Anatomy and physiology of the human eye : effects of mucopolusaccharidoses

disease on structure and function a review

Abstract
The current paper provides an overview of current knowledge on the structure and function of
the eye. It describes in depth the different parts of the eye that are involved in the ocular
manifestations seen in the mucopolysaccharidoses (MPS). The MPS are a group of rare
inheritable lysosomal storage disorders characterized by the accumulation of
glycosaminoglycans (GAGs) in cells and tissues all over the body, leading to widespread tissue
and organ dysfunction. GAGs also tend to accumulate in several tissues of the eye, leading to
various ocular manifestations affecting both the anterior (cornea, conjunctiva) and the posterior
parts (retina, sclera, optic nerve) of the eye.

Introduction
The mucopolysaccharidoses (MPS) are a group of inheritable lysosomal storage disorders,
characterized by the progressive accumulation of incompletely degraded glycosaminoglycans
(GAGs) in tissues and organs due to a deficiency in one of the enzymes involved in GAG
catabolism (Table 1). All MPS types have a progressive course and involve multiple organs.
They share several common clinical features, but with variable degrees of severity. Typical
features of the MPS include coarse facial features, affected hearing and vision, cardiorespiratory
problems, reduced joint mobility, organomegaly and skeletal deformities (dysostosis multiplex,
dwarfism) (Fig. 1).1 Patients with MPS IH (Hurler syndrome), MPS III (Sanfilippo syndrome)
and the severe form of MPS II (Hunter syndrome) typically show mental retardation. Patients
with MPS IV (Morquio syndrome) show bony lesions specific for that disorder (dwarfism with
short trunk and neck). There is a wide spectrum of phenotypes and progression rates within any
one MPS type.
Table 1. The mucopolysaccharidoses (MPS)
MPS type
Name
Enzyme deficiency
MPS IH, IS, IH/S Hurler, Scheie, Hurler/Scheie -L-iduronidase
MPS II
Hunter
Iduronate-2-sulfatase
Sanfilippo A
Heparan N-sulfatase
Sanfilippo B
N-acetylglucosaminidase
MPS III
Sanfilippo C
Acetyl CoA:-glucosamine N-acetyltransferase
Sanfilippo D
N-acetylglucosamine-6-sulfatase
Morquio A
N-acetylgalactosamine-6-sulfatase
MPS IV
Morquio B
-galactosidase
MPS VI
Maroteaux-Lamy
N-acetylgalactosamine-4-sulfatase
MPS VII
Sly
-D-glucuronidase

MPS type
MPS IX

Table 1. The mucopolysaccharidoses (MPS)

Name
Enzyme deficiency
Natowicz
Hyaluronidase

Figure 1. Typical features of the mucopolysaccharidoses (MPS). (a) Claw hand of a patient with
MPS IH/S (Hurler/Scheie). (b) Umbilical hernia in a child with MPS VI (Maroteaux-Lamy). (c)
Coarse facial features in a child with MPS VI.
Characteristic ocular features in patients with MPS include corneal clouding, glaucoma,
retinopathy, optic disc swelling and optic atrophy.25 Ocular problems in patients with MPS are
among the first symptoms to arise and can ultimately result in visual impairment or blindness.4,5
This review of the anatomy and physiology of the normal eye and overview of changes in
structure and function seen in MPS disease was presented at the International Symposium MPS
and the eye: What do we know and how can we treat, which was held on 79 October 2009 in
Venice, and provided the introduction necessary to focus on diagnosis and treatment of eye
disease in this patient group.

Introduction to the anatomy and physiology of the eye

The eye is one of the most complex organs of the human body. In the human eye, three layers
can be distinguished (Fig. 2). The outer region consists of the cornea and the sclera. The cornea
refracts and transmits the light to the lens and the retina and protects the eye against infection
and structural damage to the deeper parts. The sclera forms a connective tissue coat that protects
the eye from internal and external forces and maintains its shape. The cornea and the sclera are
connected at the limbus. The visible part of the sclera is covered by a transparent mucous
membrane, the conjunctiva. The middle layer of the eye is composed of the iris, the ciliary body
and the choroid. The iris controls the size of the pupil, and thus the amount of light reaching the
retina; the ciliary body controls the power and shape of the lens and is the site of aqueous
production; and the choroid is a vascular layer that provides oxygen and nutrients to the outer
retinal layers. The inner layer of the eye is the retina, a complex, layered structure of neurons that
capture and process light. The three transparent structures surrounded by the ocular layers are
called the aqueous, the vitreous and the lens.

