Current Perspectives of Diabetic Retinopathy

A Photo-Essay for Health Professionals-

 

John G. O'Shea MD, Robert B. Harvey FRCSE

Epidemiology

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lDiabetes is one of the most serious challenges to health care world-wide. According to recent projections it will affect 239 million people by 2010- doubling in prevalence since 1994.

Diabetes will affect 28 million in western Europe, 18.9 million in North America 138.2 million in Asia,  1.3 million in Australasia.

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lDiabetes mellitus is the most common cause of blindness amongst individuals of working-age ( 20-65 years). The prevalence of blindness due to DR in Western Communities is estimated as between 1.6-1.9/ 100,000

About 8% of UK BD8 registrations are due to diabetes.

 

( The World Health Organisation (1992) definition of  blindness is vision less than 3/60 in the better eye with best available spectacle correction. )

 

Presentation

lAbout 2% of type 2 diabetics have CSME at diagnosis and 10.2% have other signs of DR already present when their diabetes is discovered.
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Mitchell and co- workers found that 15.8 % of undiagnosed diabetics in an elderly Australian population had signs of DR, according to the recent Blue Mountains Eye Study. Indeed it may often take from 9-12 years for type 2 diabetes to be diagnosed

A Classification of Diabetic Retinopathy

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A useful clinical classification according to the types of lesions detected on

lfundoscopy is as follows:
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lNon-proliferative diabetic retinopathy (NPDR)
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lMild non-proliferative diabetic retinopathy
lMicroaneurysms
lDot and blot haemorrhages
lHard ( intra-retinal ) exudates
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lModerate-to-severe non-proliferative diabetic retinopathy
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lThe above lesions, usually with exacerbation,  plus:
lCotton-wool spots
lVenous beading and loops
lIntraretinal microvascular abnormalities ( IRMA )
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lProliferative diabetic retinopathy
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lNeovascularization of the retina, optic disc or iris
lFibrous tissue adherent to vitreous face of retina
lRetinal detachment
lVitreous haemorrhage
lPre retinal haemorrhage
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lMaculopathy
lClinically significant macular oedema  (CSME )
lIschaemic Maculopathy
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Pathogenesis of Diabetic Microangiopathy and Characteristic Fundus Lesions
 

lHyperglycaemia causes-
lBM thickening
lnon enzymaitc glycosylation
lincreased free radical activity
lincreased flux through the polyol pathway
losmotic  damage
lHaemostatic abnormalities of the microcirculation-
lIt has also been postulated that platelet abnormalities in diabetics may contribute to diabetic retinopathy. There are three steps in platelet coagulation: initial adhesion, secretion, and further aggregation. It has been shown that the platelets in diabetic patients are "stickier" than platelets of non-diabetics They secrete prostaglandins that cause other platelets to adhere to them (aggregation) and blockage of the vessel and endothelial damage.

Microaneurysms

lRetinal microaneurysms are focal dilatations of retinal capillaries, 10 to 100 microns in diameter, and appear as red dots. They are usually seen at the posterior pole, especially temporal to the fovea. They may apparently disappear whilst new lesions appear at the edge of areas of widening capillary non-perfusion. Microaneurysms are the first ophthalmoscopically detectable change in diabetic retinopathy.
 
lBeginning as dilatations in areas in the capillary wall where pericytes are absent, microaneurysms are initially thin-walled. Later, endothelial cells proliferate and lay down layers of basement membrane material around themselves.
 
lFibrin and erythrocytes may accumulate within the aneurysm. Despite multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina. Since fluorescein passes easily through them, many more microaneurysms are usually seen on fluorescein angiography than are apparent on ophthalmoscopy

