retinitis pigmentosa case

OPTOMETRY

I INVITED REVIEW I

Retinitis pigmentosa: understanding the clinical presentation,

mechanisms and treatment options

Michael Kalloniatis' PhD Erica L Fletcher' PhD * Department of Optometry and Vision Science, University of Auckland, New Zealand

The University of Melbourne, Australia Department ofAnatomy and Cell Biology,

Submitted: 19 January 2004 Revised: 9 February 2004 Accepted for publication: 9 February 2004

Clin Ex$ Optom 2004; 87: 2: 65-80

Retinitis pigmentosa (RP) is a leading cause of human blindness due to degeneration of retinal photoreceptor cells. Causes of retinal degeneration include defects in the visual pigment, defects in the proteins important for photoreceptor function or in enzymes involved in initiating visual transduction. Despite the diversity of genetic mutations identified in inherited forms of retinal dystrophy, there is a common end result of photoreceptor death and functional blindness. In this review, pertinent anatomical and physiological pathways involved in RP and the underlying genetic mutations are outlined, including a discussion on the inheritance patterns revealed by advances in molecular biological techniques. Characteristics of progression rates of visual field loss and current management options will provide useful clinical guidelines for the management of patients with RP.

Key words: cGMP, degeneration, gene mutations, retina, retinal transplants, retinitis pigmentosa, visual field, vitamin A

RETINAL STRUCTURE/FUNCTION AS IT RELATES TO IDENTIFIED GENE MUTATIONS IN RETINITIS PIGMENTOM

Retinitis pigmentosa (RP) reflects a heter- ogenous group of inherited ocular diseases representing the most recurrent retinal dystrophies, with a worldwide prevalence of 1:3000 to 1:5000.' Inherited forms of retinal degeneration are largely focused on gene mutations within photoreceptors or W E cells leading to devastating loss ofvisual function, often progressing to functional blindness. The chief gene mutations leading to the RP phenotype24 relate to defects in the activation/de-activation of the visual pigment or pathways involved in the visual phototransduction cascade. To better manage patients with RP, it is important to review

the basic structure of the retina and the key pathways involved in the visual response affected in the disease process.

The visual process begins with light absorption in the photoreceptor outer segment with subsequent encoding occurring through interactions between the five other major classes of retinal n e ~ l r o n s . ~ . ~ Photoreceptor cells (rods and cones), bipolar cells and ganglion cells form the 'through' pathway, while horizontal cells, amacrine cells and interplexiform cells form the 'lateral' or 'modulatory' pathways (Figure 1). The complex interplay between the different retinal neurons leads to the encoding of spatial, temporal and chromatic information that is subsequently relayed by ganglion cells to the central visual pathway~.~.'-'I In addition to neural cells, several glial cells are localised

in the retina, with the major retinal glial cell being the Miiller cell" (Figure 1). Mtller cells are intimately involved in a range of activities essential for normal retinal functions that include neurotransmit- ter and metabolite metabolism, and chromophore recycling. The retinal pigment epithelial (RPE) cells are considered part of the retina and are involved in a multitude of functions essential for neural retinal function. These include the transport and storage of vitamin A deriva- tives (retinoids), recycling of the visual pigment , outer photoreceptor segment phagocytosis and anti-oxidant functions.'J3

Activation and deactivation of the visual pigment The visual pigment within the photorecep tor outer segment is composed of an in-

Clinical and Experimental Optometry 87.2 March 2004

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Retinitis pigmentosa Kulloniutis and Fletcher

ing of Mata and colleagues14 that all trans retinol to 11-cis retinol conversion can occur in Miiller cells, explains the reason why MUer cells have long been known to contain retinoid binding protein^.'^.'^ With the 11-cis retinol available to cone photoreceptors, pigment regeneration can occur after cones convert 1 1 4 s retinol to 1 l-cis retinal: a reaction known to occur in isolated cone photoreceptors but not in rod photo receptor^.'^

Figure 1. Schematic of the mammalian retina showing the different retinal layers and the rod and cone circuitry. The cone pathway involves a unique set of cone bipolar cells that synapse onto ganglion cells. The signal in both the rod and cone pathway is modified by horizontal cells in the OPL and amacrine cells in the IPL. The rod pathway has one type of bipolar cell that synapses with a unique amacrine cell (MI amacrine cell), which subsequently passes the information to the cone pathway via conventional synapses or via gap junctions (gi) with cone bipolar cells. These latter cells synapse onto ganglion cells and hence, ganglion cells carry both the rod and cone signals. Miiller cells span the entire retina. The blood supply in most mammalian retinas involves the outer blood supply from the choriocapillaris and the inner blood supply through the central retinal artery. The inner blood supply has capillary beds in both the inner and outer plexiform layers (for simplicity they are not shown in this diagram). The locations of the outer and inner retinal blood vessels imply that the mid-retina has poor vascular coverage. Abbreviations: ORBV = outer retinal blood vessels, RL = receptor layer, OPL = outer plexiform layer, INL = inner nuclear layer, IPL = inner plexiform layer, GCL = ganglion cell layer, NFL = nerve fibre layer, IRBV = inner retinal blood vessels, HC = horizontal cell, BC = bipolar cell, AC = amacrine cell, HCCB = horizontal cell cell body, HC-AT = horizontal cell axon terminal, GC = ganglion cell

trinsic membrane protein (opsin) and a chromophore (vitamin-A derivative). Light activation leads to a conformational change in the chromophore (1 l-cis to all- trans conformational change), that initi- ates a series of protein changes within the opsin closing the ion channels in the outer segment (Figure 2). The activated form of the visual pigment (Rh* for rhodopsin) , must be deactivated to ensure that subsequent light can be detected. The rhodopsin deactivation process begins by

multiple phosphorylations catalysed by rhodopsin kinase, followed by the binding of a protein (arrestin) that terminates the activation properties of rhodopsin.