Figure 2. Schematic illustration of the structure of the eye and the ocular barriers. The primary
physiologic blockage against instilled drugs is the tear film. Cornea is the main route for drug
transport to the anterior chamber (I). The retinal pigment epithelium and the retinal capillary
endothelium are the main barriers for systemically administered drugs (II). Intravitreal injection

is an invasive strategy to reach the vitreous (III). The administered drugs can be carried away
from the anterior chamber either by venous blood flow after diffusing across the iris surface (1)
or by the aqueous outflow (2). Drugs can be removed away from the vitreous through diffusion
into the anterior chamber (3) or by the bloodretinal barrier (4). Adapted from Barar J et al.6

The cornea
The cornea is the most anterior part of the eye, in front of the iris and pupil. It is the most densely
innervated tissue of the body, and most corneal nerves are sensory nerves, derived from the
ophthalmic branch of the trigeminal nerve.7 The cornea of an adult human eye has an average
horizontal diameter of about 11.5 mm and a vertical diameter of 10.5 mm, and a curvature that
remains rather constant throughout life.8 The optic zone (pre-pupillary cornea), which provides
most of the cornea's refractive function, has a diameter of 4 mm and is located in the centre of
the cornea, anterior to the pupil, in photopic conditions. The cornea is avascular and the branches
of the anterior ciliary arteries stop at the limbus where they form arcades that supply the
peripheral cornea.9 Therefore, the peripheral and central cornea are very distinct in terms of
physiology and pathology.
Five layers can be distinguished in the human cornea: the epithelium, Bowman's membrane, the
lamellar stroma, Desemet's membrane and the endothelium (Fig. 3).10 The surface of the corneal
epithelium is covered by the tear film, which protects the corneal surface from chemical, toxic or
foreign body damage and from microbial invasion and smoothes out micro-irregularities of the
surface of the epithelium.10 It consists of an outer lipid layer and an inner water-mucous layer.
The mucous layer interacts with the epithelial cells, allowing the tear film to spread with each
eyelid blink.

Figure 3. Schematic presentation of the different layers of the cornea. Reproduced from Daniels
JT et al.,11 with permission of John Wiley and Sons.
The corneal epithelium is composed of two to three layers of superficial cells, two to three layers
of wing cells and one layer of basal cells.10 The surface of the superficial epithelial cells is
irregular due to the presence of microplicae (ridge-like folds of the plasmalemma) that interact
with the overlying tear film. The cells of the corneal epithelium are renewed every 710 days
from a pluripotent stem cell population, which resides in the palisades of Vogt at the
corneoscleral limbus. The stem cells differentiate into transient amplifying cells when they
migrate to the central cornea.11,12 Recent research has also identified oligopotent stem cells in the
corneal epithelium of mice and pigs, suggesting that the limbus is not the only niche for corneal
stem cells.13 The corneal epithelium is extremely impermeable and stable due to the presence of
cell junctions.10 It is also anchored very strongly to the basal lamina. The latter is secreted by the
basal cells and mainly consists of type IV collagen and laminin. Because innervations are
essential for the physiology of the epithelium, practically all epithelial cells are in contact with
nerve cells.

The corneal lamellar stroma (500-m-thick) provides structural integrity to the cornea. Stromal
keratocytes secrete collagen and proteoglycans, which are ultimately fundamental for the
transparency of the cornea and hydration. The stroma is separated from the epithelium by the
Bowman's layer, an acellular zone of 1015 m beneath the basal lamina. The bulk of the
stromal extracellular matrix consists of collagen fibrils arranged in 200250 parallel lamellae
that run from limbus to limbus.14 The network of collagen fibrils is responsible for the
mechanical strength of the cornea and its regular organization is essential for corneal
transparency. In the pre-pupillar cornea, the fibrils are packed more compact than in the
peripheral cornea, probably contributing to the mechanical strength and dioptric stability in the
cornea.15 The stromal collagen fibrils are surrounded by proteoglycans consisting of keratan
sufate or chondroitin sulfate/dermatan sulfate side chains. These proteoglycans have an
important structural function and help regulate hydration. Keratocytes are the predominant cell
type in the stroma and play a role in maintaining its organization. These stellar-shaped cells
contact to each other by long cytoplasmatic extensions (morphologic and functional syncytium)
and also interact with the corneal epithelium.
The corneal endothelium consists of a single layer of five- to seven-sided cuboidal cells with
little or no self-renewing potential. The endothelial cell density at birth in a normal cornea is
35007000 cells/mm2. They secrete the Descemet's membrane that separates the endothelium
from the stroma. This elastic membrane thickens with age and is composed of an anterior layer
with a banded appearance and a posterior layer with an amorphous texture.16 The endothelium
possesses intracellular and membrane-bound ion transport systems that establish an osmotic
gradient from a relatively hypo-osmotic stroma to a hypertonic aqueous. The osmotic gradient
produces a net fluid flux from the stroma to the aqueous that produces a constant percentage of
water in the stroma (78% H2O), which is essential for the clarity and transparency of the
cornea.10 This process is called deturgescence. Corneal oedema may develop if deturgescence is
disturbed for some reason.
Incident light on the cornea can be transmitted, absorbed or scattered. In a normal transparent
cornea, visible light is not absorbed and scattering is negligible. Only irregularities with
dimensions similar to the wavelength of visible light (400700 nm) will affect the retinal image.
An increase of corneal scattering can arise in case of corneal oedema, the relaxation of collagen
fibrils, haze (extracellular matrix production by keratocytes) or irregularities due to surgery.17