Perifoveal microaneuryisms and haemorrhages
 

Retinal Haemorrhages

lWhen the wall of a capillary or microaneurysm is sufficiently weakened, it may rupture, giving rise to an intraretinal haemorrhage. If the hemorrhage is deep (i.e., in the inner nuclear layer or outer plexiform layer), it usually is round or oval ("dot or blot") 
lDot haemorrhages appear as bright red dots and are the same size as large microaneurysms.  Blot haemorrhages are larger lesions they are located within the mid retina and often within or surrounding areas of ischaemia. (1,4,)
lIf the hemorrhage is  more superficial and in the nerve fiber layer, it takes a flame or splinter shape, which is indistinguishable from a hemorrhage seen in hypertensive retinopathy. They often absorb slowly after several weeks. Their presence strongly suggests the co-existence of systemic hypertension.
 
lDiabetics with normal blood pressure may have multiple splinter haemorrhages. Nevertheless, when an ophthalmologist sees numerous splinter haemorrhages in a diabetic patient, the patient's blood pressure must be checked because a frequent complication of diabetes is systemic hypertension.
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Cotton Wool Spots
Cotton wool spots result from occlusion of retinal pre-capillary arterioles supplying the nerve fibre layer with concomitant swelling of local nerve fibre axons. Also called "soft exudates" or "nerve fibre layer infarctions" they are white, fluffy lesions in the nerve fibre layer. Fluorescein angiography shows no capillary perfusion in the area of the soft exudate. They are very common in DR, especially if the patient is also hypertensive

Hard exudates ( Intra-retinal lipid exudates )
lHard exudates ( Intra-retinal lipid exudates ) are yellow deposits of lipid and protein within the sensory retina. Accumulations of  lipids leak from surrounding capillaries and microaneuryisms, they may form a circinate pattern. Hyperlipidaemia may correlate with the development of hard exudates.
 

 

 

 

 

lAccumulations of lipids leak from surrounding capillaries and microaneuryisms, they may form a circinate pattern.
Late non proliferative changes

 

Intra-retinal microvascular abnormalities ( IRMA) are abnormal, dilated retinal capillaries or may represent intraretinal neovacularization which has not breached the internal limiting membrane of the retina.
l They indicate severe non-proliferative diabetic retinopathy that may rapidly  progress to proliferative retinopathy. Venous beading has an appearance resembling  sausage-shaped dilatation of the retinal veins. It is another sign of severe non proliferative diabetic retinopathy.

Diabetic Maculopathies

 

Characteristics of Clinically Significant Macular (O)Edema ( CSME )

lMacular oedema is thus an important manifestation of DR because it is now the leading cause of legal blindness in diabetics. The intercellular fluid comes from leaking microaneurysms or from diffuse capillary leakage .It should be stressed however that current regimes now lay emphasis on the treatment of retinal thickening by grid laser than direct treatment of microaneuyrisns and other discreet lesions.

lThe leading cause of  visual loss amongst  diabetics. Diagnosed by stereoscopic assessment of retinal thickening, usually by slit lamp biomicroscopy.
 
lDefined as the presence of one or more of the following, ( Modified Airlie -House Criteria )
 
lRetinal oedema  within 500 microns of the centre fovea.
lHard exudates within 500 microns of fovea if associated with adjacent retinal thickening
 
lRetinal oedema that is one disc diameter or larger,  any part of which is within one disc diameter of the centre of the fovea. 
lLaser grid photocoagulation reduces the risk of visual loss by 50% at  2 years
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Ischaemic Maculopathy

Maculopathy in type 1 diabetics is often due to drop out of the perifoveal capillaries with non perfusion and the consequent development of an ischaemic maculopathy.

lEnlargement of the foveal avascular zone (FAZ) is frequently seen on fluorescein angiography.  Ischaemic maculopathy is not uncommon in type 2 diabetics, maculopathy in this group may show both changes due to ischaemia but also retinal thickening.

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Proliferative diabetic retinopathy

Retinal ischaemia due to widespread capillary non perfusion results in the production of vasoproliferative substances and to the development of neovascularization. Neovascularization can involve the retina, optic disc or the iris( rubeosis iridis).

lRubeosis iridis is a sign of severe proliferative disease, it may cause intractable glaucoma.
 
lBleeding from fragile new vessels involving the retina or optic disc can result in vitreous or retinal haemorrhage. Retinal damage can result from persistent vitreous haemorrhage.
 
lPre-retinal haemorrhages are often associated with retinal  neovascularization,  they may dramatically reduce vision within a few minutes.

