Download guidelines for diabetic retinopathy executive summary

GUIDELINES FOR DIABETIC RETINOPATHY
EXECUTIVE SUMMARY
Diabetic retinopathy remains the major sight threatening eye disease in the
working age population in the developed world and is increasing as a cause of
blindness in other parts of the world. Recent information from major population
studies (DCCT, UKPDS) regarding the importance of optimal management of
diabetes, and its associated conditions, on the development of complications, is
beginning to change the epidemiology of visual handicap. However, this is offset
by the increase in the prevalence of diabetes overall. Current therapies for
diabetic retinopathy are effective particularly for proliferative disease. These
guidelines represent a consensus document outlining the epidemiology, clinical
features and recommendations for population screening, detection, diagnosis and
management of various forms of diabetic retinopathy. Some special problems are
discussed as well as aspects of counselling for patients at different stages of the
disease. The Guidelines are advisory and are not intended as a set of rigid rules,
since individual patients will require tailored treatment for their particular
condition. However, it is hoped that if used appropriately, they will lead to a
uniformly high standard of management of patients with diabetic retinopathy.
PREFACE
Diabetic retinopathy is a potentially blinding disease affecting many
individuals in the working age group. The aim of the guidelines is to provide advice
on best management of different aspects of diabetic eye disease, based on
evidence taken form the literature and published trials of therapies plus consensus
opinion of an expert panel convened by the Royal College of Ophthalmologists
which was representative of a range of groups with an interest in this condition. In
addition opinion was taken from the consultant body of practicing
ophthalmologists within the UK, registered with the College of Ophthalmologists.
EVIDENCE is graded on three levels:
Level 1
Level 2
Level 3
evidence was based on results of randomised controlled trials (RCTS)
power calculations or other recognised means were used to
determine statistical validity of the conclusion.
evidence was based on results of case studies, case series or other
non-randomise prospective or retrospective analysis of patient data.
evidence was based on expert opinion, consensus opinion or current
recognised standard of care” criteria where no formal case series
analysis was available.