Regeneration of the photopigment Subsequent to the phosphorylation and arrestin binding, the chromophore (all- trans retinal) detaches from the opsin and begins its regeneration via the RPE or Miiller cells'4 (Figures 3 and 4). The find-

Phototransduction cascade Activation of the visual pigment (Rh* in rod photoreceptors or the long- middle- or short-wavelength photopigment for cone photoreceptors), allows for the binding of a series of membrane-associated proteins involved in the visual transduction cascade. The first protein to bind, transducin, is in the Gfamily of proteins, which are often associated with processes linked with signal amplification. The binding and activation of transducin subsequently leads to activation of phosphodiesterase (PDE): the enzyme hydrolysing 3' 5' cyclic guanyl monophosphate (cGMP), the intermediary compound controlling cation ion entry in the photoreceptor outer segment. The hydrolysis of cGMP leads to closure of cation channels with a subsequent photoreceptor hyperpolarisa- tion to a light The production of cGMP is dependent on the enzyme guanylate cyclase, the activity of which is modulated by a calcium-sensitive enzyme, guanylate cyclase activation protein (GCAP: also referred to as recoverin). Guanylate cyclase maintains a steady state level of cGMP with the activity of this enzyme markedly increasing secondary to GCAP activation (subsequent to calcium concentration changes in the photorecep tor outer segment2u-22 (Figure 4).

Rhodopsin gene mutations cause the majority of RP, although gene mutations in different catalytic units of PDE, peripherin and the cyclic nucleotide gated channel proteins are also known to cause RP. Gene mutations alter proteins such as transducin, rhodopsin kinase, arrestin, and proteins forming the voltage gated calcium channel. A few rhodopsin gene mutations cause congenital stationary


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Retinitis pigmentosa Kalloniatis and Fletcher

night blindness; gene mutations in guanylate cyclase may cause cone dystrophy or a form of Lebers congenital amaurosis; whereas a well-defined gene mutation in the RPE (RPE65) causes another form of Lebers congenital amaurosis; the gene encoding the alpha subunit of the cone cGMP gated channel is mutated in rod monochromacy. Other gene mutations may cause syndromes associated with RP that include Laurence-Moon/Bardet- Biedl and Ushers syndrome as well as other RP-like conditions involving metabolic defects such as Refsums disease. Recent reviews on the molecular biology of RP and other inherited retinal dystrophies are provided by several arti- cless.2328 and Daiger and co-worker? maintain an up-to-date website at the address http://www.sph.uth.tmc.edu/Retnet/, which outlines genes causing inherited retinal dystrophies. In addition, clinical trial information can he obtained from the National Institutes of Health (USA) address http://clinicaltrials.gov/ct/gui.

RP INHERITANCE PAITERNS AND CLINICAL CHARACTERISTICS

RP inheritance patterns The advent of molecular techniques has lead to the identification of a number of genes that are thought to he causally linked to the onset of RP. This suggests that there is a number of possible genetic origins, all of which result in the same degenerative process. As a general rule, retinal conditions that demonstrate a bilateral involvement, loss of peripheral vision, predominantly rod dysfunction (elevated rod threshold shown by electo- physiological methods or psychophysi- cally) and progression of photoreceptor dysfunction are classified as RP. Clini- cal presentation may he varied hut include symptoms of night blindness (nyctalopia) with elevated dark adaptation thresholds (predominantly rod hut also cone thresholds), abnormal electroretinographic a- and h-wave, difficulty with mobility secondary to visual field constriction, acquired blue-yellow (tritan) colour vision defect, abnormal retinal pigmentation,

Figure 2. Simplified photoreceptor outer segment under dark and light adaptation. The non- specific cationic channel is maintained in the open state by cGMP, allowing sodium, calcium and magnesium (not shown) ions to enter the outer segment. Light leads to activation of rhodopsin (R), tranducin (T) and phosphodiesterase (the different subunits are shown with the alpha and beta identified), causing hydrolysis of cCMP to GMP, closing the cationic channels and driving the photoreceptor away for the equilibrium potential of these ions (hyperpolarising the photoreceptor).

including mid-peripheral hone spicules, arterial narrowing; optic nerve pallor, pre- disposition to myopia, posterior subcap- sular cataract and vitreous changes.30-3z Visual disturbances occur when visual acuity is relatively unaffected and careful choice of colour vision tests may reveal the acquired tritan colour vision defect early in the disease pro~ess.~~~ M o st of the ocular signs noted earlier are evident in more advanced stages of the condition.

Massof and associate^^^ reported on the existence of two general categories of RP patients dependen t on the relative involvement of rod and cone photoreceptors. Patients with Type 1 RP display an early diffuse and preferential loss of rod sensitivity (hence early nyctalopia) and later progression and regionalised loss of visual field. Patients with Type 2 RP have a regionalised and progressive combined loss of rod and cone sensitivity with late difficulty with night vision, typically in adulthood. The inheritance patterns in RP are classified into autosomal dominant, X-linked, simplex and multiple^.'^^^^^^ Heckenlively, Boughman and Friedmansfi

averaged data from five studies (n = 2,406) and showed that RP could he classified as autosomal recessive in about 31 per cent of cases, autosomal dominant in approximately 16 per cent, X-linked in around nine per cent and simplex/multiplex in approximately 44 per cent. Calculations from the Danish RP register showed that the prevalence and distribwion were not significantly different from those published from around the world, with auto- soma1 recessive (18.8 per cent), autosomal dominant (8.4per cent), X-linked (14.4 per cent), simplex (43 per cent), multiplex (11.2 per cent), with 4.2 per cent being unclassified. The prevalence rate for all forms of RP in Denmark was 1:3,333 to 4,000 for females and 1:2,500 to 2,857 for males. It is likely that the prevalence of the various forms of RP within the Australian and New Zealand populations are similar.

Autosomal dominant classification is primarily based on an established parent- to-child transmission. Autosomal recessive classification is based on established inheritance within different family groups consistent with Mendelian characteristics.


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Figure 3. A schematic of the rhodopsin activation, deactivation and the recycling of the visual pigment. The recycling of the chromophore for cone photoreceptors involving retinoid transport and recycling through Miiller cells (Mata and colleaguees") is not shown. Rhodopsin is an integral membrane protein with an amino terminal (N-) and a carboxyl terminal (C), where the binding of tranducin occurs. Activated rhodopsin (RW) is deactivated via the action of rhodopsin kinase (Rh-kinase) causing multiple phosphorylations (P(n)) and the binding of arrestin leads to separation of the chromophore from the opsin. The chromophore, in the form of all-trans retinal is converted to all-trans-retinol before leaving the retina to be converted to 1 l-cis-retinol and 1 14s-retinal, before reentering the photoreceptor outer segment to bind to the opsin. The retinoids in the RPE also arrive via the complex containing retinoid binding protein (RBP), thransthyretin (Tr) and all-trans retinol (AT-retinol). Retinoids can also be stored in the form of retinyl esters. The scheme of the RPE and rod photoreceptor has the cyclic nucleotide channels identified by cG and the voltage gated calcium channels in the axon terminal by vCa. Other abbreviations: RPE = retinal pigment epithelium, 0s = outer segment, IS = inner segment, N = nucleus, AT = axon terminal