 

Above- Proliferative retinopathy and Iris Neovascularisation (NVI)
 

 

Late Disease

 

Contraction of associated fibrous tissue formed  by  proliferative disease tissue can result in deformation of the retina  and tractional retinal detachment
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There are two characteristic types of diabetic retinal detachments: those caused by traction alone (non-rhegmatogenous) and those caused by traction and retinal break formation (rhegmatogenous)

 

lCharacteristics of nonrhegmatogenous detachment in PDR include the following: (1) the detached retina is usually confined to the posterior fundus and infrequently extends more than two thirds of the distance to the equator; (2) it has a taut and shiny surface; (3) it is concave toward the pupil; and (4) there is no shifting of subretinal fluid.

 

 

Screening and Monitoring the Progress of Diabetic Retinopathy

 

Cost effective community screening for DR

lThe current consensus of opinion from Europe and the United States is that screening for DR by suitably trained and experienced practitioners is cost effective and results in reduced morbidity due to blindness.
lAn inter -disciplinary approach is commonly used, optometrists for example, are becoming increasingly involved in the care of diabetics.
 
lThe characteristics of a good screening programme being that the target patients in the community are found and seen at the prescribed intervals, and that the practitioners who conduct the screening have adequate training, that is they must be familiar with both the manifestations of diabetic eye disease and, if possible, with slit lamp biomicroscopy or with methods of  photoscreening.
 

lPatient education and growing community awareness concerning diabetes is likely to bring newly diagnosed and undiagnosed diabetics into the screening system.

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Ophthalmoscopic methods of diabetic screening

Screening should include the following:

The history of any visual symptoms or changes in vision

l2. Measurement of visual acuity  (unaided, with spectacles / pinhole as necessary)
l3. Iris examination by slit lamp biomicroscopy  prior to pupil mydriasis.
l4. Pupil mydriasis. ( tropicamide 0.5 % ) -the risk of precipitating angle closure glaucoma is actually very small.  Patients should  be accompanied by a relative and instructed not to drive home.
l5.  Examination of the crystalline lens by slit lamp biomicroscopy.
 
l6. Fundus examination by slit lamp biomicroscopy using diagnostic contact lens or slit lamp indirect ophthalmoscopy.
lThe direct ophthalmoscope enables adequate examination of only the posterior pole whilst the indirect ophthalmoscope provides insufficient magnification. Slit lamp examination ( using either indirect ophthalmoscopy with a convex aspheric lens or diagnostic contact lens)  yields much more information by providing  stereoscopic assessment of retinal thickening and proliferative retinopathy, particularly important when assessing possible retinal traction. It is therefore imperative to facilitate cost-effective screening more that more practitioners are trained in slit lamp biomicroscopy of the fundus with emphasis on detection and monitoring of diabetic eye disease.

The use of ophthalmoscopy however has the disadvantage that there is no hard record, which makes quality assurance more difficult.

  Audit of test positives or of adverse events is not sufficient for quality assurance purposes, and patients would need to be recalled to assess test negatives, for which attendance rates may be very low.

     The personnel performing the examination require considerable training and accreditation.