RECOMMENDATIONS for practice are based on treatment protocols and
measures which were recognised to improve patient care and/or quality of life
based on
Level A
Level B
Level C
strength of evidence was universally agreed
where the probability of benefit to the patient outweighed the risks
where it was recognised that there was difference of opinion as to
the likely benefit to the patient and decision to treat would be based
after discussion with the patient
2
CONTENTS
SECTION 1. TERMINOLOGY AND DISEASE DEFINITION
1.1 Definition of Diabetic Retinopathy
1.2 Classification of Diabetic Retinopathy
1.3 Definitions of the Complications of Diabetic Retinopathy
SECTION 2. THE EPIDEMIOLOGY OF DIABETIC EYE DISEASE
2.1 Introduction
2.2 Prevalence of eye disease in people with diabetes
2.3 Incidence of Eye Disease in People with Diabetes
SECTION 3. RISK FACTORS AND THEIR MANAGEMENT, INCLUDING
COUNSELLING FOR DIABETIC RETINOPATHY
3.1 Introduction
3.2 Duration of Diabetes
3.3 HbA1c and glycaemic control
3.4 Hypertension
3.5.Age
3.6 Pregnancy
3.7 Renal Disease
3.8.Hyperlipidaemia
3.9. Smoking
3.10. ACE Inhibition
3.11. Aspirin and thrombolytic therapy
3.12. Antioxidants.
3.13. Alcohol
3.14. Counselling for Diabetic Retinopathy
SECTION 4. CLINICAL FEATURES OF DIABETIC RETINOPATHY
4.1 Non-proliferative (background/pre-proliferative) retinopathy
4.2 Proliferative diabetic retinopathy
4.3 Maculopathy
SECTION 5. SCREENING FOR DIABETIC RETINOPATHY
5.1 Introduction
5.2 Development of screening for diabetic retinopathy
5.3 Evidence for the effectiveness of screening
5.4 Organisation of screening services
5.5 Screening methodology
5.6 Grading and referral
5.7 Population to be screened
5.8 Frequency of screening
5.9 Quality standards
5.10 Role of ophthalmologist
SECTION 6. LASERS and LENSES
3
6.1 Method of laser application
6.2 Lasers
6.3 Side effects of lasers
SECTION 7. MANAGEMENT OF DIABETIC MACULOPATHY
7.1 Introduction
7.2 Definition
7.3 Recommendations for treatment
7.4 Treatment protocols for diabetic maculopathy
SECTION 8. MANAGEMENT OF NVE
8.1 Introduction
8.2 Definition
8.3 Evidence for current standard of treatment
8.4 Recommendations for treatment
8.5 Treatment protocols
8.6 New vessels on the iris (Rubeosis iridis)
SECTION 9. MANAGEMENT OF NVD
9.1 Introduction
9.2 Definition
9.3 Evidence for current standard of treatment
9.4 Recommendations for treatment
9.5 Treatment protocols
SECTION 10. VITRECTOMY IN DIABETIC EYE DISEASE
10.1 Indications
10.2 Vitreous / subhyaloid haemorrhage
10.3 Haemolytic ghost-cell glaucoma
10.4 Retinal detachment
10.5 Severe widespread fibrovascular proliferation
10.6 Iris / angle neovascularisation with vitreous opacity
10.7 Anterior hyaloidal fibrovascular proliferation / retrolental
fibrovascular proliferation
10.8 Vitrectomy for diabetic macular disease
SECTION 11. CATARACT
11.1 Introduction
11.2. Aims of surgery for Cataract
11.3 Cataract Surgery in patients with diabetes
11.4, Cataract surgery and vitrectomy in patients with diabetes
11.5. Cataract surgery, new vessels, rubeosis and risk of worsening
retinopathy
11.6. Visual outcomes of cataract surgery
11.7 Cataract surgery and progression of diabetic retinopathy
APPENDIX
4
SECTION 1. TERMINOLOGY AND DISEASE DEFINITION
1.1
DEFINITION OF DIABETIC RETINOPATHY
Diabetic retinopathy is a chronic progressive sight-threatening disease of the
retinal microvasculature associated with the prolonged hyperglycaemia and other
conditions linked to diabetes mellitus such as hypertension.
1.2
CLASSIFICATION OF DIABETIC RETINOPATHY
Diabetic retinopathy is a potentially blinding disease in which the threat to
sight comes through two main routes: growth of new vessels leading to intraocular
haemorrhage and possible retinal detachment with profound global sight loss, and
localised damage to the macula / fovea of the eye with loss of central visual
acuity. Classification and severity grading of diabetic retinopathy have historically
been based on ophthalmoscopically visible signs of increasing severity, ranked into
a stepwise scale from no retinopathy through various stages of non-proliferative or
preproliferative disease to advanced proliferative disease. However, this may not
accurately reflect functionally severe disease since maculopathy with severe visual
loss may occur in the presence of moderate ophthalmoscopic signs. Two different
approaches to classification have emerged: (a) those designed to cover the full
range of retinopathy and aimed at the ophthalmologist that are based on the
original Airlie House / EDTRS classification and (b) those which are proposed for
use in population screening.
1.2.1 Full disease classifications
These have developed from the original Airlie House classification
developed for the Early Treatment Diabetic Retinopathy Study (ETDRS)(1) aimed at
grading retinopathy in the context of overall severity of ophthalmoscopic signs.
Modified and simplified versions have been developed and used for research
programmes and in clinical practice. A simplified version was developed for the
first version of these guidelines in 1997 (2). A reduced version of the ETDRS
classification aimed at countries without systematic screening programmes has
recently been endorsed by the American Academy of Ophthalmology Guidelines
Committee(3) and used in clinical trials (eg ETDRS, see later). The latter
classification was developed in recognition of the need for a clinical grading
system that would reflect the vision threatening risk of diabetic retinopathy. This
describes three stages of low risk non-proliferative retinopathy, a fourth stage of
severe non-proliferative retinopathy and a fifth grade of proliferative retinopathy.