X-linked is also based on established family inheritance based on Mendelian characteristics. Simplex reflects isolated cases with one affected member and multiplex where at least two family members are affected. Often, simplex and multiplex cases were thought to reflect autosomal recessive inheritance patterns, however, when simplex and multiplex cases are taken together, there are too many simplex cases compared with predictions by Mendelian genetic^.^^^^^^'^^* FishmanSg

reported 60 per cent with a known Men- delian inheritance pattern, whereas in a recent Danish study,' 40 per cent of the patients were characterised by a known inheritance pattern. Considering that it is estimated that one in 50 carries a gene for the recessive form of RP,40 a key consideration in this classification is the exclusion of consanguinity. Consanguinity would significantly increase the odds of carrying the same mutated gene.'

A new evolving concept in the inherit-

ance of many conditions, including some forms of RP or syndromes associated with RP (Usher type 1; RDS/ROMl; Bardet- Biedl), is referred to as ~ l i g o g e n i c . ~ ~ Poly- genic traits are disorders that occur through poorly understood interactions between many genes and the environ- ment. Such an environmental interaction could explain the higher correlation between perinatal stress and some simplex forms of RF' reported by Stone and col- l e a g u e ~ . ~ * , ~ ~ The authors suggest the existence of a non-hereditary explanation for photoreceptor death (such as perinatal stress), for some simplex RP. This suggestion awaits further experimental evidence and the exclusion of polygenic and oligogenic inheritance. Oligogenic traits are primarily genetic in nature but require synergistic action of mutant alleles at a small number of loci to exhibit the phe- n ~ t y p e . ~ ' For example, if heterozygous mutations in either the RDS gene or the ROMl gene were present, individuals were asymptomatic, whereas if gene mutations were evident in both the RDS and ROMl gene, patients would exhibit the RP phenotype despite the fact that the mutations were in two distinct genes.49 In addition, it may be possible to modify the expression of an autosomal dominant gene by the effect of a mutation in a second or third gene.41

In the classical analysis of inheritance patterns in RP, when considering the high number of simplex and multiplex cases, variously the typical RP phenotype does not follow classical Mendelian inheritance patterns, the expressivity or penetrance is altered,',35 or other non-genetic mechanisms are in p l a ~ e . ~ ~ * ~ ' For example, we now know that human subjects with specific gene mutations such as that affecting a photoreceptor structural protein peripherin (peripherin/RDS gene mutation), display marked variations in the age of onset and progression of the disease and exhibit oligogenic inheritance patterns, offering one explanation for the high prevalence of simplex and multiplex cases in RP.23*43*44 Wang and associates45 outlined the following clinical implications of gene mutations. Different gene mutations of the same gene result in different clinical pres-


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entations, (for example, different mutations in the rhodopsin gene give rise to different clinical presentations: allelic heterogeneity); mutations in different genes lead to the same disease phenotype, (for example, mutations in peripherin/RDS and rhodopsin gene both lead to typical RP: non-allelic heterogeneity); mutations in different genes at different loci lead to the same phenotype (for example, in Ush- er's syndrome: locus heterogeneity); the expression is different for the same genetic defect (expressivity) ; the defective gene is not expressing leading to variations in visual function (penetrance).45 The evolution of our understanding of polygenic and ohgogenic disorders and further work on potential environmental factors will allow us to better understand the high number of simplex/multiplex cases of RP.

The examination of family members is essential to assist in the identification of the hereditary nature of the condition. In particular, patients with possible X-linked recessive RP require careful assessment of the mother. Dr Mary Lyon proposed that in every somatic cell of a female, only one X-chromosome is functioning, that is, one X-chromosome in every cell is randomly inactivated during development. The Lyon hypothesis predicts that every female carrier of X-linked RP will have two cell populations: one with normal activity and one with mutant a~tivity.~"~' Thus, in X- linked RP, female carriers should display signs and symptoms of RP; a common finding, although there is considerable vari- a b i l i t ~ . ~ " . ~ ~ Female carriers may display a tapetal reflex, irregular pigmentation in the posterior pole, WE atrophy and pigment stippling and may express a phenotype typical of more advanced RP.4R-50

Visual function in Rp Traditionally it has been thought that the progression of visual dysfunction is slow- est in those with autosomal dominant RP, followed by recessive (including simplex/ multiplex) RP and the fastest are those that are X-linked.35 The advent of molecular biological techniques to classify RP patients has provided useful insights to com- plement studies supporting this clinical

Figure 4. Schematic of the key pathways controlling cGMP concentration. Activated rhodopsin (Rh*) activates transducin (T*), which binds the two gamma inhibitory subunits of phospodiesterase to activate the enzyme (PDE*) and hydrolyse cGMP. Steady state production of cGMP from guanyl tri-phosphate (GTP) is maintained by guanylate cyclase, the activity of which is controlled by the calcium-sensitive guanylate cyclase activation protein (GCAP).

view5' and those that found no significant difference in progression between the different genetic subgroups.52 In a major study of 172 typical RP patients followed from 2.5 to 10 years, Massof and col- l e a g u e ~ " ~ reported some key features of visual field changes measured with Goldmann perimetry. Two key parameters will be reviewed here: the time constant (tc) , reflecting the time taken to lose one half of the remaining visual field, and the critical age (Ac: extrapolated age of onset). These parameters reflect photopic visual fields that represent cone loss secondary to rod loss or concurrent rod and cone loss. I t follows that such measurements overestimate the age of onset of sco- topic visual field loss by an unknown amount because we do not know when rod photoreceptor degeneration begins in classical RP.

