had a complete resolution of the corneal opacities. However, the best
corrected visual acuity (BCVA) was good in these 4 patients, in comparison with patients in
other international studies, partly maybe due to early intervention with glasses for hyperopia.
No patient has needed corneal transplantation, developed cataract and/or glaucoma.
A recent follow-up has been made of five of seven Swedish patients with MPS I who had
SCT before 23 months of age. The median age in the group was 8 years, BCVAwas ≥ 0.5 in
the majority of the patients despite mild/moderate opacities while high hyperopia (+4.0 to
+9.0 spherical equivalent) was present in all patients. Keratometry values were low and axial
lengths short in comparison with reference material (Fahnehjelm, Törnquist& Winiarski
accepted ACTA Ophthalmol April 2010) Our hypothesis is that the storage of GAG will lead
to increased rigidity of the cornea and sclera, with a flattening of the curvature of the cornea
and a reduction of the refractive power of the corneal surface. This, together with the reduced
axial length, can explain the high incidence of hyperopia in the MPS I patients. Detection of
refractive errors and prescription of glasses are important in order to avoid amblyopia.
Photochromatic glasses were shown to be beneficial in minimizing photophobia, increasing
comfort and optimizing visual function.
To conclude, children with MPS 1-H show a variety of ocular symptoms. Early SCT seems
beneficial in reducing, but not eliminating, corneal opacities. The clinical evaluation of MPS
I children in their early years offers a challenge to the paediatric ophthalmologist.
Retinoscopy might be difficult to perform due to dull fundus reflexes and/or severe
photophobia but is important to measure the refraction since high hyperopia is common. It is
possibly caused by storage of glucasaminoglucans that affect the refractive power of the
cornea. Intraocular pressure is often recorded as falsely high, due to corneal stiffness.
In the future, stromal transplantation of mesenchymal cells might be a solution for reduction
of corneal opacities. Enzyme replacement therapy has so far not been shown beneficial in
reducing corneal opacities, probably due to reduction of enzyme transport to the avascular
cornea.
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency
LCHAD (Long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency is a life-threatening
disorder of deficient fat metabolism. The LCHAD enzyme catalyzes the β-oxidation of fatty
acids and has the highest specificity towards chain lengths of 14-22 carbon atoms. The disease
is inherited in an autosomal recessive manner and is the second most common β-oxidation
defect in Sweden with an estimated incidence of 1:100.000. As triglycerides offer an
important source of energy, a defect in the degradation can have deleterious effects during
catabolic states.
The diagnosis is usually established within the first eight months of life, based on life
threatening hypoketotic hypoglycaemia accompanied by liver enlargement, muscular
hypotonia and hypertrophic cardiomyopathy. Measurements of dicarboxylic and 3-hydroxy
fatty acids in plasma followed by mutation analysis contribute to the diagnosis. Emergency
treatment with glucose infusion followed by a diet with reduced intake of fat (approximately
20% of calories), mainly composed of medium chain triglycerides, supplemented with
vitamins, minerals and essential fatty acids, has resulted in reversion of the above symptoms.
Neonatal death is a major risk. The surviving children have a fasting intolerance making night
feeds necessary in the majority of cases and necessitating hospital care and glucose infusion
during febrile infections.
Long-term complications include peripheral neuropathy, mental retardation and
chorioretinopathy. Flattened and hypopigmented retinal pigment epithelium cells and
secondary loss of choriocapillaris macrophages have been demonstrated in the central parts,
while the peripheral parts of the ocular fundii have been normal (Tyni et al. 1998b). The
retinal findings can be graded: Stage 1 is a normal/ pale fundus with normal visual acuity and
electroretinograhy (ERG); Stage 2 a fundus with clumping of the retinal pigment epithelium
in the posterior pole and ERG deterioration(Figure 3); Stage 3 a fundus with progression to
chorioretinal atrophy , and Stage 4 a fundus with additional posterior staphyloma and
extinguished ERG (Tyni et al. 1998a).