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Photoscreening

lAn alternative to slit lamp biomicroscopy  is the photoscreening of diabetic patients with a fundus camera. Photoscreening  is very popular in some parts of the United Kingdom and the USA - the physician or ophthalmologist subsequently examining the photographs for evidence of DR -  this approach also obviates the need to be proficient with a slit lamp and also provides a permanent record of the contemporary status of  DR. The camera can also be bought to remote rural areas and the pictures later examined.
 
lPhotoscreening will not always detect subtle signs of DR , such as retinal thickening, but a success rate of 80-92% in detecting DR is claimed by researchers. There are numerous photographic techniques used ranging from a single photograph to a  9 photograph collage.  Three photographs spread across the posterior pole are now widely regarded as being most cost efficient.
lSensitivities for the detection of sight-threatening retinopathy are lower with instant polaroid photographs.
lDigital images have the advantage that they are easier to acquire, store and transfer than 35mm film, and that images can be reviewed with the patient at the time of screening. patients also find the lower intensity flash more comfortable

EFFECTIVENESS OF DIFFERENT SCREENING METHODS

Direct ophthalmoscopy

       Studies from the UK have shown sensitivity levels for the detection of sight-threatening diabetic retinopathy of 41-67% for general practitioners, 48-82% for optometrists, 65% for an ophthalmologist, and 27-67% for diabetologists and hospital physicians using direct ophthalmoscopy.

lIndirect ophthalmoscopy

       There are few studies specifically assessing the use of dilated slit-lamp indirect ophthalmoscopy, but it does appear that the required standards may be achieved by trained individuals. Sensitivities for the detection of referable retinopathy by optometrists have been found to be 77-100%, with specificities of 94-100%.

lPhotographic methods

       The use of mydriasis results in improved sensitivity for the detection of sight-threatening retinopathy and fewer ungradeable images.  Sensitivities for the detection of sight-threatening diabetic retinopathy of 87-100% have been found for a variety of trained personnel reading mydriatic 45 retinal photographs, with specificities of 83-96%.

lThe results were similar between different personnel performing the grading, including trained non-medical graders. it appears that there is good agreement in the grading of retinopathy between 35mm colour film and digital images despite the lower resolution of the latter.

lIn the United Kingdom the National Screening Committee has recently considered the issues surrounding screening for diabetic retinopathy and after wide consultation has provided recommendations on screening and the practicalities of a national programme. Details of these can be seen on the website: www.diabetic- retinopathy-screening.nhs.uk
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Principal recommendations of the National Screening Committee (UK) -

Annual screening for all diabetic patients aged over 12 years, or post-puberty.

lThe screening programme should be accessible to all patients with diabetes. The exact details of a programme for a particular area will be determined by local factors.
lThe proposed national programme would be rolled out over a period of 3-4 years, as both funding and trained staff become available.
lDigital imaging is the preferred modality.
lQuality assurance should be included in any programme.
lDirect ophthalmoscopy should not be used as a primary method for systematic screening as it does not meet the required quality criteria.
lIndirect slit-lamp ophthalmoscopy may meet the sensitivity and specificity requirements but requires considerable skills and training, and it is hard to perform adequate quality assurance.
 
 

Therapeutics

 

MEDICAL- General aspects of the ocular care of diabetics

lFactors that can worsen diabetic retinopathy- and indeed the general prognosis of diabetes, include poor diabetic control, systemic hypertension,hyperlipidaemia, cigarette smoking, diabetic nephropathy, anaemia, pregnancy and cataract surgery

Glycaemic control
lIt is now proven that good diabetic control may slow the development and progression of diabetic retinopathy in both type 1 and type 2 diabetes.
 
lFor example, the United Kingdom Prospective Diabetes Study 1998 (UKPDS)  followed 5,102 newly diagnosed type 2 diabetics prospectively since 1977. Those diabetics who were intensively treated and achieved tight control with either insulin or suphonylurea had diabetic endpoints 12% lower than less well  controlled diabetics.
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Overall there was a 25% reduction in microvascular end points in the group exhibiting good glycaemic control
 

Systemic hypertension and DR in type 2 diabetes

lRecent literature indicates that there is a striking correlation between the presence of systemic hypertension and progression of  diabetic retinopathy. Recent studies have delineated the role of treating associated hypertension and the slowing of the progress of DR. It is important to note that many type 2 diabetics will need a combination of anti-hypertensive agents to lower their blood pressure.

Cotton wool spots and flame shaped heamorrhages on fundoscopy often indicate concomitant hypertension.