When using bright small targets [Goldmann II/4e (0.22 degrees)], the time constant was found to be tc = 7.4 f 4.7 years (ISD range of 2.7 to 12.1 years); whereas the use of a bright larger target [Goldmann V/4e (1.72 degrees)] resulted

in a time constant = 8.4 f 4.9 years ( E D range of 3.5 to 13.3 years) ..y5 There was no significant difference in the time constant for visual field progression across the different genetic subtypes, providing support for the proposition that, on average, visual field progression is consistent for RP subtypes that are broadly classified. The time constants and ranges noted above provide useful guidelines for the likely progression of patients with RP. The second parameter investigated by Massof and col- leaguess5 was the critical age value (that is, age of onset ofvisual field loss). For the Goldmann II/4e target, Ac was 22 f 13.8 years ( E D range 8.2 to 35.8 years) and for the Goldmann V/4e target, 28 f 13.9 years (1SD range of 14.1 to 41.9 years).35 Massof and c011eagues~~ report close to significant difference (p = 0.07) for differences in type 1 versus type 2 RF', implying that the age of onset demonstrates some variability. The study of Haim' has a younger mean age of onset (six to18 years of age) but includes atypical RP cases. The data of Massof and colleaguess5 more accurately reflect the patient pool of RP


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patients likely to be encountered in optometric practice.

Berson and associates53 followed 94 patients over three years and found visual field loss (approximately five per cent of field per year), which is half that predicted by Massof and colleague^.^^ The key finding was that a minimum of two years was required to follow visual fields. Visual acuity and dark adaptation ( 1 1 degrees central) remained unchanged over three years and 77 per cent showed significant reduction in the electroretinogram (16 per cent amplitude loss per year). There was no significant difference in loss of electroretinogram amplitude across genetic subtypes, supporting the view that broadly classified RP cases follow a similar time course in changes of visual function.

With the advent of molecular biological genotyping, several studies have focused on visual function measurements in patients with specific gene mutations causing RP. Berson and c o - ~ o r k e r s ~ ~ stud- ied 17 cases with an autosomal dominant form of RP (P23H: proline to histidine sub- stitution at position 23 of the rhodopsin molecule) and found that median onset of night blindness was at 13 to 14 years. As a group, these patients displayed better visual acuity and larger ERG amplitudes compared with 131 subjects with other autosomal dominant rhodopsin gene mutations. However, there was considerable heterogeneity within families. At 37 years, visual fields ranged from greater than120 degrees to less than 21 degrees and Berson and co-~orkers '~ proposed that some patients may have functional vision up to 70 years of age. In another form of rhodopsin autosomal dominant gene mutation (P347L: proline to leucine amino acid sub stitution at location 347), Berson and co- w o r k e r ~ ~ ~ reported considerable he teroge- neity within families with onset of night blindness often at early childhood (n = 8 cases). This group of patients with the P347L gene mutation displayed smaller ERG amplitudes and visual fields compared with 140 unrelated subjects with autosomal dominant rhodopsin gene mutations. Mobility was impaired between 12 and 27 years of age.55 Although the number of subjects in these original stud-

ies was small, the characteristic of gene mutations involving the C-terminus (for example, P347L) of rhodopsin being more severe than that involving the N-terminus (for example, P23H) has held up in a subsequent study encompassing a spectrum of rhodopsin gene mutations at these two terminals.56 The G and N-terminus are il- lustrated in Figure 3. The same amino acid switch (proline to alanine) at two different locations (P23A versus P347A), resulted in a greater loss in all visual functions measured for the Gterminus located gene mutation (P347A).56 Gene mutations at loci encoding the C-terminal may impact function, for example, by slowing the deactivation of activated rhodopsin, whereas gene mutations at loci encoding the N-terminal impact on the delivery of rhodopsin to the outer segment (see be- low for further comments). The use of genetic phenotyping invariably will lead to a better understanding of the RP phenotype including visual function progression characteristics.

The following two case studies illustrate the usefulness of appreciating the inheritance pattern and the use of appropriate visual function testing in routine clinical practice.

years earlier with a 2/1000 white target were reported to be five degrees (R and L) . There was no detectable visual field in the mid-to-far periphery and automated visual fields were conducted to obtain the extent of the remaining visual fields (Figure 5h). The visual fields were largely confined to the central five degrees, although some more peripheral locations were detected. The visual fields have remained stable over a three-year follow up.

Although this is an example of advanced RP, it illustrates several points. This patient displayed the characteristics of Type 2 RP with what appears to be regionalised and progressive combined loss of rod and cone sensitivity with late difficulty with night vision in adulthood. The age of presentation secondary to functional mobility dif- ficulties was within the critical age predic- tion from the results of Massof and colleague^.^^ The fact that a male cousin was affected with a similar condition indi- cates that autosomal recessive may be a mode of inheritance, although the possi- bility of oligogenic inheritance should also be con~idered.~' On further questioning, it was ascertained that the parents of both affected members were related and therefore consanguinity of the parents may be a factor in the inheritance pattern.

CASE I

A 44year-old female with typical RP was diagnosed at age 29 years after seeking an ophthalmic examination because of 'trip- ping over her children's toys'. Nyctalopia was not a problem at the time of diagnosis. A first cousin (male) was also affected but there was no other family history reported (her parents and the parents of her affected cousin had normal vision). Her siblings were examined and were unaffected (Figure 5a). Visual acuity with spec- tacle correction was RE 6/18, LE 6/21 but corneal topography indicated a kerato- conus-like appearance and the patient was referred for a hard contact lens assessment and fitting. Visual acuity of 6/ 15 (R and L) was achieved with her new hard contact lenses and the patient gained a marked improvement in confidence in mobility and a perceptual improvement in contrast levels. Bjerrum visual fields conducted two

CASE 2

A 54year-old male with typical RP had been diagnosed at age 44 years. Nyctalo- pia was first noticed about 10 years before diagnosis. There was no history of consanguinity and the patient had no siblings. The mother may have had abnormal vision (but was deceased), with one sister and one brother being normal. The patient complained of nyctalopia but avoided go- ing out at night. There was a detectable 30 Hz flicker ERG signal indicating cone function and mobility was excellent under photopic conditions. A previous report had noted that after automated perimetry, 'the patient has only 10 to 15 degrees of central vision'. The patient was referred for evaluation of dark adaptation and re- assessment of visual fields using Goldmann perimetry. Visual acuities were 6/6 R and L and dark adaptation thresholds were


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Patient#l A w

Cousin

Figure 5. Pedigree showing the affected members in two families (a). Automated visual field results of Patient 1 showing severe restriction to within the central five degrees (b).

elevated approximately 0.8 log units for the cone component with no detectable rod function (that is, the rod dark adaptation thresholds were elevated by about four log units and the dark adaptation curve was monophasic). Goldmann W/4e (Figure 6 has the right eye results) showed an annular loss located only around the region of maximal rod density. Visual fields were normal under photopic conditions outside this range for both eyes.