In addition macular oedema is determined as absent or present and further subclassified on the basis of involvement of the centre of the macula.
1.2.2 Population screening classifications
The National Screening Committee(NSC) (4)has adopted a classification for
use in England and Wales aimed at detection of that level of retinopathy
5
sufficiently severe to merit referral of the patient for expert ophthalmological
opinion and possible treatment. A Scottish Diabetic Retinopathy Grading Scheme
has also recently been introduced(5). The NSC classification adopts a simplified
approach to grading retinopathy based on features which a non-ophthalmologist /
accredited photographic grader might be faced with in a population of diabetic
patients. This classification identifies four types of presentation of fundus disease,
namely retinopathy (R), maculopathy (M), photocoagulation (P) and unclassifiable
(U) (see Appendix).
1.2.3 Differences between classification systems
There is considerable overlap between the various classifications. They all
recognise the two basic mechanisms leading to loss of vision: retinopathy (risk of
new vessels) and maculopathy (risk of damage to the central fovea).
The differences between classifications relate mainly to levels of
retinopathy and also to terminology used. Below are described the similarities and
differences in both classifications, with the aim of permitting ready crossreference. Where alternative terminology is in common use this is shown in
parentheses.
1.2.3.1 Retinopathy
Diabetic retinopathy is classified according to the presence or absence of abnormal
new vessels as:
•
•
non-proliferative (background/preproliferative) retinopathy
proliferative retinopathy
Each has a different prognosis for vision.
1.2.3.2 Non-proliferative
proliferative)
diabetic
retinopathy
(NPDR)
(background/pre-
In the international (AAO) classification, NPDR is graded as:
•
mild
•
moderate
•
severe
In the NSC-UK classification, NPDR is graded as:
•
background (Level R1)
•
pre-proliferative (Level R2)
In the Scottish Diabetic Retinopathy Grading Scheme, NPDR is graded as:
•
mild background (Level R1)
•
moderate background (Level R2)
•
severe background (Level R3)
1.2.3.3 Proliferative diabetic retinopathy (PDR)
6
PDR (Level R3 in the NSC-UK grading and R4 in Scotland) is described
according to
(a) location
•
new vessels on the disc (NVD) or within 1 disc diameter (DD)of the margin of
the disc
•
new vessels elsewhere in the retina (NVE) (more than 1DD from the
disc)
and
(b) severity
early PDR, PDR with high risk characteristics, florid PDR and gliotic PDR.
“Involutionary” PDR is used to describe new vessels which have regressed in
response to treatment or (rarely) spontaneously.
The different classifications referred to above can be approximately mapped to
each other as shown in Table 1.1
Table 1.1
Approximate equivalence of currently used alternative classification systems for
diabetic retinopathy
ETDRS (ref 1)
NSC (ref 4)
SDRGS (ref 5)
10
None
20
Microaneurysms only
35
Mild NPDR
43
Moderate NPDR
47
Moderately severe
NPDR
53A-D
Severe NPDR
53E
Very severe NPDR
61 Mild PDR
65 Moderate PDR
71,75 High risk PDR
81,85 Advanced PDR
R0
None
R1
Background
R0
None
R1
Mild BDR
AAO (ref3)
International
No apparent
retinopathy
Mild NPDR
RCOphth
(ref2)
None
Low risk
Mod NPDR
R2
Preproliferative
R3
Proliferative
High risk
R2
Moderate BDR
R3
Severe BDR
Severe NPDR
R4
PDR
PDR
PDR
Legend
7
ETDRS = Early Treatment Diabetic Retinopathy Study; AAO = American Academy of
Ophthalmologists; NSC = National Screening Committee; SDRGS = Scottish Diabetic
Retinopathy Grading Scheme; NPDR = Non-proliferative diabetic retinopathy; BDR =
Background diabetic retinopathy; PDR = Proliferative diabetic retinopathy; HRC =
high risk characteristics
1.2.4. Diabetic maculopathy (DM)
Retinopathy which affects the macula is separately described as diabetic
maculopathy.