 

lThe hypertension in diabetes study was launched within  the original UKPDS study in 1987.
 
lThe study compared diabetics whose blood pressure was tightly controlled ( BP < 150/85)with ACE inhibitors and beta blockers with a cohort whose blood pressure was less tightly controlled. (BP <180/ 95 ) Median follow up was 8.4 years.
 
lThe reduction of macrovascular events was significant with a 32% reduction in diabetes related deaths. There was a 44% reduction in stroke and a 34% reduction in overall macrovascular disease.
 
lUKPDS is  a unique study in that it also looked at microvascular end points in type 2 diabetics. Overall the tight control group had a 37% reduction in microvascular disease, this was a more striking reduction than tight glycaemic control.
 
lThis effect was manifested as a reduction  of  the risk of having to undergo laser photocoagulation by 34%.
 
Systemic hypertension and DR in type 2 diabetes

lThe risk of reduction of visual acuity was lowered by 47%.

lAtenolol and Captopril were equally effective in reducing the risk of progression of retinopathy in type 2 diabetics.
 
lThe Hypertension Optimal Treatment ( HOT ) study indicates that the lowest incidents of cardiac events occurs when blood pressure is lowered to 82.6 mmHg diastolic and 136 mmHg systolic.
 

Angiotensin Converting Enzyme (ACE)  inhibitors in Type 1 diabetes

 

lThe EUCLID study is currently investigating the prophylactic treatment of type 1 diabetics with the Angiotensin Converting Enzyme (ACE) Inhibitor Lisinopril  and the progression of nephropathy and other microvascular disease including DR . Preliminary reports are of a specific benefit are encouraging, with a claimed 50% reduction in progression of DR in type 1 diabetics.

lThe study did not look at maculopathy- so that implications are unclear for type 2 diabetics, although no specific advantage of ACE inhibitors (Captopril) over Atenolol was seen in UKPDS.
Hyperlipidaemia and diabetic maculopathy
 

There is evidence in the literature that diabetics who have exudative maculopathy with extensive lipid exudes benefit from active treatment of hyperlipidaemia

Diabetic nephropathy

 

lDiabetic nephropathy accelerates the progression of retinopathy, especially macular oedema, inter alia via increased levels of fibrinogen and lipoprotein and associated hypertension.
lThe visual prognosis is often  better if the nephropathy is treated by renal transplantation rather than by dialysis
l Any anaemia resulting from renal disease must be aggressively treated.
lDiabetic retinopathy is a common prelude to the development of  renal disease.
Tightening Glycaemic control
 
lTightening of glycaemic control may initially produce worsening of retinopathy. The postulated mechanism includes lowering of retinal blood low or overproduction of IGF-1 by the liver.
lIt is therefore recommended that monitoring of retinopathy is increased if major changes to glycaemic control are made particularly in previously poorly controlled diabetics.  Ideally glycated haemoglobin ( HbA1c) should be maintained below 7%.

Pregnancy

Pregnancy may accelerate the progression of diabetic retinopathy. Frequency of monitoring NPDR should therefore be increased.Women who begin a pregnancy with no retinopathy, the risk of developing diabetic retinopathy is about 10%.
lThose with DR at the onset of pregnancy may show progression, with increased haemorrhages, soft exudates, and macular edema. There is no doubt that women who maintain good metabolic control during pregnancy have fewer spontaneous abortions and fewer children with birth defects.
lThose with untreated PDR at the onset frequently do poorly unless they are treated with panretinal photocoagulation. Finally, patients with previously treated PDR often do not worsen during the pregnancy.
lWomen who begin pregnancy with poorly controlled diabetes and who are suddenly brought under strict control frequently have severe deterioration of their retinopathy and do not always recover after delivery
Cataract surgery

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Cataract surgery may lead to progression of pre-existing macular oedema and proliferative diabetic retinopathy. However, cataracts may impede fundoscopy and therefore interfere with the treatment of diabetic retinopathy. If possible, diabetic retinopathy should be treated prior to cataract surgery

