Age-related macular degeneration (AMD) is a slow, progressive by fdjerue7eeu


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									Continuing Professional Development              .                                                  .
                                           John P Mathews FRCS Ed, Divya Mathews FRCS Ed and Simon P Kelly FRCOphth

       Age-related macular degeneration
       An overview
                                                  ge-related macular degeneration (AMD) is a slow, progressive

      ABDO has awarded this article
           2 CET credits (LV).            A       and painless eye condition. It is the leading cause of
                                                  blindness in Western societies, with up to a third of the
                                                  population over the age of 70 affected to some degree. It
                                          accounts for almost 50% of those registered as blind or partially
                                          sighted in the UK1. This article provides an overview of the clinical
                                          features, pathophysiology and management including an update on
                                          recent treatment developments of AMD.

                                         Age-related maculopathy (ARM) is defined          years. The Beaver Dam Eye Study also
       The College of Optometrists has   by the International Epidemiological Study        reported that 1.7% of people over 65 years
        awarded this article 2 CL CET    Group2 as a disorder of the macular area,         of age had the exudative form of AMD in
       credits. There are 12 MCQs with   apparent after 50 years of age. Early stages      one eye6.
            a pass mark of 60%.          are characterised by discrete whitish-yellow
                                         spots identified as drusen, increased             Risk factors
                                         pigment or hyperpigmentation associated           Gender: In the Beaver Dam Eye Study,
                                         with drusen, sharply demarcated areas of          women 75 years or older had twice the
                                         depigmentation or hypopigmentation of the         incidence of early AMD and seven times the
                                         retinal pigment epithelium and associated         incidence of late AMD as men.
                                         drusen. These changes predispose to the           Ethnicity: Caucasians are more likely to have
                                         development of late stage ARM, referred to        choroidal neovascularisation than other
                                         as age-related macular degeneration (AMD).        ethnic groups7.
                                         AMD is characterised by geographic atrophy,       Genetics: Several studies have reported that
                                         choroidal neovascularisation (CNV),               a family history of AMD was the strongest
                                         pigment epithelial detachment and fibrous         predictor of its presence8-10. Mutations in the
                                         scarring which can occur in later stages.         ABCA4gene, which encodes a retinal rod
                                                                                           protein, can be associated with AMD. The
                                         Epidemiology and aetiology                        significance of these findings remain
                                         Prevalence                                        Socio-economic factors: In the Beaver Dam
                                         Ellwein and co workers3 found that in the         Eye Study, there was no association between
                                         UK, 14.1% of all visits to ophthalmologists       education, income employment status and
                                         by those over 65 were for retinal problems.       early and late AMD11.
                                         Macular degeneration accounted for the            Smoking status: Cigarette smoking has been
                                         biggest single group. In the USA, estimates       postulated to cause AMD by its depression
                                         of the prevalence of AMD in the elderly           of antioxidants and alterations in choroidal
                                         population range from four million to 20          blood flow and RPE detoxification pathways.
                                         million people.                                   In the Rotterdam Study, amongst individuals
                                             The prevalence of AMD increases with          younger than 85 years, current smokers had
                                         age. The 10-year incidence of AMD in the          a 6.6-fold increased risk of neovascular AMD
                                         Beaver Dam Eye Study4,5 (a population-            compared to those who had never smoked.
                                         based study which evaluated 4,926 adults          Former smokers had a 3.2-fold increased risk
                                         over 43 years living in Beaver Dam,               of neovascular AMD compared to non-
                                         Wisconsin) of early ARM was 12.1% and of          smokers in this age group. An increased risk
                                         late ARM, 2.1%. Individuals 75 years of age       of neovascular AMD was found in those who
                                         or older at baseline had a higher 10-year         had smoked the most. The Beaver Dam Eye
                                         incidence of the following characteristics        Study also found that people who had
                                         than people 43 to 54 years of age: larger         smoked more cigarettes were more likely to
                                         sized drusen (125µm-249µm) (26.3% vs.             develop large soft drusen and pigmentary
                                         3.3%); drusen greater than or equal to            abnormalities than people who had smoked
                About the authors        250µm (16.2% vs. 1.0%); soft indistinct           less. In the Blue Mountains Study in
        John Mathews is a Specialist     drusen (22.2% vs. 2.2%); retinal pigment          Australia, current smokers had an increased
         Registrar in Ophthalmology      abnormalities (19.5% vs. 0.8%); exudative         risk of five-year incident late ARM lesions
            based at the Manchester      macular degeneration (4.1% vs. 0%); and           and retinal pigmentary abnormalities12.
                 Royal Eye Hospital.     geographic atrophy (3.1% vs. 0%).                 Environmental factors: Light toxicity – In
            Divya Mathews is a Staff         The prevalence of visual impairment           the Watermen Study amongst 838 watermen
       grade in Ophthalmology, and       from all causes increased among the elderly       who worked on the Chesapeake Bay,
            Simon Kelly a Consultant     and, in particular, the rate of legal blindness   cumulative ocular exposure to blue light, or
       Ophthalmic Surgeon at Royal       increased from 0.1% in people aged 43 to          all wavelengths in the visible spectrum,
          Bolton Hospital NHS Trust.     54 years, to 2% in people aged 75 to 84           within the 20 years before examination was