DM is further classified as:
•
focal oedema
•
diffuse oedema
•
ischaemic or
•
mixed
DM may be
(intraretinal).
tractional due
to
vitreoretinal
pathology
or
non-tractional
In the classification systems described above various definitions of maculopathy
have been given.
EVIDENCE LEVEL 1
1.3
DEFINITIONS OF THE OCULAR COMPLICATIONS ASSOCIATED WITH DIABETIC RETINOPATHY
The ocular complication of diabetes may be specific to progression of the
ocular disease or, more commonly, may be non-specific recognised associations of
diabetes in the eye.
------------------------------------------------------------------Table 1.2
Complications linked to Diabetic Retinopathy
Specific
Non-Specific
Retinal Detachment Cataract
Rubeosis Iridis
Glaucoma
Cataract
Retinal Vein Occlusion/
Optic Disc Swelling
Optic Neuropathy
--------------------------------------------------------------------1.3.1 Non-specific ocular disease associations
1.3.1.1 Cataract
8
Cataract is defined as opacification of the lens and is common in older age
populations. Age-related cataract occurs earlier in patients with diabetes.
1.3.1.2 Glaucoma
Glaucoma is defined as loss of vision due to raised intraocular pressure and
occurs in two forms: primary or secondary. Primary glaucoma may present as acute
glaucoma or chronic glaucoma. Patients with diabetes may have a greater risk of
developing primary chronic glaucoma with loss of visual field (side vision). Patients
with PDR are at risk of developing secondary glaucoma, particularly rubeotic
glaucoma (see below).
1.3.1.3 Retinal Vein Occlusion / Optic disc swelling
Patients with diabetes are at higher risk of developing optic nerve disease
due to vascular occlusion, which is distinct from diabetes-specific optic neuropathy
(see below) and usually occurs in older patients with Type 2 diabetes and
hypertension. This may be a form of ischaemic optic neuropathy.
1.3.2 Specific complications
1.3.2.1 Retinal Detachment
Retinal detachment is caused by the accumulation of fluid between the
neural retina and the retinal pigment epithelium and in non-diabetic patients most
commonly results from a tear in the retina (rhegmatogenous retinal detachment).
In patients with PDR, tractional retinal detachment may occur due to condensation
and contraction of the vitreous gel in association with haemorrhage and fibrosis
(plus gliosis). Tractional retinal detachment may progress to combined tractional
and rhegmatogenous retinal detachment. Central vision is lost when the macula is
involved.
1.3.2.2 Rubeosis iridis and rubeotic glaucoma
Rubeosis iridis is the growth of new vessels on the iris in eyes with advanced
retinal ischaemia. Rubeosis may induce a severe form of intractable glaucoma (see
below) due to closure by fibrovascular tissue of the aqueous fluid drainage route in
the anterior chamber angle of the eye.
1.3.2.3 Cataract
A specific form of “snow-flake” cataract is recognised in younger diabetics.
In addition, a rare form of “osmotic” reversible cataract occurs in young diabetic
patients, including infants, due to rapid changes in fluid electrolyte balance in
severe uncontrolled diabetes.
1.3.2.4 Optic neuropathy
9
Patients with diabetes may rarely experience optic neuropathy, which
presents as swelling of the optic discs associated with gradual reduction in visual
acuity.
1.3.2.5 Other ocular pathology in diabetes
Ocular muscle palsies are not uncommon in association particularly with
Type 2 diabetes. In addition, corneal epitheliopathy is common and a cause of
poor epithelial wound healing especially after ocular surgery.