The retina
The retina is the tissue that lines the inner surface of the eye, surrounding the vitreous cavity.
During embryogenesis, the vertebral retina develops from the optic cup. The latter is formed by
invagination of the optic vesicle, which is an outgrowth of the embryonic forebrain. The inner
wall of the optic cup (surrounding the vitreous cavity) ultimately becomes the neural retina; the
outer wall (surrounded by the choroid and sclera) becomes the retinal pigment epithelium
(RPE).18,19 The retina is protected and held in the appropriate position by the surrounding sclera
and cornea.
The neural retina consists of six major classes of neurons: photoreceptors, bipolar cells,
horizontal cells, amacrine cells and ganglion cells, which capture and process light signals, and

the Mllerian glia, which act as the organizational backbone of the neural retina. The cells of the
neural retina are arranged in several parallel layers (Fig. 4).1820 The nuclei of the photoreceptor
cells lie in the outer nuclear layer, their outer segments lie proximal from the nuclei, close to the
RPE. The nuclei of the Mllerian glia, the bipolar cells, the amacrine and the horizontal cells are
located in the inner nuclear layer of the retina. The inner nuclear layer has plexiform layers at
both sides. In the outer plexiform layer, the photoreceptors connect with bipolar and horizontal
cells, whereas in the inner plexiform layer, bipolar and amacrine cells synapse with ganglion
cells. The nuclei of the ganglion cells lie in the ganglion layer, their axons in the nerve fibre
layer. Processes of the Mllerian glia extend throughout the retina. The apical processes form the
outer limiting membrane by making junctional complexes with one another and with
photoreceptors. The apposed end-feet of the vitreal processes form the inner limiting membrane.
Lateral processes of the Mllerian glia contact with blood vessels and neurons and form synapses
with dendrites within the plexiform layers and axons in the nerve fiber layer.18

Figure 4. The cells and layers of the retina. GCL, ganglion cell layer; ILM, inner limiting
membrane; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fibre layer; OLM,
outer limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; (R)PE, (retinal)
pigment epithelium; R&CL, rods and cones layer. Reproduced from Yanoff & Duker
Ophthalmology,19 with permission from Elsevier.
The eyes of most vertebrates contain two types of photoreceptors: rods and cones. In humans,
rods are approximately 20 times more abundant than cones.18 The photoreceptors are responsible
for phototransduction, the conversion of light into an electrical signal. For this purpose, the
membranes of the outer segment discs of the photoreceptors contain pigments. Cones, which are
responsible for colour vision, have pigments with absorption peaks in the blue, green or yellow
parts of the spectrum. Pigments of the rods have an absorption peak in the blue-green part of the
spectrum. Rods are active with low light levels, and are not involved in colour vision.
The density of rods and cones varies between different regions of the retina. In humans, about
50% of the cones are located in the central 30% of the visual field, roughly corresponding with
the macula. The macula lutea refers to an area in the retina between the temporal vascular
arcades containing xanthophylls pigment (Figs 2,5).19 Histologically, the macula has several
layers of ganglion cells, whereas in the surrounding peripheral retina the ganglion cell layer is
only one-cell thick. The excavation near the centre of the macula is called the fovea (Fig. 5). This
area of the retina is responsible for sharp central vision and contains the largest concentration of
cones in the eye.19 Visual acuity is highest in the foveola, the thin, avascular bottom of the fovea,
which contains only densely packed cone cells. Due to the high density of cone cells in the
foveola, the cone synaptic terminals and the ganglion cells to which they connect are pushed
away from its centre, resulting in elongations between the nuclei and synaptic terminals of the
cone cells, called Henle's fibres.18 At the level of the internal nuclear layer, the foveola is
surrounded by a circular system of capillaries, the vascular arcades. No photoreceptor cells are

present at the optic disc or optic nerve head where the axons from the ganglion cells exit the eye
to form the optic nerve (Fig. 5).