   28 | February 21 | 2003 OT
                                                                                    Continuing Professional Development

associated with increased prevalence of late     membrane and the presence of                    increases to approximately 30% within
AMD13. Other studies did not find                multinucleated cells are thought to play a      five years. If both large drusen and RPE
an association between increased                 role in the pathogenesis of choroidal           clumping are present, the risk to the
ultraviolet exposure and development of          neovascular membrane (CNVM), creating           fellow eye increases to nearly 60%.
AMD.                                             points of minimal or absent resistance in
Ocular factors: Hyperopia has been               Bruch’s membrane through which new              Signs and symptoms
suggested as a risk factor for AMD in several    vessels can preferentially pass.                Macular degeneration rarely results in
studies, including the Eye Disease Case-            The stimulus for CNVM formation              complete blindness. Peripheral vision is
Control Study and National Health and            appears to involve angiogenic growth            usually not affected. Patients with early
Nutrition Examination Survey I                   factors involved in the initial response to     AMD may report slightly blurred central
(NHANES I). However, the recent 10-year          the Bruch’s membrane injury20. Vessel           vision, difficulty reading, colour and
report from the Beaver Dam Eye Study did         in-growth may involve metabolic factors         contrast disturbances and mild
not confirm an association of refractive         released from tissues, mechanical factors       metamorphopsia. If geographic atrophy
error with developing AMD.                       acting on the walls of the blood vessels,       develops, they may note a corresponding
    Increased risk of AMD was found in           physical and chemical properties of             central scotoma, which can progress.
people reported as having light colour irides    extracellular matrix, pericyte-endothelial      Patients with exudative AMD experience
in youth, and in those people having dark        interactions and various peptide-signalling     painless, progressive blurring of central
colour irides in youth which changed to          molecules, such as fibroblast growth            vision. Symptoms may be either acute or
light colour in adulthood14. The increased       factor, vascular endothelial growth             insidious in onset.
risk is thought to be related to lower levels    factor and transforming growth factor               Patients who develop sub-retinal
of protective melanin in the eye.                beta. Calcification and fragmentation           haemorrhage from a CNVM, will often
    The Beaver Dam Eye Study and                 observed in the Bruch’s membrane                report an acute onset visual disturbance.
NHANES 1 suggested an association                may represent a breach in this                  They may also complain of relative or
between cataract surgery and AMD15. It is        anti-angiogenic barrier, facilitating CNVM      absolute central scotomas,
possible that the presence of a cataract may     development.                                    metamorphopsia and difficulty with
be protective against the development of                                                         reading.
AMD.                                             Clinical classification                             Patients with non-exudative AMD may
Nutritional factors: Antioxidants, such as       Two main clinical types of AMD exist,           have a combination of drusen and
vitamin C, vitamin E and the macular             referred to as the ‘dry form’ and the ‘wet      geographic atrophy (atrophy of
carotenoids, lutein and zeaxanthin, found in     form’. Blindness is usually associated with     photoreceptors, RPE and
green leafy vegetables, may protect against      the exudative, or wet form of AMD.              choriocapillaries). Those with exudative
macular degeneration by limiting oxidative       Amongst eyes with severe visual loss, 80%       AMD may have subretinal fluid, retinal
damage16,17. In some studies, higher blood       of cases are due to wet AMD, while 20% are      pigment epithelial detachments (PEDs),
levels of beta-carotenes and carotenoids         due to the dry form.                            subretinal lipid or subretinal
were associated with a decreased risk of             The dry, or non-exudative form involves     haemorrhage visible in the affected eye.
macular degeneration. A high lipid intake        atrophic changes in the RPE and in the          These may be in addition to RPE changes
and increased serum cholesterol level, on        photoreceptors accompanied by drusen.           and drusen.
the other hand, are risk factors for             Eighty-five percent of AMD patients have            On fundoscopy, CNVM may be visible
developing AMD18. A recent study from the        dry AMD. The appearance on fundoscopy of        as greyish or pinkish yellow elevated
Netherlands showed that the prevalence rate      dry AMD may include hard drusen, soft           lesions of varying size. Other signs
of AMD in patients with low antioxidant          drusen, RPE geographic atrophy and              associated with leakage of CNVM are
intake and low lutein intake was nearly          pigment clumping. Visual loss may be            serous retinal elevation and sub-retinal
twice as high as that in patients with high      severe in dry AMD, when geographic              fluid or lipid. Occasionally, the subretinal
intake of these nutrients. Further               atrophy of the RPE develops.                    haemorrhage can break through the
specification of intake data into quartiles of       In wet AMD, CNVMs develop under the         retina and cause vitreous haemorrhage.
antioxidant intake and lutein/zeaxanthin         retina. They leak various fluid and blood       Additional signs of CNVM include
intake, showed a clear dose-response             components and ultimately cause a               subretinal pigment proliferation,
relationship19.                                  disciform scar of the retina. Fifteen percent   haemorrhagic PEDs, RPE tears, and
                                                 of patients with AMD have this exudative        subretinal fibrosis.
Pathophysiology                                  form.                                               In advanced cases, an area of
Metabolic debris, which consists of                  The Macular Photocoagulation Study          collection of subretinal fibrosis, known as
incomplete degradation and clearance of          (MPS)21 found that patients, who present        disciform scar is seen. This often appears
phagocytosed rod and cone membranes,             with CNVM in one eye and small drusen in        as yellow or white. However, it may
accumulates in the retinal pigment               the fellow eye, have a 42% risk of CNVM         sometimes be darker in colour.
epithelium (RPE). Progressive engorgement        development in the fellow eye within five       Blood, lipid exudates and localised
of these RPE cells leads to lipofuscin           years. If either large drusen or RPE clumping   detachment of sensory retina may be
formation. Cellular breakdown of Bruch’s         is present, the risk of CNVM development        present.