Presently, there are 12 living children diagnosed with LCHAD deficiency in Sweden. One
patient has been treated for 18 years and is one of the longest treated worldwide. Ten of the
patients have been included in our study (Fahnehjelm et al. 2007). They all showed
chorioretinal changes of different severity. This is a higher frequency than previously reported
and may be explained by a longer ocular follow-up. Hence, the present regimen seems not to
prevent but possibly to delay the development of ocular symptoms. The ERG responses
correlated with the stages of chorioretinopathy, suggesting that disturbance of the retinal
neuro-epithelium paralleled the damage of the retinal pigment epithelium and the progressive
loss of choroid vessels.
All patients were treated with Omega 3 (docosahexaenoic acid /DHA/) to keep DHA within
normal levels. Low plasma levels of essential fatty acids, especially DHA, have previously
been suggested as a contributing factor for the retinopathy (Gillingham et al. 1999). A
correlation between DHA levels and VA measured by Sweep VEP (Gillingham et al. 2005)
has been seen in these children. The accumulation of long-chain 3-hydroxyacylcarnitines has
also been found to be negatively correlated to ERG amplitude (Gillingham et al. 2005).
In conclusion, children with LCHAD-deficiency should have an ocular examination within
the first month of diagnosis and thereafter annually. The ophthalmologist has an important
role in early detection, since LCHAD deficiency may be difficult to diagnose. Unusual
chorioretinal findings, especially if there is a history of neonatal hypoglycaemia or failure to
thrive, should lead to the suspicion of LCHAD deficiency. Fundus photography and repeated
ERGs should be performed. Furthermore, it is important that an ocular evaluation is done of
all patients with a suspected defect in the beta oxidation system.
Mitochondrial diseases
Mitochondrial diseases lead to dysfunction of the respiratory chain affecting the cellular
energy metabolism of all organs, giving rise to a variety of symptoms from any organ at all
ages. With an estimated minimum prevalence of 1/5000 the mitochondrial diseases can be
regarded as one of the most common groups of inborn errors of metabolism. The respiratory
chain consists of five enzyme complexes (I-V) located in the mitochondrial inner membrane
with the main function to generate adenosine triphosphate (ATP). This process is under dual
genetic control, with communication between the nuclear and mitochondrial genomes.
Isolated complex I deficiency is the most common mitochondrial respiratory chain defect.
There is a wide variety of clinical phenotypes. Subacute necrotizing encephalopathy (Leigh
syndrome) and Leigh-like syndrome are common manifestations in infants.
Causative mutations are found in mitochondrial DNA (mtDNA) as well as in nuclear DNA
(nDNA). Mutations in mtDNA are maternally inherited while nuclear mutations most often
are autosomal recessively inherited. In children, a multi-system disease is often seen, with a
failure to thrive, encephalopathy, visual and hearing impairment, severe muscle weakness and
dysfunction of the heart, liver, kidneys, and endocrine organs.
Mitochondrial disease may lead to ocular problems. Dominant optic atrophy (DOA) and
Leber’s hereditary optic atrophy (LHON) are both non-syndromic optic neuropathies with
mitochondrial aetiology. Optic nerve hypoplasia (ONH) has also been described in relation to
mitochondrial disease.
In a recently Swedish study (Fahnehjelm et al 2010), ocular or visual problems were much
more common than previously reported, occurring in 12 of 13 patients with mitochondrial
disease. Optic atrophy occurred in 5 out of the 12 patients with an ocular diagnosis. One
patient had a unilateral thickening of the nerve fibre layer and teleangiectatic microangiopathy
in his left eye, similar to previously reported findings in asymptomatic carriers with LHON
mutations. Motility problems with dysmetric saccades, asymmetrical smooth pursuits,
instability in fixation, and gaze paralysis were common indicating an involvement of extra
ocular muscles, brainstem, basal ganglia and cerebellum, which also was confirmed with MRI
pathology. Flash and/or pattern VEP were pathological in 60% of the patients.
With regard to the extra-ocular muscles, it is interesting to note that the abundant
mitochondria in these energy-demanding muscles have been shown to respire at slower rates
than mitochondria in skeletal muscles. The activity of complex I has shown to be lower than
in normal extra-ocular muscle, which could explain the eye movements abnormalities in the
patient in the present study, since saccadic and pursuit movements are energy dependent and
thus sensitive to mitochondrial dysfunction.