This patient also fits into the Type 2 RP with a critical age still within one standard deviation of the upper limit predictions5 of 42 years. With the mother potentially affected, the possible modes of inheritance include X-linked or autosomal dominant. Because the patient has no siblings and did not intend to procreate, genetic counselling was not required. The extent of the visual field should be evident from observing the mobility of the patient, with Goldmann perimetry providing quantita- tive data on the extensive remaining (photopic) visual field in this typical RP patient.

Figure 6. Visual fields of Patient 2 using W/4e target on the Goldmann perimeter. The only area of absolute visual field loss under photopic conditions was an annular scotoma centring around the 15-degree meridian.


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HOW DO YOU MANAGE THE PATIENT WITH RETINITIS PIGMENTOSA?

Most patients with RP are likely to present for an eye examination when night vision and/or mobility are affected and therefore the critical age estimate of Massof and col- leagueP is a useful guide. Early adulthood is the most likely presentation time for an optometric examination.

The diagnosis should be confirmed by electrophysiology and genetic counselling should be undertaken, as well as low vision service delivery. Other family members should be examined, particularly the mother of a male RP sufferer who may have an X-linked inheritance pattern.

Goldmann visual field assessment should be used (loss occurs in the mid- to far-periphery) and visual fields should be followed for a minimum of two years to estimate the time constant for visual field loss. An estimate of the visual field progression rate is given by the time constant estimate of tc = 8.4 f 4.9 years when using the V/4e target.

Time of onset of visual field loss can be combined with the time constant to obtain a reasonable predictor of remaining duration of functional photopic vision.

When using broad classifications such as autosomal dominant or X-linked, genetic subtype is not a reasonable predictor of severity and progression.

MECHANISMS OF RETINAL DEGENERATION

The location of the gene mutation leads to different functional deficits Mutations on the rhodopsin gene lead to autosomal dominant forms of retinitis pigmentosa in humans and a canine model, and introducing this human gene in the rat or mouse genome leads to transgenic rodent models of retinitis p i g r n e n t o ~ a ~ ~ . ~ ~ - ~ ~ (for example, P23H rat). Why a rhodopsin gene mutation causes retinal degeneration is unclear. Rhodopsin is an integral membrane protein that com- prises the bulk of the outer segment pro-

teins. The gene mutation may change the tertiary structure of the protein and alter the structural role of rhodopsin.23 Using the P23H rat model of RP, Illing and asso- ciatesM showed that rhodopsin was prone to form high molecular weight oligomeric species in the cytoplasm of transfected cells, accumulating in aggresomes (pericentiolar inclusion bodies). These cellular changes make rhodopsin suscep- tible to degradation by the ubiquitin- dependent proteosome system. In effect, mutated P23H rhodopsin is a potential cytotoxin mimicking neurodegenerative diseases of the central nervous system.

On one hand, gene mutations that en- code structural proteins, such as peripherin (peripherin/RDS) and rod outer segment protein 1 (ROM-1) lead to RP characterised by 'slower' degeneration in rodent models (hence the term retinal degeneration slow or rds mouse) and may account for about five per cent of auto- soma1 dominant RP in human^.^^^^^^ On the other hand, the mutant rhodopsin may have an alteration to protein structure that subsequently modifies the phototransduction role of this protein. Based on the modelling of the a-wave in RP, Birch and associates6* proposed that the reduced maximum response, low gain and slower activation are due to an abnormality within the activation stages of the transduction cascade. They suggest a prolonged lifetime of activated rhodopsin (Rh*) and may reflect a mechanism similar to light-induced retinal damage. Other findings suggesting abnormal photopigment kinetics include reduced rod bwave amplitude and delayed implicit time54 and delayed time course of dark adaptation after large bleach.63 In s u p port of this concept of abnormal activation, in a model of congenital night blindness due to rhodopsin gene mutations, the mutant rhodopsin remained constitutively activated and thus would cause desensiti- sation of photoreceptors.M

Photoreceptor degenerations such as a human form of autosomal recessive retinitis pigmentosa, the rd mouse and Irish Setter dog model are caused by defects in photoreceptor cCMP-phosphodiesterase a ~ t i v i t y ~ - ~ ~ . ~ ~ (Figure 7). In the rd mouse model, a substantial increase in retinal

cGMP appears to precede both photoreceptor and inner retinal In vitro experiments have demonstrated a causal link between increases in cCMP levels and retinal degenerati~n.~~.~.~~~~".~' Incubation of isolated human retina, in the presence of PDE inhibitors or cCMP analogues, leads to degenerative changes that are proportional to the concentration of the drug used and the period of expo- sure. Over an eight-hour period, the presence of high concentrations of PDE inhibitor or cGMP analogue induced vesiculation of rod inner segments, and cone morphological changes. A combina- tion of PDE inhibitor and cGMP analogue in the incubation medium virtually de- stroyed every rod in the specimen over the same incubation p e r i ~ d . ~ ' The use of iodoacetate, a known inhibitor of glycolysis, which also inhibits sulfhydryl- containing enzymes such as PDE, results in elevated cGMP levels (within 35 min- utes) and visible photoreceptor degeneration within a day.72

Despite such studies and the established elevation of cGMP in animal models of RP,67*68 the mechanism by which cCMP leads to photoreceptor degeneration re- mains unresolved. Elevated cyclic nucleotide (cGMP) levels in the outer segment of photoreceptors would place photoreceptors effectively in a state of high activity or 'constant darkness'. The functional significance of 'constant darkness' is that photoreceptors must maintain their dark current at a considerable energy cost.79 It has been established by S te i r~be rg~~ that photoreceptors are in a state of physiological hypoxia in the dark: a hypoxia that does not lead to functional deficits, presumably due to the lowered energy demands during the light cycle.

Anomalies in the delivery or recycling of the chromophore leads to a spectrum of RP conditions including a well characterised form of Leber's congenital amaurosis involving RPE65, an RPE protein associated with ch romophore recy- ling.^.^^ The Royal College of Surgeons (RCS) rat, is an established model for retinal degeneration with the primary defect being a failure of phagocytosis of photoreceptor outer segments by the


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RPE.76R" In both humans and the RCS rat, a mutation in a tyrosine kinase receptor gene (Mertk"'."') has been identified as the genetic defect.