                                                                                                              29 | February 21 | 2003 OT
Continuing Professional Development         .                                                  .
                                      John P Mathews FRCS Ed, Divya Mathews FRCS Ed and Simon P Kelly FRCOphth

                                       Management                                     Treatment
                                       History and clinical evaluation                Laser photocoagulation
                                       Visual acuity both for distance and near       Despite a growing interest in AMD, the
                                       viewing should be recorded and is              options for treatment remain limited.
                                       usually reduced. The Amsler grid should        Treatment is currently mainly targeted at
                                       be used to test for central scotoma and        the neovascular form of the disease using
                                       metamorphopsia. Evaluation of AMD              laser photocoagulation. The MPS and
                                       patients includes slit lamp                    several other studies demonstrated that
                                       biomicroscopy with the non-contact             laser photocoagulation of CNVM helps
                                       lens and/or fundus contact lens.               prevent a large decrease in visual acuity
                                                                                      compared to no treatment, i.e.
                                       Investigations                                 observation. Patients enrolled for laser
                                       Colour photography and fundus                  photocoagulation had extrafoveal CNVM,
                                       fluorescein angiography: Colour                i.e. those located from 200-2500µm from
                                       fundus photography and rapid sequence          the foveal centre, or juxtafoveal CNVM,
                                       fundus fluorescein angiography (FFA)           i.e. within 1-199µm from the foveal
                                       are the standard investigations. This test     centre, but not under it22. Poorly defined
                                       is indicated in patients with large soft       CNVMs were not included in that study.
                                       drusen or signs of wet AMD with                    In the extrafoveal CNVM group, the
                                       symptomatic visual loss because                proportion of eyes with severe visual loss
                                       of the possibility of CNVM in these            (SVL) (defined as six or more lines of
                                       eyes. Subretinal haemorrhage and               vision on a high contrast test chart) in
                                       lipid will block the choroidal                 control versus the treated eyes was:
                                       fluorescence.                                  • 41% control versus 24%
                                           The MPS described two important                in treated group at one year
                                       patterns of CNVMs on angiography.              • 63% control versus 45%
                                       These are ‘classic’ or ‘occult’ types of           in treated group at three years
                                       CNVM. Classic CNVMs appear as                  • 64% control versus 46%
                                       discrete lesions (lacy pattern) with early         in treated group at five years
                                       hyper-fluorescence and with late leakage
                                       of the fluorescein dye into the overlying      In the juxtafoveal CNVM group,
                                       neurosensory retinal detachment.               similarly, the proportion of eyes which
                                       Occult CNVMs appear as either late             experienced SVL in control eyes versus
                                       leakage of undetermined source or              treated eyes was:
                                       fibrovascular PEDs.                            • 45% control versus 31%
                                           Fibro-vascular PEDs appear on FFA              in treated group at one year
                                       as an irregular elevation of RPE, which        • 58% control versus 49%
                                       is associated with stippled leakage into           in treated group at three years
                                       an overlying neurosensory retinal              • 65% control versus 55%
                                       detachment in the early and late frames            in treated group at five years
                                       of the angiograms. This is as opposed to       Angiography should, ideally, be
                                       serous PEDs, which show more rapid             performed within 72 hours prior to laser
                                       homogenous filling of the lesion in the        photocoagulation, as CNVM morphology
                                       early frames. They have well defined           and resulting treatment parameters can
                                       hyper-fluorescent contours.                    change rapidly. Patients are monitored
                                           Other investigations: Digital              periodically, within the first three months
                                       indocyanine green (ICG) video                  after treatment and then as required. They
                                       angiography has been available in some         are observed closely for CNVM in the
                                       centres for several years and may be           fellow eye. They are instructed to present
                                       useful in the evaluation of patients with      immediately to the relevant healthcare
                                       poorly delineated CNVMs or in the              professional, if any changes in central
                                       presence of haemorrhage. In either             vision occur, particularly if new
                                       primary, i.e. first occurrence, or             metamorphopsia or scotomas on Amsler
                                       recurrent occult CNVM, ICG                     grid testing, are reported.
                                       angiograms in selected cases may allow             The Subfoveal Recurrent CNVM
                                       detection of a more localised area of          Study23 addressed the efficacy of laser
                                       CNVM or feeder vessels and be a further        photocoagulation for extrafoveal or
                                       aid to laser photocoagulation. Unlike          juxtafoveal CNVM which had recurred
                                       fluorescein, the ICG molecule is               through the centre of the fovea. Patients
                                       strongly bound to plasma proteins. This        with classic, well-demarcated CNVM
                                       prevents diffusion of the compound             which had recurred through the centre of
                                       through the fenestrated choroidal              the fovea were treated.
                                       capillaries thereby facilitating the study     1. At three months, the proportion
                                       of the choroidal circulation. It is                experiencing SVL in the control group
                                       therefore useful in studying the                   compared with treated eyes was 9%
                                       choroidal vasculature in patients with             versus 14%.
                                       retinal haemorrhage. CNVM are seen as          2. At two years, the proportion
                                       localised hot spots or as diffuse hyper            experiencing SVL was 28% versus 9%
                                       fluorescent plaques using this                     (control vs. laser-treated eyes,
                                       technique.                                         respectively).