10
SECTION 2
THE EPIDEMIOLOGY OF DIABETIC EYE DISEASE
2.1 INTRODUCTION
Diabetes mellitus results in considerable morbidity and mortality, affecting
about 180 million people worldwide(6). The disease is classified according to two
distinct groups of patients: type 1 diabetes (previously known as ‘insulin
dependent’ or ‘juvenile onset’) and type 2 diabetes (non-insulin dependent, adultonset) which is characterized by insulin resistance in peripheral tissues and an
insulin secretory defect of the beta-cell(7). Type 2 diabetes is classified also by
clinical stage, to those controlled by healthy living, those who need oral
medication, and those who need insulin. The new WHO classification also
recognises other types of secondary diabetes eg after pancreatic disease and a
fourth category of gestational diabetes but these conditions are not considered in
this document.
Between 70 to 90% of known diabetic patients have type 2 diabetes(8). An
estimated 50% more remain undiagnosed(9, 10). In the UK white population, rates
of known diabetes range from 2 - 4%. Type 2 diabetes is commoner in ethnic
minority peoples and those who are socio-economically deprived.
Diabetes increases risk for developing many irreversible complications(11).
These can be largely divided into macrovascular and microvascular complications.
The macrovascular complications include cerebro-vascular disease, coronary heart
disease and peripheral vascular disease. The microvascular complications include
eye disease (diabetic retinopathy), nerve disease (diabetic neuropathy) and kidney
disease (diabetic nephropathy). The other main eye complication, cataract, is
usually not specific to diabetes, but the risk of developing cataract is greater in
people with diabetes.
The prevalence of these complications in a general population relates to the
prevalence, type and duration of diabetes. Therefore, the predicted rise in
numbers of adults with diabetes will be accompanied by an increase in the number
of diabetic complications.
In people with diabetes, cataracts and retinopathy are the most significant
cause of visual impairment and blindness, and people with diabetes are 25 times
more likely than the general population to become blind(12). In developed
countries, diabetic eye disease represents the leading cause of blindness in adults
under 65 years(13).
2.2. PREVALENCE OF EYE DISEASE IN PEOPLE WITH DIABETES
2.2.1 Definitions
Point prevalence: the proportion of cases of a disorder or disease in a
particular population at a particular point in time.
11
Lifetime prevalence: the proportion of the population who have a history of
a given condition at a particular point in time.
2.2.2 Prevalence of diabetic retinopathy
There is a wide range of prevalence estimates. Those studies that
specifically report the prevalence of retinopathy at diagnosis (rather than pooled
prevalence data from patients who may have had varied exposure to the disease),
suggest that the prevalence of retinopathy of any severity in people with newly
diagnosed diabetes is dependent upon the type of diabetes (type 1 or type 2).
Generally, the prevalence of retinopathy at diagnosis of type 1 diabetes is
reportedly low, between 0% and 3% (14-17), while a higher proportion of those
with newly diagnosed type 2 diabetes have evidence of DR (6.7–30.2%)(14, 18-25).
Studies not confined to newly diagnosed diabetes show the prevalence of DR
in type 1 and type 2 diabetes strongly correlates with duration of disease, and in
type 2 diabetes with the clinical stage as shown by the need for insulin.
Sub-clinical diabetic retinopathy, shown by retinopathic changes on
fluorescein angiography in people with no photographic abnormalities are
common, and of patients so defined in the Diabetes Control and Complications
Trial (DCCT, see below), 67% had retinopathy within 5 years of diabetes onset.
The United Kingdom Prospective Diabetes Study (UKPDS, see below) found a
higher prevalence of retinopathy (39% in men and 35% in women) in newly
diagnosed type 2 diabetes than have other studies.
Population based studies from the UK generally show lower rates of
retinopathy: of 10,709 diabetes patients identified through health district audit
and data linkage, 16.5% had retinopathy(26). In addition, more recent UK
prevalence studies suggest that improvements in treatment of diabetes have led to
lower rates of retinopathy, particularly of the sight threatening type(27-31).
2.2.3. Prevalence of diabetic macular oedema
The prevalence of macular oedema has also been found to be related to the
duration of the disease and in type 2 diabetes the clinical stage as shown by the
need for insulin treatment(32).