Figure 5. The fundus of the eye showing the macula, the fovea and the optic disc.
The RPE is a monolayer of cuboidal epithelial cells intercalated between the photoreceptors and
the choriocapillaris, a layer of capillaries adjacent to the innermost layer of the choroid. The RPE
incorporates about 3.5 million epithelial cells arranged in a hexagonal pattern, with a density that
is relatively uniform throughout the retina. At the apical side, the cells of the RPE form long
microvilli that reach up between the outer segments of rod photoreceptors.19 Numerous pigment
(melanin and lipofuscin) granules are present in the apical cytoplasm of RPE cells. Important
functions of the RPE include the maintenance of photoreceptor function (phagocytosis of
photoreceptor wastes, regeneration and synthesis of pigments), retinal adhesion, storage and
metabolism of vitamin A, the production of growth factors necessary for nearby tissues and
wound healing after injury or surgery.19,2124 In addition, the RPE plays an important role in the
bloodretinal barrier (BRB) function, which will be discussed later.
The retina receives its blood supply from two circulatory systems: the retinal and the choroidal
blood vessels.18,19 The retinal circulation supplies the inner retina, except for the avascular foveal
zone. The outer avascular retinal layers receive their nutrients by diffusion from the choroid
vessels. The choriocapillaris is fenestrated, which allows leakage of molecules to the RPE.
Specialized transport systems in the RPE control the transportation of fluid and nutrients to the
photoreceptors.
Retinal function depends on several factors, including the region of the retina being illuminated,
the wavelength and intensity of the light stimulus and the state of light adaptation.

Visual pathways
Light that enters the eye via its anterior components travels through the different layers of
transparent neurons of the retina where it is captured by the photoreceptors at the back of the
retina. As visual images are inverted as they pass through the lens, the right half of the image is
projected on the nasal retina of the right eye (and the temporal retina of the left eye), whereas the
left half of the image is projected on the temporal retina of the right eye (and the nasal retina of
the left eye).
The neurons of the neural retina translate the visual information into nerve impulses, which
travel through the optic nerve to the brain. The photoreceptors, the bipolar cells and the ganglion
cells form a direct pathway to the brain (Fig. 4). The horizontal and amacrine cells form lateral
pathways that modify and control the signal that passes through the direct pathway.19 The axons
of the ganglion cells first travel towards the nerve fibre layer at the vitreal surface and then
towards the optic disc, where they make a sharp turn to the optic nerve. The optic nerve extends

from the eye to the optic chiasm. The next synapses lie deep in the brain, in the lateral geniculate
nuclei (LGN).18 Both LGN receive information from both eyes, but only from one half of the
visual field. This is due to a hemidecussation of both optic nerves in the optic chiasm, before
they reach the LGN. Neurons from the LGN send their axons to the ipsilateral primary visual
cortex. The left primary visual cortex receives information from the right visual field, and vice
versa.
A lesion in one or both optic nerves will result in visual loss in one or both eyes, respectively.
This will be apparent in the optic disc, which may become swollen or develop pallor (optic
atrophy). Increased intracranial pressure results in the swelling of both optic discs
(papilloedema) that may cause optic atrophy when untreated. The hallmarks of chiasmal lesions
are defects that affect the temporal visual field in each eye. A lesion behind the optic chiasm is
characterized by homonymous visual field defects occurring in both eyes (e.g. the temporal field
in one eye and the nasal field in the other eye).

Ocular barriers
The transport of fluids and solutes in the eye is controlled by several membranes and barriers.
These barriers can hamper the delivery of topical ocular drugs (i.e. eye drops) and systemically
(i.e. orally or intravenously) administered drugs.
Topical ocular drugs, mostly given as eyedrops, are the most frequently used dosage forms for
treating ocular diseases. The first barrier to cross for these drugs is the tear film, which rapidly
removes instilled compounds from the eye, resulting in low bioavailability. Other membranous
barriers are located in the cornea, the conjunctiva, the irisciliary body and the retina.25,26
Depending on the physiochemical characteristics of the compounds, delivery of drugs can occur
through the corneal route and/or the conjunctival/scleral route (Fig. 2). The corneal route is the
main route for delivery of drugs to the anterior chamber. Permeation of hydrophilic drugs and
macromolecules through the corneal epithelium is limited by the presence of tight junctions
between adjacent outer superficial epithelial cells.10 The abundant presence of hydrated collagen
in the stroma may hamper the diffusion of highly lipophilic agents. The endothelium is more
permeable and allows the passage of hydrophilic drugs and macromolecules between the
aqueous and the stroma due to the presence of leaky tight junctions called desmosomes or
macula adherens. The passage of topical ocular drugs through the corneal route depends on their
lipophylicity, molecular weight, charge and degree of ionization. Particularly small lypophilic
drugs can easily permeate through the cornea. After crossing the cornea, the drug diffuses into
the aqueous and to the anterior uvea.
The non-corneal or conjunctival/scleral route is usually less efficient for drug delivery, but may
be used for the delivery of hydrophilic and larger molecules, which cannot easily diffuse through
the corneal epithelium.25 Unlike the cornea, the conjunctiva has a rich vasculature and a large
amount of the administered drug crossing it is removed by the systemic circulation. The
remaining drug penetrates through the sclera, which is more permeable than the cornea, but less
permeable than the conjunctiva. The passage of drugs from the anterior to the posterior segments
of the eye is not very efficient due to the aqueous turnover. Therefore, ocular surface