   30 | February 21 | 2003 OT
                                                                                      Continuing Professional Development

Laser-treated eyes in the subfoveal recurrent      ‘classic’ or ‘predominantly classic’ subfoveal   neovasularisation in animal models of
studies also experienced treatment benefit         CNV. It is uncertain whether it is necessary     CNVM28. The outcomes of on-going clinical
with respect to reading speed and contrast         to continue treatment once vision has            investigations of intravitreal injections of
sensitivity.                                       stabilised.                                      the steroid drug triamcinolone are awaited.
    The main limitations of this procedure is          The role of PDT in the UK in the NHS         Thalidomide, which inhibits angiogenesis,
that photocoagulation to the foveal centre         remains limited, at present, by evolving         is also being studied for AMD-related
usually results in immediate loss of vision.       guidelines from the National Institute for       CNVM.
Secondly, only a small proportion of               Clinical Excellence (NICE) – a special
patients with recurrences had classical            Health Authority for England and Wales           Radiation therapy
recurrent CNVM on angiography that was             and a part of the NHS. Its role is to provide    CNVMs are composed of endothelial cells,
eligible for treatment. Furthermore, 50% of        patients, health professionals and the public    which proliferate more rapidly than the
the treated patients developed a further           with authoritative, robust and reliable          endothelial cells of the retina, and may be
recurrent CNVM within two years24. Only            guidance on current ‘best practice’. The         more sensitive to radiotherapy than the
patients with a small, subfoveal CNVM              recent Final Appraisal Determination (FAD)       retinal vasculature. Consequently, radiation
lesion were treated by this technique due to       from NICE recommended that PDT therapy           therapy has been suggested as a treatment
the blinding central scotoma following             should be made available for patients with       for subfoveal CNVMs.
laser.                                             wet macular degeneration who have “classic            The recently published Medical Research
                                                   with no occult” CNV and a best corrected         Council multi-centre study29 looked at
                                                   visual acuity of 6/60 or better. The change      external beam irradiation to subfoveal
Novel treatments                                   from their earlier recommendation, that          CNVM. Treatment was given in six fractions
                                                   only patients with “wholly classic CNV”          to a total dose of 12Gy in 203 patients. The
Photodynamic therapy                               could be treated, will now allow patients        visual outcome among treated patients was
Photodynamic therapy (PDT) is a newer              with classic or predominantly classic CNV        little or no different than amongst controls
treatment modality for AMD. This relies on         to receive treatment. However, they              (observation only) at 12 or 24 months after
photochemical injury to the vessel wall and        recommend that this latter treatment only        treatment. Similarly, several other
selective damage to CNVM. It can be used           be undertaken as part of on-going or new         non-randomised studies have shown no
to treat diseased areas selectively while          clinical studies. Discussions as to the          therapeutic benefits with external beam
potentially sparing the overlying retina. PDT      meanings of some of the terms used are           irradiation treatment.
offers a potential valuable therapeutic            continuing at the time of writing. The most          However, Bergink and co-workers did
benefit for the treatment of CNVM,                 up-to-date information can be found on the       find some benefit from radiotherapy. They
especially subfoveal CNVMs25,26.                   NICE website at                    randomised 74 patients with classic, occult
    Photodynamic compounds are special                 A 15mg vial of verteporfin (sufficient for   or mixed subfoveal CNVM to observation
compounds which react when stimulated              one PDT treatment) costs £850 (British           versus external beam irradiation30. Six
with a specific wavelength of light. An inert      National Formulary 43, September 2002).          non-standard fractions of 4Gy (total 24Gy)
substance, usually a benzoporphyrin                The high cost of the dye and the limited         were used. At one-year follow up, 52.2% of
derivative, is injected into the peripheral        health economic and patient quality of life      the observation group versus 32% of the
bloodstream. After a length of time                outcomes evidence available to date, are         treatment group lost three or more lines of
(minutes or hours), the substance enters all       posing issues for NHS practitioners and          visual acuity (P = 0.08). Six or more lines of
cells of the body, but is then cleared from        purchasers.                                      visual acuity loss was observed in 40.9% of
healthy cells preferentially. The dye remains                                                       the observation group versus 8.8% of the
associated with proliferative cells (such as       Transpupillary thermotherapy                     treatment group (P=0.002).
new blood vessels). A low power laser,             Transpupillary thermotherapy (TTT)
calibrated to a specific wavelength of             involves slowly heating the subfoveal            Surgery
non-thermal red light, then activates the          choroidal neovascular complex with the           Macular translocation surgery is designed
photosensitive drug to form peroxides. The         infrared (810nm) diode laser light to            for patients with potential for central
result is cell death in these tissues. The laser   occlude the CNVM. The infrared wavelength        neurosensory retinal function. The
is said not to be powerful enough to cause         is thought to penetrate the retina and RPE       procedure should be performed before
any damage on its own.                             to maximally affect the CNVM, while              irreversible damage to the fovea has
    Verteporfin (Visudyne®) is one such dye        minimising thermal injury to the outer           occurred. In this technique, the retina is
which can be given intravenously. The              retina. Treatment is performed with a large      shifted away from the underlying subfoveal
maximum absorption is near 689nm. The              single spot, which covers the entire             CNVM. The entire retina is rotated 360˚31.
treatment of wet AMD with photodynamic             complex. This technique may play a role in       This is a complex vitreo-retinal surgical
therapy, known as the TAP Study, found that        occult subfoveal CNVM in addition to             procedure and is not without significant
those patients with predominantly classic          classic CNVM treatment.                          risks for intra-operative and post-operative
CNVMs benefited from PDT treatment in                                                               complications. Another technique,
terms of a reduction in the risk of losing         Pharmacological therapy                          described by de Juan et al32, involves limited
three or more lines of vision27. Over the          A balance between endogenous inhibitors          macular translocation. In this procedure,
course of one to three months, the blood           and stimulators of angiogenesis normally         pars plana vitrectomy is followed by
vessels treated with PDT may open again            controls ocular angiogenesis. Angiogenic         detachment of the temporal retina through
and leakage may recur. Re-treatment may            factors such as vascular endothelial growth      one or more retinotomies. The retina is
thus be required at three-month intervals, if      factor (VEGF), growth hormone (GH) and           reattached after the sclera has been
there is evidence of continued leakage from        insulin-like growth factor (IGF) have been       surgically foreshortened.
the blood vessels. Stability of vision and         detected in CNVM.                                    Direct surgical excision of subfoveal
resolution of leakage may, nevertheless, be           Interferon-alpha is known to inhibit          CNVM has also become possible and is
achieved in many of these affected patients.       vascular endothelial proliferation and           currently being studied in the Submacular
PDT has received approval from the US              migration in the laboratory. However, it has     Surgery Trial in USA. The recently published
Food & Drug Administration (FDA) and               not proved effective in clinical trials in AMD   Swedish study33 on the surgical removal of
European agencies. The working party of the        patients.                                        sub macular CNV found that such surgery
Royal College of Ophthalmologists is of the           Non-steroidal anti-inflammatory               does not appear to improve visual acuity in
opinion that PDT with verteporfin will             agents such as indomethacin, sulindac            patients over 50 years of age.
benefit selected groups of patients with           and steroids have been shown to inhibit              It should be noted that all these surgical