In a chimeric model, where both normal rhodopsin and mutated rhodopsin were present in the same retina, uniform retinal degeneration was evident, although the progression was slower than in the cor- responding transgenic mice.Rg The finding of Huang and associatesHS has important implications for the autosomal dominant form of RP. I t implies that the gene mutation per se does not lead to photoreceptor degeneration but that the mutant product triggers other not yet fully understood events (see discussion earlier), leading to degeneration of photoreceptors that do not have defective rhodopsin. These findings for the rhodopsin gene mutation differ from previous work using chimeras, for the RCS rat rds mouse6' and the rd mouse.a In these three chimeric models (RCS, rd, rds), the retinal degeneration occurs in a patchy manner, implying that the genetic defect is largely confined to the anomalous cells, unlike the rhodopsin gene mutation model of Huang and asso- c i a t e ~ . ~ ~ However, it was not clear whether the chimeric models (RCS, rd, rds) were followed to completion considering the different time courses in the diverse animal models of RE4

From a clinical viewpoint, variations in rod and cone sensitivity profiles suggest that the diversity in photoreceptor degeneration is evident in human forms of the condition. Massof and Finkelsteins4 assessed rod and cone sensitivity and reported the existence of three groups of patients: 1. subjects with only cone mediated re-

sponses throughout their visual field 2. subjects with both rod and cone thresh-

old elevation with the rod/cone threshold differences being similar to those expected in normal subjects

3. subjects with cone mediated central vision, rod and cone mediated mid- peripheral vision and far-peripheral function mediated by rods.R4

When genetic classification was used in three family groups displaying different gene mutations of the peripherin/RDS gene, all displayed similar psychophysical

Anatomy Electroretinogram

1 +a-wave

Figure 7. Anatomical and physiological changes in degenerating (rd/rd and control C57 mouse retina). Nissl stained sections of the trf mouse retina at post-natal age 49 shows an absent photoreceptor layer with a few cone photoreceptors (asterisk). The inner nuclear layer (arrow) is also reduced in size compared to the control adult retina (C57 mouse). The electroretinogram shows a normal appearance for the control (C57) animal with clear a- and bwaves, whereas the degenerating mouse (rd/rd) at the same age had effectively no detectable signal. Scale bar is 50 microns and stimulus intensity was 2.50 log cd.s.m-* (Gibson, Kalloniatis and Vigrys, unpublished data).

and electrophysiological characteristics with rod and cone threshold elevations for the different gene mutations.44 Although there was variability in the degree of visual dysfunction within each group, the peripherin/RDS gene mutations appear to fall within category two of Massof and Finkel~tein.~~

Despite differences in the underlying genetics causing the RP phenotype and other proposed environmental mecha- n i s m ~ , ~ ~ * ~ ' the established pathway of cell death is through apoptosis, a form of programmed cell death.7R.R5 Although the mechanism(s) leading to apoptosis in RP is not fully understood, an area of interest has been retinal metabolism.

Retinal metabolism The major glial cell in the retina is the Miiller cell, which spans the entire length of the retina and is intricately related to

retinal function and development.86.RR Normal retinal function is dependent on tight metabolic coupling between neurons and glia and the provision of oxygen and g l u c ~ s e . ~ ~ ~ ~ Glucose is the major substrate for retinal and brain metabolism but in mammalian retina, the major product of glucose utilisation is lactate, even under aerobic ~ o n d i t i o n s . ~ ' ~ ~ ~ The dense mito- chondria] packing within photoreceptor inner segments accounts for the high rate of metabolism of the retina,92.94 with both glycolytic and aerobic pathways used by photore~eptors.9~ Photoreceptor cells have a high energy demand because of: 1. the maintenance of an ionic gradient

via the Na/KATPase pump (maintains the dark current)

2. the large turnover of cyclic nucleotides in the outer segment including hydrolysis of guanyl tri-phosphate to form cCMP

3. multiple phosphorylations of photo-


73


pigment (an essential step in deactivation of opsins) .

One role of glial cells appears to involve initial glucose catabolism with the carbon skeleton provided to neurons predominantly in the form of lactate (with the last step pyruvate to lactate catalysed by the enzyme lactate dehydrogenase [LDHlYo). Consequently, the major enzymes of glycolysis and glycogen synthesis a r e localised in Miiller cells and studies have demonstrated Miiller cell metabolism of glucose in mammalian retina,w,gfi Lactate is an essential metabolic substrate of retinal metabolism involving the trafficking of the carbon skeleton of glucose between glial cells and neurons, the 'lactate trafficking hypothesis' of Tsacopoulos and Magi~tretti.9~ The hypothesis centres on the contention that glial cells in the retina and brain metabolise glucose and provide the carbon skeleton (lactate) to neurons for conversion to pyruvate, which fuels aerobic metabolism. In the retina, Poitry- Yamate, Poitry and Tsacopoulossg have demonstrated tracking of lactate from neurons to glia. Disruption of this shuttle using a range of lactate transport inhibitors severely impairs retinal functiongs however, the fact that photoreceptors can use both glycolytic and aerobic metabolic pathwdysy5 suggests that lactate trafficking reflects only part of the metabolic pathways available to retinal neurons.

A stable source of metabolic substrate is required to maintain a high metabolic activity of the retina.w.y2.95,9H One example of high energy demand is the requirement to maintain the cyclic nucleotide gated channel in the open state in the dark. The high metabolic demand is due to the high activity of the sodium/potassium ATPase in the inner segment.73 In theory, the continuously high metabolic demand in cases of elevated cGMP provides a parsimoni- ous explanation for a mechanism induc- ing photoreceptor degeneration. In contrast, retinal degeneration caused by light damage, or that due to continuously activated rhodopsin, would have a different underlying cause because the cyclic nucleotide channel would not be makinga high contribution to energy demand.