The prevalence of clinically significant MO (i.e. MO which threatens central
visual function; CSMO) is reportedly low in patients with type 1 diabetes (5%)(33,
34) and type 2 diabetes (2%)(35) in the first years following diagnosis. However,
this increases to more than 20% in people who have had type 1 diabetes for 25
years(33).
2.2.4. Effect of gender on prevalence of diabetic retinopathy
There is little evidence of a difference in prevalence of retinopathy
between genders. One UK report has suggested a higher prevalence of visual
impairment in females based on data of blind or partially sighted registrations(36).
12
2.2.5. Effect of ethnicity on prevalence of diabetic retinopathy
This has been studied in the US where in the third National Health and
Nutrition Examination Survey in the USA, the prevalence of retinopathy was 46%
higher in blacks and 84% higher in Mexican-Americans than whites with
diabetes(37).
The studies in the UK report either a similar prevalence of retinopathy
between people of African, Black West Indians, Jamaicans, European and Indian
origin with type 2 diabetes(38), or in one report less in Indian Asians compared
with White Europeans(39).
Rates of blindness or visual loss are also variously reported: one report has
suggested an ethnic and gender difference in the likelihood of being registered
blind or partially sighted, with an interaction between gender and ethnicity: there
was a higher proportion of visually impaired females than males (P < 0.05), but
rates were lower than expected in female Indo-Asians.
2.2.6 Prevalence of cataract in people with diabetes
The point prevalence of cataract increases with age, and is higher in ethnic
minority groups such as the Indo Asian person, compared to the prevalence in the
general population. One report indicated a prevalence of 30% compared to 3% in
people aged under 60 years and 78% compared to 54% in those aged 60 years and
over(36). The age of onset of cataract seems to be earlier in Asians.
2.3. INCIDENCE OF EYE DISEASE IN PEOPLE WITH DIABETES
2.3.1 Definition
Disease incidence is the number of new cases of a particular disease
occurring over a defined time period. It may also be expressed as the percentage
of cases progressing to the next stage of a disease over a defined time period. It
may also be expressed as the number of patients per 100 or per 1000 patient years
(see below).
2.3.2 Incidences of diabetic retinopathy in people with diabetes
The 4-year incidence of any retinopathy with type 1 diabetes enrolled in the
WESDR was 59%(40). The 4-year incidence of any retinopathy in type 2 patients
was 34%, and if on insulin, 47.4%. Progression of retinopathy is more frequent in
type 1 diabetes (41% over 4 years) and insulin needing type 2 diabetes (34%) than
non –insulin treated (25%).
Progression to proliferative retinopathy (PDR) was 10% over 4 years in type
1,and 7% and 2% in type 2 treated with or without insulin respectively. In type 1,
insulin-treated type 2 and non-insulin-treated type 2, the 4-year incidence of
13
CSMO was 4%, 5% and 1%, and the incidence of legal blindness was found to be
1.5%, 3% and 2.5%, respectively(40).
The 10-year incidence of any retinopathy, macular oedema or visual loss in
the WESDR was 90%, 20% and 9% in type 1 diabetes, 79%, 25% and 33% in insulintreated type 2 diabetes and 67%, 14% and 21% in non-insulin-treated type 2
diabetes, respectively(41). In subjects who have since been followed-up for 14
years(34), regression occurred in 17% of patients.
In the UKPDS, 22% of those with no sign of DR at baseline developed DR at 6
years, and in 29% of patients with baseline DR, DR progressed 2 or more steps on
the ETDRS scale after 6 years’ disease duration(42). The risk of photocoagulation
increased in relation to baseline DR severity.
Recent studies have suggested that the data from these early studies does
not reflect current incidences which are lower in frequency, mostly related to
improvements in management of diabetes rather than of the retinal
complications(29, 32, 43). In addition, there are a number of more recent
incidence studies relevant to the population of diabetic patients in the UK(43, 44).
2.3.3. Incidence of cataract in people with diabetes
The incidence of cataract was 29 (17-46) 1000-person-years-1 in one
study(45), another of hospital diabetic clinic attenders showed the incidence of
cataract was 10.4 (95% confidence interval, 9.0, 11.9) per 1000 person-years,
higher in females(46).