                                                                                                                 31 | February 21 | 2003 OT
Continuing Professional Development                 .                                                  .
                                              John P Mathews FRCS Ed, Divya Mathews FRCS Ed and Simon P Kelly FRCOphth

                                              options are limited. In practice, they          vegetables, foods rich in lutein and
                                              require lengthy and complex surgical            zeaxanthin, and stopping cigarette smoking,
                                              manoeuvres. Surgery to realign the              are both beneficial and sensible lifestyle
                                              extraocular muscles is often required in        choices which can be recommended to
                                              addition to the vitreo-retinal procedure.       patients.
                                              These procedures are less than ideal for the
                                              elderly patients affected by AMD.               Rehabilitation
                                                                                              For the majority of patients, the provision
                                              Diet and micro-nutrients                        of low vision aids (LVAs) and support from
                                              The recently published large Age-Related        visual impairment community workers is
                                              Eye Disease Study (AREDS) looked at             the cornerstone of management.
                                              the value of long-term dietary                  Registration with the local authority, as
                                 Figure 1.1   supplementation on severe AMD                   blind or partially sighted, facilitates access
                                              development34.                                  to these and other services37. Several types of
                                                                                              benefits are available either as of right, or at
                                              The AREDS categories were:                      the discretion of the local authority
                                              • Category 1. No AMD; few or small              concerned.
                                                drusen. It should be noted that most
                                                people over 60 years have some small          Referral guidelines
                                                drusen.                                       The current Royal College of
                                              • Category 2. Mild AMD; several small           Ophthalmologists guidelines38 recommend
                                                drusen or a few medium-sized drusen           that as a mild, low risk disease, AMD
                                                in one or both eyes, or pigment               requires no special management and can be
                                                abnormalities.                                managed in the community. Optometrists
                                              • Category 3. Moderate AMD; many                should carry out routine examinations and
                                                medium-sized drusen (63-125 microns)          refraction. Reassurance and advice about the
                                Figure 1.2      or one large drusen (larger than 125          value of magnification and lighting may be
                                                microns) in one or both eyes.                 helpful. Patients do not necessarily require
                                              • Category 4. Advanced AMD; advanced            referral to the Hospital Eye Service (HES).
                                                AMD, or vision loss due to AMD in one         Referral is indicated from the primary sector
                                                eye only.                                     when there is rapidly developing visual
                                                                                              failure but still reasonable vision suggestive
                                              Participants in the moderate and                of exudative disease, which might benefit
                                              advanced, i.e. Category 3 or 4, AMD             from urgent assessment and laser treatment.
                                              groups had a lower risk of progression to       Cases of significant visual loss needing
                                              advanced AMD and visual acuity loss in          accurate diagnosis, LVA assessment and/or
                                              the good eye if they took both                  needing partially sighted or blind
                                              antioxidants (vitamin C 500mg, vitamin E        registration should also be referred to the
                                              400IU and beta carotene 15mg) and zinc          HES for certification purposes and social
                                              (80mg as zinc oxide and copper, 2mg as          needs assessment. Practitioners need to
                                              cupric oxide) compared with a placebo for       remember that AMD can often be
                                Figure 2.1    seven years. There is no evidence at present    concurrent with other diseases, such as
                                              that people with early signs of AMD,            cataract and glaucoma, which need to be
                                              i.e. Category 1 or 2 groups, should take        identified and treated appropriately.
                                                  The recent Australian study found no
                                              protective or deleterious effect of the daily   Case examples
                                              dietary supplementation of 500IU of
                                              vitamin E alone on incidence or                 Patient 1
                                              progression of AMD.                             Subfoveal CNVM, classical type
                                                  The recent AREDS results suggest that       A 79-year old female patient presented with
                                              supplementation is beneficial to those          a three to four-month history of reduced
                                              patients with Category 3 or 4 AMD. Note,        vision and distortion in the left eye
                                              however, that copper supplementation is         (VA 6/18).
                                              needed to prevent the copper deficiency
                                Figure 2.2    anaemia otherwise caused by this high           Figure 1.1 – Fundus photograph of the left
                                              intake of zinc. Secondly, it should be          eye showing well defined grey lesion at the
                                              noted that in other studies, beta-carotene      fovea.
                                              has been linked to an increased risk of
                                              lung cancer in smokers35.                       Figure 1.2 – Mid-phase of the angiogram of
                                                  The AREDS findings are drawn from a         the left eye shows predominantly classical
                                              relatively well-nourished American              CNVM.
                                              population. To apply these findings more
                                              generally, these results need to be             Six months later, and after two PDT
                                              replicated by other large, well-conducted       treatments, vision in the left eye is 1/18.
                                              randomised controlled trials in other
                                              populations36. Studies in the future            Patient 2
                                              will need to investigate the use of lutein      Occult subfoveal CNVM
                                              or zeaxanthin as an alternative to              An 82-year old lady was referred with a
                                              beta-carotene.                                  six-week history of blurred vision and
                                Figure 3.1        Increasing dietary intake of fruits and     distortion in the left eye (VA 6/18).