In conclusion, patients with complex I deficiency suffer different ocular disorders including
optic atrophy and eye motility problems. The patients with severe somatic dysfunctions and
brain damage also had the most severe visual impairment, motility dysfunctions and ocular
pathology.
Conclusions
Young patients with inherited errors of metabolism and ocular manifestations present
challenges to paediatric ophthalmologists but also make everyday practice multi-dimensional
and exciting. The patients offer an opportunity to cooperate with colleagues from different
disciplines. This encourages new clinical research and supplies opportunities to design
various multidisciplinary scientific studies, hopefully resulting in clinical progress, beneficial
outcomes and clinically relevant follow-up programs/clinical guidelines for ocular
manifestations in children with inborn errors of metabolism.
References
Fahnehjelm K T, Törnquist A L, Malm G & Winiarski J (2006): Ocular findings in four
children with mucopolysaccharidosis I-Hurler (MPS I-H) treated early with haematopoietic
stem cell transplantation. Acta Ophthalmologica Scandinavica 84: 781-785.
Fahnehjelm K T, Törnquist A L, Olsson M & Winiarski J (2007): Visual outcome and
cataract development after allogeneic stem-cell transplantation in children. Acta
Ophthalmologica Scandinavica 85: 724-733.
Fahnehjelm, K T, Olsson M, Naess K, Wiberg M, Ygge J, Martin L, V Döbeln U (2010:
Visual function, ocular motility and ocular characteristics in patients with mitochondrial
complex I deficiency. ACTA Ophthalmologica Jan 8. Epub ahead of print.
Gillingham M, Van Calcar S, Ney D, Wolff J & Harding C (1999): Dietary management of
long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and
survey. J Inherit Metab Dis 22: 123-131.
Gillingham M B, Weleber R G, Neuringer M, Connor W E, Mills M, van Calcar S, Ver
Hoeve J, Wolff J & Harding C O (2005): Effect of optimal dietary therapy upon visual
function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional
protein deficiency. Mol Genet Metab 2005 Sep-Oct;86(1-2):124-33.
Gullingsrud E O, Krivit W & Summers C G (1998): Ocular abnormalities in the
mucopolysaccharidoses after bone marrow transplantation. Longer follow-up. Ophthalmology
105: 1099-1105.
Tyni T, Kivelä T, Lappi M, Summanen P, Nikoskelainen E & Pihko H (1998a):
Ophthalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused
by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy.
Ophthalmology 105: 810-824.
Tyni T, Pihko H & Kivelä T (1998b): Ophthalmic pathology in long-chain 3-hydroxyacylCoA dehydrogenase deficiency caused by the G1528C mutation. Curr Eye Res 17: 551-559.
Wraith J E (2005): The first 5 years of clinical experience with laronidase enzyme
replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 6: 489-506.
Acknowledgements
The Editors wish to thank
Publications Produced or Supported by the
Bernadotte Foundation
1. Retinopathy of Prematurity. Reports from the Nordic Countries. Hans Fledelius, Gerd
Holmström, Gunnar Lennerstrand, Eds. Acta Ophthalmologica, Volume 71,
Supplement 210, 1993.
2. Eye Movements in Reading. Jan Ygge and Gunnar Lennerstrand, Eds. Wenner-Gren
International Series, Volume 64, Pergamon Press,Oxford, 1994.
3. Pediatric Ophthalmology; some recent advances. Gunnar Lennerstrand, Ed. Acta
Ophthalmologica Scandinavica, Volume 73, Supplement 214, 1995.
4. Advances in Strabismus Research: Basic and Clinical Aspects. Gunnar Lennerstrand
and Jan Ygge, Eds. Wenner-Gren International Series, Volume 78, Portland Press,
London, 2000.
5. Barnögonsjukdomar. Aktuell svensk forskning. Maj Ödman and Gunnar Lennerstrand,
Eds. Johansson & Skyttmo Förlag, Stockholm, 2000.
6. Advances in Pediatric Ophthalmology Research. Reports presented at the 20th
anniversary of the Sigvard & Marianne Bernadotte Research Foundation for Children
Eye Care. Gunnar Lennerstrand and Gustaf Öqvist Seimyr, Eds. 2010.