Laser Photocoagulation

 

 

SURGICAL-Panretinal laser photocoagulation for proliferative DR

lThe mainstay of treatment of diabetic retinopathy is retinal laser photocoagulation, an ablative treatment. Laser therapy is highly effective; the rate of severe visual loss at 2 years due to proliferative disease can be reduced by 60%. 
lLaser photocoagulation causes a retinal burn which is visible on fundoscopy.  Retinal and optic disc neovascularization can regress with the use of retinal laser photocoagulation.
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lRubeosis iridis requires urgent panretinal photocoagulation to prevent ocular pain and blindness from glaucoma.

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The technique of laser photocoagulation delivery involves the application of eyedrops

l( for pupil dilatation and corneal anaesthesia ) and the application of an  optical contact lens. Mild proliferative retinopathy is usually treated with at least 600 burns placed between the retinal equator and the retinal vascular arcades. A complete panretinal photocoagulation treatment requires at least 1500 burns.

 


Although laser therapy can be highly effective in preventing blindness, it is associated with numerous complications.
lRetinal vein occlusion can follow inadvertent photocoagulation of a retinal vein. Rarely, there may be loss of central acuity from inadvertent photocoagulation of the fovea.
lVitreous haemorrhage can follow photocoagulation of retinal or  choroidal vessels.
lThere may be visual field restriction, decreased contrast sensitivity,  impaired night vision or impaired colour vision.
lVisual field constriction may impair fitness to drive although ophthalmologists increasingly strive to avoid this most undesirable problem, for example by avoiding confluent laser burns.  
lA recent study indicates that 88% of diabetics who have undergone  laser photocoagulation would pass the Esterman binocular field test which is the legal criterion for fitness to drive in the United Kingdom, even if both eyes were treated. 42% of uniocular fields failed to make the criterion of a 120 degree horizontal field. Patients who have already lost the sight in one eye therefore have  a significant chance of  failing to meet legal  parameters for fitness to drive in the United Kingdom.
lHeadache can sometimes follow laser therapy.  The headache is usually
lrelieved with rest and simple analgesia. Glaucoma must be excluded if the headache is severe or persistent.

Macular laser grid therapy for CSME
 

lThe indications for laser therapy now include CSME which is treated with a macular laser grid or treatment of focal lesions such as microaneuryisms. Early referral and detection of disease is important as treatment of maculopathy is far  more successful if undertaken at an early stage of the disease process.
lThere is a reduction in the rate of loss of vision by 50% at 2 years with macular grid therapy. 

 

Vitrectomy

 
lVitrectomy, plays a vital role in the management of severe complications of diabetic retinopathy.
lThe major indications are nonclearing vitreous hemorrhage, traction retinal detachment, and combined traction/rhegmatogenous retinal detachment. Less common indications are macular edema with a thickened and taut posterior hyaloid, macular heterotopia, and tight preretinal macular hemorrhage.

Summary

 

lThe early detection of diabetic retinopathy leads to a marked reduction of morbidity due to visual loss. 

 
lMajor international studies all  indicate therapy is best instituted before serious complications develop, screening of our diabetic population and of our elderly population to detect undiagnosed DR should therefore be undertaken.
 
lKey lesions of diabetic retinopathy have been described and screening protocols summarised.
 
lLaser photocoagulation, the principal form of therapy,  is also described as are means of modifying lifestyle to decrease the morbidity of diabetic retinopathy.
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Contact Us

Author : John G. O'Shea MD

  Illustrations: Robert Harvey FRCSEd (from Practical Ophthalmology,  2002 Palmtrees Publishing)

Webmaster:  David Kinshuck FRCS

      Rob Harvey

      E-mail Address  :  rob_harvey@msn.com

    

    

Correspondence-

Birmingham and Midland Eye Centre, Dudley Rd,  Birmingham B18 7QH,  U.K.

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