   32 | February 21 | 2003 OT
                                                                                     Continuing Professional Development

Figure 2.1 – Fundus photograph of the left
eye showing irregular elevation of RPE and
hemorrhage at the fovea.

Figure 2.2 – Late phase angiogram of the
left eye showing a stippled pattern of
leakage and staining at the fovea. This type
of CNVM is not amenable to current

This patient has been advised Amsler grid
monitoring of the right eye. VA in the right
eye was 6/6 and in the left eye, 6/36 on her                                      Figure 3.2                             Figure 3.3
last review.

Patient 3
Classical juxtafoveal CNVM
A 74-year old male with a six-month history
of decreased vision and a black shadow in
front of the right eye. Vision in the right eye
was 6/36.

Figure 3.1 – Fundus photograph of the
right eye showing round grey lesion
surrounded by subretinal fluid inferonasal
to the fovea (juxtafoveal).

Figure 3.2 – Early phase angiogram of the
right eye, demonstrates early and distinct,                                        Figure 4.1                            Figure 4.2
well defined hyperfluorescence.
   This patient underwent argon laser

Figure 3.3 – Fundus photograph of the
right eye following laser treatment.

Patient 4
Classical juxtafoveal CNVM with
An 80-year old male with a three-month
history of reduced central vision and
distortion of the right eye. AMD had been
diagnosed in the left eye four years
previously. Vision in the right eye was 6/18                                       Figure 4.3                            Figure 4.4
and in the left eye, 1/60.
    This patient underwent argon laser
treatment to the right eye, following which       Figure 4.3 – Fundus photograph of the
the vision improved to 6/12. Three months         right eye showing a grey lesion (recurrence
later, he noticed a sudden deterioration in       of SRNVM) with laser scars from previous
vision. Vision was 6/60.                          treatment superior to it.
    He has since been referred for
photodynamic therapy.                             Figure 4.4 – Late phase angiogram of the
                                                  right eye showing laser scar with recurrence
Figure 4.1 – Fundus photograph of the             of SRNVM inferior to the scar.
right eye shows a greyish area in juxtafoveal
location.                                         Figure 4.5 – Fundus photograph of the left
                                                  eye showing a large area of subretinal
Figure 4.2 – Mid phase angiogram of the           fibrosis inferonasal to the fovea
right eye, showing leakage of the membrane.       disciform scarring).                                                   Figure 4.5

                                                                                                       33 | February 21 | 2003 OT
Continuing Professional Development                    .                                                  .
                                                 John P Mathews FRCS Ed, Divya Mathews FRCS Ed and Simon P Kelly FRCOphth

                                                                                                 The authors would like to thank the
                                                                                                 Medical Illustration Department, Bolton
                                                                                                 Hospitals NHS Trust, for the fundus
                                                                                                 photographs reproduced. They would also
                                                                                                 like to thank Ms C. Lim FRCOphth,
                                                                                                 Consultant Ophthalmic Surgeon, Queens
                                                                                                 Medical Centre, Nottingham University
                                                                                                 Hospital NHS Trust, and Mr P. Bishop PhD,
                                                                                                 FRCS, FRCOphth, Consultant
                                                                                                 Ophthalmologist, Manchester Royal Eye
                                                                                                 Hospital, for kindly reviewing the
                                   Figure 5.1                                       Figure 5.2   manuscript.