The interconversion of pyruvate/lactate

is catalysed by LDH, which comes in various isoenzymes. Graymoreg9 first reported the metabolic alteration in LDH isoenzyme distribution in the RCS rat compared to control rat retina. He showed a dramatic alteration in the distribution of LDH isoenzymes with a marked reduction of one of the LDH isoenzymes (LDH5) at P7, an age when photoreceptors have not differentiated in the rat retina and well before anatomical alterations are evident in the RCS rat.7g*'w~Lo' The RCS rat also displayed little change in total LDH activity before degenerationIo2 but the LDH isoenzyme distribution was altered early (at P7), before photoreceptor degenera- t i ~ n . ~ ~ However, Bonavita, Ponte and AmoreIo2 demonstrated a major loss of LDH activity after degeneration in the RCS rat retina indicating that LDH activity is a sensitive indicator of photoreceptor retinal function. In addition, the RCS rat shows altered glucose utilisation and transport 9s*105-105 and neurochemical studies have demonstrated alterations before, during and after the degenera t i~n . '~ . '~ ' Miiller cells display abnormal metabolism of glutamate and altered neurochemistry before degeneration that continue during the degenerative phase involving the amino acids glutamate, GABA, aspartate, glutamine and arginine. The latter change involves neurochemical changes during/ after degeneration, involving the amino acids glycine and taurine, as well as u p take of glutamate, GABA and g ly~ ine .~~ , " '~ More recently, Kalloniatis and associates Io6 showed that cation channels are constitutively open in many photoreceptors des- tined to degenerate, before apoptotic markers are evident. Open cation channels would place photoreceptors in a state of constant depolarisation increasing the energy demand'* or may initiate apoptotic mechanisms.

In the rd mouse model, metabolic anomalies have also been demonstrated before degeneration. NoellIo7 showed an increase in oxygen uptake, glucose utilisation and lactic acid production (aerobic) detectable at P8 in the rd mouse retina, followed by a rapid decrease from P12. Metabolic substrate concentrations and high energy phosphate compounds do not

show major differences between normal and rd mice,108,Lo9 especially at P15 to P20. The changes in oxygen consumption, glucose utilisation and lactic acid produc- tionlo7 identify an early metabolic dysfunction in the rd mouse, well before photoreceptor cells die through apoptosis at around P10 in the rd mouse."n The chief conclusion that can be drawn from such work is that in two disparate models of retinal degeneration, the RCS rat (caused by a mutation of the tyrosine kinase gene (MERTK8i*82) and the rd mouse (caused by a mutation of the PDE genem), both display metabolic anomalies before photoreceptor degeneration.

Adult onset retinal degeneration mimicking RP There are forms of adult onset photoreceptor degeneration mimicking RP associated with malignancies, including melanoma associated retinopathy (MAR) a n d cancer associated retinopathy (CAR).1"-114 In these conditions, individuals suffering from small-cell carcinoma of the lung/breast or melanomas produce antibodies as part of the body's response to cancer. These antibodies are produced against epitopes on the cancer cells that also recognise a range of proteins in the retina.'"."2."5 Circulating serum antibodies must enter the retina, presumably through breaks in the blood retinal bar- rier and consequently destroy retinal neurons leading to RP-like signs and symptoms in these individuals. '"J"J~~ Although proposed, an immunological aetiology in typical RP has not been supported by experimental data.llfi Heckenlively and co- workerstJ7 found eight instances of serum anti-recoverin immunoglobulins in a sam- ple of 521 typical RP cases, implying that an immunological aetiology is not a likely mechanism in most cases of RP.

TREATMENT OPTIONS: WHAT DO YOU TEU YOUR PATIENT WITH INHERITED RETINAL DYSTROPHY?

In certain inherited forms of retinal dystrophy, where biochemical pathway anomalies lead to the degeneration, diet control of foods containing ornithine or


74


increasing residual enzyme activity with vitamin B6 has been beneficial in gyrate atrophy or a diet to decrease phytanic acid aids in Refsum disease.116."" The methods undertaken to modify the progression of retinal degeneration in RP include medical intervention, for example, vitamin A, cardizem (diltiazem); activation of inher- ent protection systems, for example, growth factors may reduce apoptosis; replacement of mutated gene; replacement of affected cells, for example, RPE/neural retinal transplants; and retinal prosthesis (Sharma and Ehinger116 and Lund and co- workers'lg provide comprehensive recent reviews).

Modifying retinal degeneration in animal models of RP Photoreceptor degeneration in rodent models can be affected through a variety of measures, including modified oxygen levels,'20-'22 retinal pigment epithelial transplant,IZ2 creating chimera^,'^ growth factors or apoptosis inhibitors123,124 or different light levels.'25 Frasson and associates reported an exciting development in the treatment of RP using a calcium channel blocker (D-cis-diltiazem) in the rd mouse retina (PDE gene mutation). They reported that an L-type calcium channel blocker slowed the progression of retinal degeneration in the rd mouse. L-type calcium channels are present on photo- r e c e p t o r ~ , ~ ~ ~ although the physiology of these channels in cones does not reflect responses elicited by classic L-type calcium channels.IZ8 The fact that D-cis-diltiazem modulated cone calcium channels is important because it means that pharmacological manipulation may be a viable treatment option (see Hart and colleagues12* for discussion) but the exact mechanism of action of calcium channel blockers is unclear.12'i~lm Frasson and associates proposed that elevated cGMP levels lead to photoreceptor depolarisation, with calcium channel blockers preventing further depolarisation via calcium entry into the cell. Several other studies have not found a beneficial effect of D-cis-diltiazem in the rd mouse,"" in the P23H rat model"' or the PDE6B mutant rcdl canine model.1s2 There are several explanations for these

negative findings, which include differences in experimental conditions, dosing regime and animal strain.12"

Although at the experimental stage with many problems to overcome, gene therapy has led to some exciting results in animal models. The benefits of gene therapy have been hindered by problems including tar- geting the gene to the right cells, getting the new gene integrated into the genome and expressed, controlling the new gene and suppressing expression of deleterious genes in autosomal dominant RI?'33 In autosomal recessive RP, introduction of a healthy gene into dividing cells (in both the rd mouse and rds mouse models) led to modified photoreceptor degeneration, although the technique was restricted to in utero use.134,135 In a large animal model of retinal degeneration, a canine with a form of Leber's congenital amaurosis (RPE65 gene mutation), Acland and co-

successfully applied gene therapy in congenital amaurosis. They reported ERG and other parameters consistent with improved visual function over 100 days post-treatment, providing the first strong evidence of gene therapy for a condition causing a devastating early loss of vision.'% This model also requires perinatal intervention.

Growth factors or apoptosis inhibitors, for example, bFGF, are involved in nerve cell differentiation and growth and have proved useful in animal models such as the rd mouse and rds mouse.'" Growth factors may work by reducing apoptosis but other apoptosis retarding methods are in experimental phases. They require re- peated intra-vitreal injections and growth factors may have other undesirable ac- tions."' Even when rod death is delayed by survival factors, photoreceptors still experience deconstruction of their phenotypes and fail to function.