administered drugs usually do not reach the posterior segments of the eye (retina, vitreous,
choroid) in sufficient therapeutic concentrations.
Intravenous and intravitreal administrations appear to be the main strategies for treating posterior
segment infections/diseases. However, intravenous administration has limited success primarily
due to the exclusion of the eye from the systemic circulation. Of the ocular barriers, the BRB
selectively controls traverse of substances and pharmaceuticals after systemic and periocular
administration to the retina (Fig. 2). Despite some similarity, the BRB differs from the blood
brain barrier (BBB) by the functional presence of its outer barrier that is formed by the RPE. The
inner barrier is formed by the endothelial cells of retinal vessels (Fig. 6).18,25,26 Both barriers
display restricted tight junctions, by which the permeation/transfer of hydrophilic substances and
macromolecules can selectively be regulated in inward and outward directions, that is, blood to
vitreous and vice versa.26 Transcellular passive permeation is the main route for the
inward/outward traverse of small molecules across the BRB, whereas the paracellular
permeability of RPE is quite low. Besides, there exists an inverse correlation between the
molecular weight and permeability. For example, in isolated bovine RPE choroids, the inward
permeability differs between dextrans with various molecular weights (i.e. 2.36, 0.46 and
0.27 107 cm/s for 4, 40 and 80 kDa macromolecules).27 The following equation represents
overall flux of drug across the BRB: J = C P S = C CL, with J (g/min), C (g), P (cm/s)
and S (cm2) representing the overall flux of the drug, the concentration gradient of the drug, the
permeability in the barrier and the surface area of the barrier. CL represents the drug clearance
into the tissue.27

Figure 6. The retinal cellular architecture. The schematic structure of the retinal pigmented
epithelial (RPE) cells and the retinal capillary endothelial (RCE) cells represent the outer and
inner retinal barriers, respectively. RPE and RCE are the main organization of the transport
limiting layers. The outer layer of the RPE displays tight barriers due to the presence of tight
junctions (zona occludens). The inner RCE cells possessing tight junctions are non-fenestrated
compared with choroidal capillary endothelial cells that are fenestrated. Adapted from Barar J
et al.6
Various pharmaceuticals appear to be substrates/inhibitors of carrier- or receptor-mediated
transporters, which might open the door to a more advanced intraocular delivery and targeting.
Although the current knowledge on ocular drug transporters within the BRB is far from
complete, the functional expressions of many transporters have been reported, including efflux
and influx transport machineries such as organic anion transporter, organic cation transporter and
organic anion-transporting polypeptide. The expression of clathrin and caveolin-1 in retinal
vascular endothelial cells highlights the importance of the endocytic pathway for circulation of
hormones, peptides and proteins.28,29

Intravitreal injection may be associated with patient non-compliance and endophthalmitis,

cataract, astigmatism and retinal detachment. To avoid such complications, a variety of
innovative drug delivery systems [e.g. Vitrasert (Bausch & Lomb Inc., Rochester, NY, USA) for
6 months constant release of ganciclovir from the pars plana area of the vitreous;
Retisert(Bausch & Lomb Inc., Rochester, NY, USA) for 2.5 years constant release of
fluocinolone acetonide] have been exploited. More recently, a branched PEGylated anti-vascular
endothelial growth factor (VEGF) aptamer [pegaptanib sodium marketed as Macugen (OSI
pharmaceuticals Inc., Long Island, NY, USA] was approved by the Food and Drug
Administration for the treatment of neovascular age-related macular degeneration (AMD).
Ranibizumab Lucentis (developed and marketed by Genentech Inc., South San Francisco, CA,
USA and Novartis International AG, Basel, Switzerland) is a recombinant humanized
monoclonal antibody fragment that targets VEGF-A and reduces neovascularization and leakage
in wet AMD. Unlike RhuMAb VEGF [bevacizumab, Avastin (developed and marketed by
Genentech Inc., South San Francisco, CA, USA and Roche Applied Science, Basel, Switzerland)
148 kDa], ranibizumab (48 kDa) is able to penetrate the retina and enter the subretinal space
after intravitreal injection because of the notable size difference.26
Enzyme replacement therapy (ERT), that is, replacement of a defective or absent enzyme by a
recombinant variant, has raised high expectations for the treatment of some devastating ocular
diseases such as ocular manifestations of MPS I and VI. For example, Naglazyme (BioMarin
Pharmaceutical Inc., Novato, CA, USA) (galsulfase marketed by BioMarin) is a variant form of
the polymorphic human enzyme, N-acetylgalactosamine-4-sulfatase. The intravenously
administered galsulfase can be taken up into lysosomes and increase the catabolism of GAGs.30,31
Such lysosomal uptake is most likely mediated by the binding of mannose-6-phosphateterminated oligosaccharide chains of galsulfase to specific mannose-6-phosphate receptors.30 The
effectiveness of ERT on the central nervous system and ocular manifestations of MPS needs
further investigations, as its traverse through the BBB and BRB is not fully understood.
There is growing interest in ocular gene therapy for treating inherited retinal degenerations, such
as Leber's congenital amaurosis due to defects in the gene encoding the enzyme RPE65.32,33
Futuristic genomedicines for ocular diseases are deemed to become more effective therapeutics
by exploiting molecular Trojan delivery systems for safe shuttling (e.g. antisense, ribozyme and
short-interfering RNA [siRNA]) and targeting the desired biomarkers.34,35 There is particularly
much excitement about the potential of the siRNA.
Encapsulated cell technology (ECT) and cell therapy also appear to have treatment potentials for
ocular diseases. ECT implants consist of living cells encapsulated within a semipermeable
polymer membrane and supportive matrices, which are genetically engineered to produce a
specific therapeutic substance to target a specific disease or condition. Once implanted, it allows
the outward passage of the therapeutic product.36 This may be a novel treatment strategy for
some life-threatening diseases (e.g. MPS), for which an in situ source for ERT could be
developed.