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                                                                                                     partial sight in England and Wales
                                                                                                     1990-1991 (Studies on Medical and
                                                                                                     Population Subjects No. 57). HMSO,
                                                                                                 2. The International ARM epidemiological
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                                                                                                     PP (1996) Use of eyecare services
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                                                                                                     (1992) Prevalence of age-related
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                                  Figure 6.3                                       Figure 6.4    6. Klein R et al (1995) The relationship of
                                                                                                     age related maculopathy, cataract and
                                                                                                     glaucoma to visual acuity. Invest.
  Patient 5                                      of decreased vision in both eyes for the past       Ophthalmol. Vis. Sci. 36: 182-191.
  Severe dry AMD (soft drusen)                   six months. Vision in the right eye was 6/12    7. Jampol LM and Tielsch J (1992) Race,
  A 66-year old male patient was noticed to      and in the left eye, 6/18.                          macular degeneration and the Macular
  have age-related changes in his right eye                                                          Photocoagulation Study.
  while he was being reviewed for pigment        Figure 6.1 – Fundus photograph of the               Arch. Ophthalmol. 110: 1699-1700.
  epithelial detachment in the left eye, which   right eye showing mixed drusen (soft and        8. Hyman LG et al (1983) Senile Macular
  progressed to a disciform scar. He was         hard drusen) at the macula.                         Degeneration: a case control study.
  asymptomatic in his right eye. Vision in the                                                       Am. J. Epidemiol. 118: 213-227.
  right eye was 6/9 and in the left eye,         Figure 6.2 – Fundus photograph of the left      9. Silvestri G, Johnston PB and Hughes AE
  counting fingers.                              eye showing confluent drusen at the                 (1994) Is genetic predisposition an
     This patient was a chronic smoker and       macula.                                             important risk factor in age-related
  was given dietary advice and advised to stop                                                       macular degeneration? Eye 8: 564-568.
  smoking. He was discharged with Amsler         Three years later, retinal examination          10. Klaver CCW et al (1997) Familial
  grid monitoring.                               showed disciform scarring with subfoveal            aggregation of age related macular
                                                 involvement in each eye. Vision in the right        degeneration in the Rotterdam Study.
  Figure 5.1 – Fundus photograph of the          eye was 2/60 and in the left eye, 2/36. She         Invest. Ophthalmol. Vis. Sci. 38: S967.
  right eye showing extensive soft drusen at     was registered blind.                           11. Klein R et al (1994) The relation of
  the macula.                                                                                        socio-economic factors to age-related
                                                 Figure 6.3 – Fundus photograph of                   cataract, maculopathy and impaired
  Figure 5.2 – Mid phase angiogram of the        the right eye showing a large area of               vision: The Beaver Dam Eye Study.
  right eye showing staining of the drusen. No   subretinal fibrosis at the fovea                    Ophthalmology 11: 1969-1979.
  leakage was seen.                              (disciform scarring).                           12. Mitchell P, Wang JJ, Smith W, Leeder SR
                                                                                                     (2002) Smoking and the 5-year
  Patient 6                                      Figure 6.4 – Fundus photograph of                   incidence of age-related maculopathy.
  Mixed and confluent drusen                     the left eye showing a large area of                The Blue Mountains Eye Study.
  leading to disciform lesion                    fibrosis involving fovea (disciform                 Arch. Ophthalmol. 120: 1357-1363.
  A 77-year old female patient with symptoms     scarring).                                      13. Taylor HR et al (1992) The long term

    36 | February 21 | 2003 OT
                                                                                     Continuing Professional Development

    effects of visible light on the eye.          randomized clinical trials.                     approach for age related macular
    Arch. Ophthalmol. 110: 99-104.                Arch. Ophthalmol. 109: 1220-1231.               degeneration. Graefes Arch. Clin. Exp.
14. Cruickshanks KJ, Klein R and Klein        23. Macular Photocoagulation Study                  Ophthalmol. 231: 635-641.
    BE (1993) Sunlight and age-related            Group (1993) Laser photocoagulation         32. De Juan E et al (1998) Translocation
    macular degeneration. The Beaver              of subfoveal neovascular lesions of             of the retina for management of
    Dam Eye Study. Arch. Ophthalmol. 111          age related macular degeneration.               subfoveal choroidal neovasularization
    (4): 514-8.                                   Updated findings from two clinical              11: A preliminary report in humans.
15. de Juan E Jr, Loewenstein A, Bressler         trials. Arch. Ophthalmol. 111 (9):              Am. J. Ophthalmol. 125: 635-646.
    NM et al (1998) Translocation of the          1200-9.                                     33. Berglin et al (2001) The Swedish
    retina for management of subfoveal        24. Macular Photocoagulation Study                  national survey of surgical
    choroidal neovascularization II: a            Group (1986) Recurrent choroidal                excision for submacular choroidal
    preliminary report in humans.                 neovasularization after argon laser             neovascularization (CNV). Acta.
    Am. J. Ophthalmol. 125 (5): 635-46.           treatment for neovascular                       Ophthalmologica Scandinavica 79 (6):
16. Mares-Peralma JA et al (1995) Dietary         maculopathy. Arch. Ophthalmol. 104:             580-584.
    fat and age-related maculopathy.              503-512.                                    34. Age-Related Eye Disease Study
    Arch. Ophthalmol. 113: 743-748.           25. Dougherty TJ et al (1998)                       Research Group (2001) A
17. Taylor HR, Tikellis G, Robman LD,             Photodynamic therapy.                           randomized, placebo-controlled,
    McCarty CA and McNeil JJ (2002)               J. Nat. Cancer Inst. 90 (12): 889-905.          clinical trial of high-dose
    Vitamin E supplementation and             26. Harding S (2001) Photodynamic                   supplementation with vitamins C
    macular degeneration: randomised              therapy in the treatment of subfoveal           and E, beta-carotene, and zinc for
    controlled trial. BMJ 325: 11.                choroidal neovascularisation.                   age-related macular degeneration
18. Goldberg J, Flowerdew G, Smith E et           Eye 15: 407-12.                                 and vision loss. AREDS Report
    al (1988) Factors associated with         27. TAP Study Group (1999)                          No. 8. Arch. Ophthalmol. 119:
    age-related macular degeneration.             Photodynamic therapy of subfoveal               1417-1436.
    An analysis of data from the first            choroidal neovascularization in             35. The Alpha-Tocopherol, Beta Carotene
    National Health and Nutrition                 age-related macular degeneration                Cancer Prevention Study Group
    Examination Survey. Am. J. Epidemiol.         with verteporfin. One year results              (1994) The effect of vitamin E and
    128 (4): 700-10.                              of 2 randomized clinical trials. TAP            beta carotene on the incidence of
19. Snellen ELM, Verbeek ALM, van den             Report 1. Arch. Ophthalmol. 117:                lung cancer and other cancers in male
    Hoogen GWP, Cruysberg JRM and                 1329-45.                                        smokers. New England Journal of
    Hoyng CB (2002) Neovascular               28. Chandler DB et al (1985) The effect             Medicine 330: 1029-35.
    age-related macular degeneration and          of triamcinolone on a refined               36. Evans JR (2003) Antioxidant vitamin
    its relationship to antioxidant intake.       experimental model of proliferative             and mineral supplements for
    Acta. Ophthalmologica Scandinavica 80         vitreoretinopathy. Am. J. Ophthalmol.           age-related macular degeneration
    (4): 368-371.                                 99: 686-690.                                    (Cochrane Review) In: The Cochrane
20. Young RW (1987) Pathophysiology of        29. Hart PM, Chakravarthy U et al (2002)            Library, Issue 1. Update Software,
    age-related macular degeneration.             Visual outcomes in the subfoveal                Oxford.
    Surv. Ophthalmol. 31 (5): 291-306.            radiotherapy study. Arch. Ophthalmol.       37. The Provision of Low Vision Care
21. Macular Photocoagulation Study                120: 1029-1038.                                 (1998) The Royal College of
    Group (1997) Risk factors for             30. Bergink et al (1998) A randomized               Ophthalmologists, London.
    choroidal neovascular membrane in             controlled clinical trial on the efficacy   38. Age Related Macular Degeneration
    the second eye of patients with               of radiation therapy in the control of          Guidelines (2000) The Royal
    juxtrafoveal or subfoveal choroidal           subfoveal choroidal                             College of Ophthalmologists,
    neovasularization secondary to age            neovascularization in age related               London.
    related macular degeneration. Arch.           macular degeneration: radiation
    Ophthalmol. 15 (6): 741-7.                    versus observation. Graefes Arch. Clin.
22. Macular Photocoagulation Study                Exp. Ophthalmol. 236: 321-325.              Further reading
    Group (1991) Argon laser                  31. Machemer R and Steinhorst UH                Berger JW, Fine SL, Maguire MG Eds
    photocoagulation for neovascular              (1993) Retinal separation, retinotomy       (1999) Age-Related Macular
    maculopathy: five year results from           and macular relocation.11. A surgical       Degeneration. Mosby, St. Louis.