Attempts have been made to transplant both RPE and neural retina but there is little evidence that this can be made viable, as the transplants must precede rod death."9,13R Surgery is still a challenge with cell survival and the formation of mean- ingful contacts for the transplanted neural retina in doubt. More importantly, for both retinal transplants, the degenerating

retina shows modified neuronal and glial s t r u c t ~ r e , ' ~ ~ J ~ ~ implying that new, rogue circuits are being formed. In retinal remodelling secondary to rod-cone retinal degeneration, there is neurite remodelling, followed by global remodelling (see animation at the following address: http:/ /prometheus.med.utah.edu/-marclab/ PER-full-remodeling.htm1). One exciting outcome of this research139 is that the neural retina is 'plastic' secondary to degeneration. If the mechanism(s) for this plasticity were understood, it would provide a means to control the formation of retinal circuitry secondary to retinal transplant.

TREATMENT OPTIONS AVAILABLE TO HUMAN SUFFERERS OF RP

Treatments that do not work include: 1. the British therapy, where patients

undertook bee stings on the nape of the neck

2. the Cuban therapy, which included electric shock therapy, ozonation of the blood, surgical implant of retrobulbar fat, vasodilators and multivitamins

3. the Russian therapy, involving intra- muscular and periorbital injection of extracted RNA from y e a ~ t . ~ ~ . ' ~ ~

Treatment options with untested prom- ise include the use of sunglasses and hyperbaric oxygen. Although sunglasses, particularly those with short-wavelength filters, are useful to minimise discomfort glare, there is conflicting evidence that they modify progression rate in human sufferers of RP.28,30 Hyperbaric oxygen levels, although modifying the ERG during the treatment period, may not alter the natural course of the disease.I4' In addition, high oxygen levels have been shown to be detrimental in more advanced stages of the disease.28

Two types of retinal implants have been proposed, epiretinal and subretinal. Direct retinal stimulation using epiretinal implants in RP patients'43 resulted in patients seeing spots of light that were usually coloured (yellow/blue/yellow-green) . Humayun and de Juan143 proposed that the resolution was up to about 1.8 degrees. This group'44 also reported that a patient could detect spots of light and possibly the


75

Retinitis pigmentosa Kalloniatis and Fktcher

direction of movement using a 16-electrode array. In a study that included both RP patients and a normal volunteer, a resolution limit of 2.25 degrees to 4.50 degrees was achieved with an electrode array in contact with the retina.'45z'46 Often the patients did not report percepts that matched the stimulation pattern and fre- quently described multiple percepts when one electrode was driven. The differing results obtained from the normal-sighted volunteer indicate that retinal degeneration alone does not explain the limited results in blind p a t i e n t ~ , I ~ ~ . I ~ ~ providing functional evidence supporting the retinal remodeling concerns of Marc and co- w o r k e r ~ . ' " ~ ~ ~ ~ Subretinal electrodes have been attempted in animal rn~dels,~~' . '*~ with results indicating that cortical activity can be induced by subcortical electrode stimulation. The long-term effect of such implants has not been assessed nor the effect of electrodes placed between the neural retina and the retinal pigment epithelium on retinal metabolic function. In addition, unlike the ear, there is considerable encoding of visual information before it is trans- mitted via ganglion cells and such sensory encoding would be required by any pros- thetic device. Technological development is still required.

A large double-masked treatment trial of vitamin A and/or vitamin E by Berson and associates 14g demonstrated a small but significant slowing in the progression of RP secondary to vitamin A (a daily dose of 15,000 IU). The use of 400 IU of vitamin E was detrimental and the authors suggest that the use of vitamin A may prolong useful vision by up to seven years. The lack of data on functional improvement, such as visual field progression, is a weakness of the study and care should be used in ad- vising patients on vitamin A considering the known toxicity of this retinoid.l16 This mode of treatment has been shown to be beneficial in other forms of retinal dystrophy and is currently recommended by the National Institute of Health (USA)'I6 (http://www.nei.nih.gov/news/ clinicalalerts/alert-rp.htm: http:/ / www.nei.nih.gov/news/pressreleases/ rppressrelease.htm). The National Insti- tutes of Health is also currently recruiting

subjects with RP for a further trial on the benefits of vitamin A (ht tp: / / clinicaltrials.gov/ct/gui) .

What do you advise your RP patient regarding current treatment options? The complexity underlying the different RP phenotypes may necessitate expert genetic counselling. Particularly for patients with known autosomal dominant mutations of RP, it may be possible to eliminate the transfer of the mutated gene. The use of pre-implantation genetic diagnosis (PGD) , where the zygome that does not contain the mutated gene is chosen for implantation, ensures that the identified mutation is not transferred. This technique has been applied extensively to inherited conditions such as blood disorders and neurodegenerative diseases, providing an additional 'treatment' option in cases where the mutation is k n ~ w n . ' ~ " J ~ '

Vitamin A at 15,000 IU daily is the recommended dose from the National Eye Institute, National Institutes of Health (USA). This therapeutic option should be undertaken after the patient consults medical and ophthalmic practitioners. The normal recommended daily intake is 2,500 IU, with three medium-sized carrots providing around 6,000 IU, just under one half the dose used in the study of Berson and associate^.'^^ Even though Sibulesky and co-workers152 found that up to 25,000 IU per day was not detrimental to visual function over five- to 12-year follow-up, consideration should be given to the following: vitamin A is contraindicated in incipient, active or recent alcoholism; liver disease, for example, history of hepatitis A or C; in children; during pregnancy (vitamin A is a teratogenic agent); during breast feeding or in malnutrition.

Anti-oxidants such as vitamin E may be detrimental. 149

Other pharmacological agents may be- come available but other potential treatment options are at the laboratory experimental phase.

ACKNOWLEDGEMENTS We thank Riki Gibson for compiling Fig- ure 7 and contribution to the schematics

in Figures 2 and 3. We are also grateful for helpful comments provided by Dr Robert E Marc a n d two anonymous reviewers.

GRANTS AND FINANCIAL SUPPORT Some of the work outlined in this review was conducted with grants from Retina Australia and the National Health and Medical Research Council of Australia. Michael Kalloniatis holds a professorship funded by the Robert G Leitl estate.

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Author's address: Professor Michael Kalloniatis Robert G Leitl Professor of Optometry Department of Optometry and Vision Science The University of Auckland Private Bag 92019 Auckland NEW ZEALAND


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