Ocular manifestations in the MPS

Membrane-bound vacuoles containing GAG deposits have been found in almost all ocular
tissues in MPS patients, where they can alter the cellular shape and tissue ultrastructure.5,37
Therefore, both the anterior and posterior segments of the eye can be affected. Characteristic
ocular features in patients with MPS include corneal clouding, glaucoma, retinopathy, optic disc
swelling and optic atrophy.25 Corneal clouding develops as a result of the intracellular and
extracellular deposition of GAG in the cornea, which can affect keratocyte size and disrupt the
regular network of collagen fibrils in the stroma.5,37,38 Narrowing of the angle secondary to GAG
accumulation within the cornea can result in raised intraocular pressure and subsequent chronic
or acute angle closure glaucoma.39 GAG deposition in the trabeculocytes and subsequent outflow
obstruction can lead to open-angle glaucoma.5 Retinopathy results from GAG deposition in the
RPE and the inter-photoreceptor matrix, leading to retinal degeneration and photoreceptor loss.4
Optic disc swelling and secondary optic atrophy can have several causes. Optic disc swelling can
arise due to chronic elevation of intracranial pressure (papilloedema), impingement of the optic
nerve due to thickening of the sclera or as a result of GAG deposition within ganglion cells.3,4,40
Ocular problems in patients with MPS can ultimately result in visual impairment or blindness.4,5
As many patients with MPS first present with ocular features, it is important that
ophthalmologists are aware of the typical clinical features of MPS and can recognize them as
being of metabolic origin, so that they can refer the patients to paediatricians for further
diagnosis. The severity of the ocular findings differs between MPS types.41

Conclusion
The anatomy and function of the eye is extremely complex and pathological events can lead to a
wide range of ocular disease manifestations that may occur. MPS patients may present with a
variety of ocular diseases in both the anterior and posterior components of the eye, resulting from
GAG accumulation in various tissues. The treatment of these ocular features warrants the
investigation of methods to circumvent various ocular barriers that hamper drug delivery.

Acknowledgements
The authors are grateful to Ismar Healthcare NV for their writing assistance, which was funded
by BioMarin Europe Ltd. The content of the manuscript is based on presentations and
discussions during a scientific meeting entitled MPS and The Eye, which took place from 7 to 9
October 2009 in Venice, Italy. This meeting was supported by an educational grant from
BioMarin Europe Ltd, London, UK. BioMarin had no role in the content presented and discussed
at the meeting. All authors participated in the development and writing of the manuscript and are
fully responsible for its content

The visual field in toxoplasmic retinochoroiditis

M R Stanford,1 E A Tomlin,1 O Comyn,1 K Holland,1 and C Pavesio2
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Abstract
Aims: To document loss of central field in patients with scars from toxoplasmic retinochoroiditis
close to the disc after resolution of disease.
Methods: Patients with a clinical diagnosis of toxoplasmic retinochoroiditis were enrolled from
four centres. Automated central visual field testing was performed when their disease had settled
and retinal photographs of the lesions were taken. The type of central field defect (whether
absolute or relative) and whether it broke out to the periphery were correlated with the size of the
retinochoroidal scar and its proximity to the optic nerve head.
Results: 69 eyes were enrolled; 16 (26%) were discarded because of poor field performance. Of
the 53 remaining eyes, 31 showed absolute defects and 20 relative defects. Scars within one disc
diameter of the disc were more likely to be associated with absolute defects breaking out to the
periphery.
Conclusion: The scarring induced by toxoplasmic retinochoroiditis is associated with
considerable field loss when it occurs close to the optic nerve head. Current treatment is unlikely
to ameliorate this situation. The degree of visual field loss should be an outcome measure for
future trials of the efficacy of treatment trials for the disease.
Keywords: visual fields, toxoplasma, retinochoroiditis