                                                                                                          37 | February 21 | 2003 OT
Continuing Professional Development                        .                                                  .
                                                     John P Mathews FRCS Ed, Divya Mathews FRCS Ed and Simon P Kelly FRCOphth

     Age-related macular degeneration - an overview
     Please note there is only ONE correct answer
     1. Vision loss in age-related macular               6. The age group most at risk of AMD is:        10.   The hazards of cigarette smoking include:
        degeneration (AMD) is:                           a. 10-20 years                                  a.    lung problems
     a. slow, progressive, painless                      b. 20-40 years                                  b.    eye problems
     b. slow, progressive, painful                       c. 40-50 years                                  c.    cardiac problems
     c. rapid, progressive, painful                      d. 55 years and above                           d.    all of the above
     d. none of the above
                                                         7. One of the risk factors                      11.   Radiotherapy for dry AMD is:
     2. The clinical signs of AMD usually include:          for development of AMD is:                   a.    the subject of a recent MRC trial
     a. superficial haemorrhages throughout              a. excessive alcohol consumption                b.    readily available
        the peripheral retina                            b. smoking                                      c.    uses magnetic resonance technology
     b. soft drusen at the macula                        c. excessive reading                            d.    none of the above
     c. cotton wool spots                                d. all of the above
     d. atrophic retinal holes                                                                           12. Lutein is:
                                                         8. A 75-year old patient with disciform         a. absorbed from dietary
     3.   Symptoms of AMD usually include:                  macular degeneration in one eye and              fruits and vegetables
     a.   transient total loss of vision                    confluent drusen with pigment dispersion     b. best usually given by
     b.   metamorphopsia                                    and 6/12 vision in the fellow eye is best        slow intravenous injection
     c.   flashes and floaters                              managed by:                                  c. both of the above
     d.   photophobia                                    a. initiation of systemic vitamin E therapy     d. none of the above
                                                         b. repeat FFA on tri-monthly bases
     4. Non-exudative or dry AMD is usually                 to detect CNVM
        characterised by:                                                                                  An answer return form is included in
                                                         c. self-monitoring with Amsler grid chart
     a. cotton wool spots                                d. protection from UV light                       this issue. It should be completed and
     b. macular drusens                                                                                    returned to:
     c. both of the above                                9. The most common cause of blindness in            CPD initiatives (C4346),
     d. none of the above                                   the working age group is:                        OT, Victoria House,
                                                         a. AMD                                              178-180 Fleet Road, Fleet, Hampshire,
     5. Exudative AMD is MOST OFTEN                      b. diabetic retinopathy                             GU51 4DA by March 19, 2003.
        characterised by:                                c. trauma
     a. development of choroidal neovascular             d. none of the above                              Under no circumstances will forms
        membrane beneath the retina                                                                        received after this date be marked – the
     b. development of choroidal neovascular               Enter your answers online at                    answers to the module will have appeared
        membrane beneath the choroid                                                                       in our March 21 issue and scores sent
                                                  for an immediate                electronically to the accrediting bodies. A
     c. both of the above
     d. none of the above                                  result. Credits gained will be sent             letter showing your results will be sent for
                                                           electronically to the accrediting bodies.       information purposes only.

   38 | February 21 | 2003 OT

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