Toxoplasmic retinochoroiditis classically presents as a focus of new retinitis adjacent to an old

chorioretinal scar. After about 6 weeks, the focus of active retinitis slowly fades leaving a further,
larger scar in its place, with resolution of other intraocular inflammatory signs.1 Whether this
process of healing can be accelerated by the use of antibiotics and/or corticosteroids has not been
established through formal clinical trials.2 Despite this, the main indications for treatment are the
presence of fresh retinitis within the macular arcade or an active lesion lying within one disc
diameter of the optic nerve head.35 In this latter situation, it has been hypothesised that the
necrotising retinitis leads to full thickness damage, with involvement of both photoreceptors and
second order neurons as well as the nerve fibre layer itself. If this were the case then the resulting
scotoma would not only be absolute in the area of photoreceptor destruction, but would also
break out to the periphery because of interruption of distal signalling. Similarly, the closer the

damage is to the disc, the greater might be the resultant scotoma because of greater involvement
of the nerve fibre layer.
Evidence supporting this hypothesis is sparse. Several textbooks on visual fields describe a
typical scotoma with breakout to the periphery and this undoubtedly occurs in some cases.6
However, since there has been no systematic examination of the visual fields after attacks of
disease have settled, we undertook a prospective study of patients presenting with new
toxoplasmic retinochoroiditis and measured their fields by automated perimetry when their
disease was clinically quiet.
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METHODS
Study design

A prospective, cross sectional, observational study of consecutive patients presenting to uveitis

clinics with a diagnosis of toxoplasmic retinochoroiditis. Patients were derived from clinics in
the United Kingdom (St Thomass Hospital and Moorfields, London), Brazil (Federal University
of Minas Gerais, Belo Horizonte), and Mauritius (Subramania Bharati Eye Hospital, Moka). The
study received ethical permission from the local ethics committee of Moorfields Eye Hospital.
Inclusion criteria

An active or inactive retinochoroidal scar consistent with toxoplasmic retinochoroiditis was

present in any position in the fundus. Wherever possible, anti-toxoplasma antibodies were
detected by serological testing. Where active disease was present, this was managed
appropriately and visual field testing was not undertaken until the lesion was considered resolved
and the ocular media had cleared (less than 1+ vitreous cells or BINO score less than 1+7).
Historical patients were recalled for this study.
Exclusion criteria

Patients who were unwilling or unable to perform visual field testing (see below) were excluded,
as well as any patient with known ocular/neurological pathology giving rise to visual field loss.
Visual field testing

Visual field testing was undertaken in a number of ways depending on the clinic attended. In the
United Kingdom, the central visual field was recorded using the Humphrey 24/2 FastPac strategy
or if unavailable a 24/2 SITA fast or SITA standard strategy. The right eye was tested first and
then the left eye. Wherever possible the test was repeated at least 4 weeks apart at a second visit
to allow for the learning curve. In Brazil, the central field was recorded using the Octopus 1-2-3,
CT1 dynamic standard and in Mauritius, the Kowa AP 3000 automated perimeter, precision

strategy was used. Specifically excluded were patients who had more than 33% fixation losses,
more than 20% false positive, or more than 20% false negative responses. Details of full
ophthalmological investigation were prospectively recorded and dilated fundus photographs
included for subsequent analysis.
Analysis of data

Field loss was assessed independently and scotomata were coded as absolute or relative; whether
these broke out to the periphery was also determined. The mean defect was recorded where
possible. Further analysis involved stratification of field loss and comparison with (a) the size of
the scar, and (b) the position of the scar in relation to the optic disc derived from retinal
photographs and drawings.
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RESULTS
Fields were recorded and photographs taken in 69 eyes. Of these, 16 (23.2%) were excluded
because of low quality of field. This subgroup was analysed to see if there were any differences
between those excluded and those included. The excluded eyes did not differ significantly in
terms of age, sex, race, visual acuity, type of field defect, size of lesion, or distance of lesion
from the disc. The remaining cohort of 53 eyes (29 R, 24 L) comprised 26 male, 22 female, mean
age 30.7 years (range 1269). These were divided among four main ethnic groupsAfroCaribbean 14 (26.4%), white 13 (24.5%), Asian Indian (Mauritian) 12 (22.6%), and Latin
American 14 (26.4%).
Of the 53 eyes in the study, 39 (73.6%) had a Snellen acuity of better than 6/12; 11 (20.8%) fell
between 6/12 and 6/60, and three (5.7%) had an acuity of worse than 6/60; 51 eyes had a
demonstrable central field defect. Absolute defects were seen in 31 eyes (60.8%), of which 18
(58.1%) showed breakout to the periphery (figs 11 and 22),), the remaining 13 (41.9%)
remaining confined to the lesion. Relative field defects were detected in 20 (39.2%) eyes.
Neither the size of the scar nor its distance from the disc correlated with the type of field defect
present.

Figure 1
A FASTPAC Humphrey 24/2 visual field of the right eye.

Figure 2
Colour fundus photograph of the right eye showing the area of retina with old
toxoplasma scars. In this case there was an absolute defect with breakout to the
periphery.

The characteristics of the field defect in relation to size of lesion are shown in table 11.. It may
be seen that there is no difference in whether the defect was relative or absolute in relation to the
size of the lesion. For all patients where the mean defect was recorded (40), 22 had an absolute
scotoma and 18 a relative one. For absolute scotomata, the average mean defect was 8.08 dB
(1.80 to 18.61, SD 4.26). For relative scotomata the average mean defect was 3.96 dB (1.10
to 9.20, SD 2.22) (p=0.0007).

Table 1
Characteristics of field defect by size of lesion

An analysis of field defects by position of lesion in relation to the optic disc is shown in table 2
2.. Lesions within one disc diameter of the optic disc were far more likely to be associated with
an absolute defect with breakout to the periphery than lesions further away.

Table 2
Analysis of field defects by position of lesion in relation to the optic disc

For lesions within one disc diameter of the disc, the average mean defect, where recorded was
8.44 dB (4.36 to 18.61, SD 4.26). For lesions outside one disc diameter from the disc, the
mean defect, where recorded was 5.39 dB (1.10 to 13.42, SD 3.67: p=0.03).

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DISCUSSION
Visual field loss arising as a result of toxoplasma retinochoroiditis, particularly when the focus of
inflammation is within one disc diameter of the optic disc is poorly documented in the literature.
Despite this, lesions occurring in this position are an indication for systemic treatment,4,5
although the benefit of this treatment has never been formally evaluated in terms of subsequent
loss of field. Anecdotal evidence suggests that where such field loss occurs, it is likely to be
absolute since all layers of the retina are involved in the inflammation induced by toxoplasmic
retinochoroiditis.
In this study we have shown that absolute field defects were seen in 31 eyes. In approximately
half of these there was breakout to the periphery, but in the other half the field defect remained
localised to correspond to the area of the scar. There was no difference in the size of the scar with
respect to whether defects were absolute or relative; however, absolute defects occurred when the
scar was close to the optic nerve head. As might be expected the average mean defect was more
for absolute compared to relative defects. Almost all (9/10) scars within one disc diameter of the
optic nerve head gave rise to absolute defects with breakout.
Formal testing of the visual fields following attacks of toxoplasma retinochoroiditis has rarely
been reported before. In a retrospective consecutive case series, Schlaegel reported the
Goldmann field findings in 60 eyes8; 35% showed a field defect within 5 of fixation, with 27%
being paracentral (from 6 to 13), and 38% being peripheral. Analysis of whether the field
defect was absolute or relative or whether it broke out to the periphery was not reported, and
many of the eyes had active uveitis at the time of inclusion.
The present study may include biases because of patient selection. For instance, not every patient
had two field tests because of the constraints of time/location. This may have contributed to the
large number (25%) of fields that had to be rejected, although analysis of the rejected patients
showed no difference in the location of scars or their size compared to the included fields.
Secondly, there may have been selection bias since patients with more visually disabling disease
tend to remain in clinics. Finally, there may also have been recall bias in the patients selected.
Despite the prospective nature of this study, patients could be included from historical data sets,
and patients with less disabling disease may have been lost to follow up.
The results of this study suggest that toxoplasmic retinochoroidal scars close to the optic nerve
head are associated with absolute field defects with breakout to the periphery. For lesions further

away from the disc, the prevalence of absolute defects with breakout reduced and lesions were
more likely to produce relative defects. This may imply less destructive disease in this location
(that is, the disease process may have only affected the outer retinal layers), but it is more likely
that this is because of the larger receptor field for distal ganglion cells.
In summary, our study has confirmed that retinochoroidal scars lying within one disc diameter of
the optic nerve head are likely to cause absolute defects with breakout to the periphery and
should still be considered an absolute indication for treatment. Furthermore, visual field testing
should form a routine part of the clinical assessment of patients when disease has settled and
should certainly be included as a tool for the measurement of treatment efficacy in future placebo
controlled studies, particularly where such loss may have functional consequences for the
patient.
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Acknowledgments
Supported in part by the Iris Fund for the Prevention of Blindness. The authors would like to
thank Professor F Orefice (Brazil) and Dr I Gaya (Mauritius) for allowing us to study their
patients.