The incidence of cataract in Type 1, non-insulin-treated and insulin-treated
Type 2 was 7, 12 and 18 per 1000 person-years, respectively(47, 48) but this was
confounded by age. Age poor metabolic control and any retinopathy were
significant independent predictors of cataract. Duration of diabetes was a
significant independent predictor of cataract for type 1 patients.
14
Table 2.1 Summary of the range of prevalence estimates in type 1, type 2
and mixed cohort diabetic patients in UK
Popula Retinopathy
Type 1
Type 2
Mixed cohort
tion
grade
UK
Any DR
33.6–36.7%
21–52%
16.5–41%
white
PDR
1.1–2.0%
1.1– 4%
1.1–8%
CSMO
2.3–6.4%
6.4–6.8%
blindness
visual loss
UK
Any DR
11.6%
South
PDR
Asian
CSMO
Blindness
Visual loss
CSMO, clinically significant macula oedema; DM, diabetes mellitus, DR,
diabetic retinopathy; IDDM, non-insulin-dependent diabetes mellitus;
NIDDM, insulin-dependent diabetes mellitus; PDR, proliferative DR
15
SECTION 3
RISK FACTORS AND THEIR MANAGEMENT
3.1 INTRODUCTION
Several risk factors exist for the development and the progression of
retinopathy, and for being registered as partially sighted or blind. Table 3.1
shows the risk factors whether they are treatable or not and the levels of
evidence.
Table 3.1 Risk factors for the development of diabetic retinopathy
Risk factor
Treatable?
duration of diabetes
HbA1c value
hypertension
pregnancy
Grade
evidence
2*
1**
1**
counselling 2
no
yes
yes
no
(but
worthwhile)
renal disease
no
age
no
ACE Inhibition& or angiotensin receptor yes
antagonists inhibition
smoking
no effect on DR
hyperlipidaemia
no effect on DR
Alcohol
yes
Antioxidants
yes
22*
23*
2*
2
None
16
of
3.2 DURATION OF DIABETES
3.2.1 Introduction
The onset of diabetes can be exactly timed in childhood (type 1
diabetes). However, there is evidence of delay from onset of diabetes to
diagnosis in adult onset type 1, and considerable delay of about 8 years in
type 2(49).
3.2.2 Definition
Duration of diabetes is defined for clinical purposes as the time from
Diagnosis of Diabetes. However, it is recognised that sub-clinical diabetes
may be present for a considerable time prior to diagnosis.
3.2.3 Relationship between duration of diabetes and retinopathy.
There is a clear relationship between the duration of diabetes and
the development of retinopathy, in both types 1 and 2 diabetes. In type 1
this is has been demonstrated in both the US Diabetes Control and
Complications Trial (DCCT) results (see later) and in a UK study (29, 50).
The relationship is not so clear in type 2 diabetes but has been shown to be
important in the United Kingdom Prospective Diabetes Study (UKPDS)
modelling of risk factors, particularly since with continuing duration there is
continuing exposure to high HbA1c values(42). The duration of diabetes is
also an important risk factor for progression of retinopathy to sightthreatening eye disease in both types 1 and 2 diabetes(43).
EVIDENCE LEVEL 1
3.3. HBA1C AND GLYCAEMIC CONTROL
3.3.1. Introduction
In most studies glycosylated haemoglobin HbA1c (DCCT aligned) is
used to estimate glycaemic control.
3.3.2. Relationship between HbA1c of diabetes and retinopathy.
In both types 1 and 2 diabetes, observational studies and randomised
controlled trials (RCT) demonstrate that for both type 1 and type 2 diabetes
improved glycaemic control (as measured by HbA1c) reduces the
development of retinopathy and reduces the chance of progression of
existent retinopathy. The benefits of treatment are directly shown in both
the DCCT (Fig.1) and UKPDS studies which are randomized controlled studies
of sufficient size to be robust for both type 1 and type 2 diabetes(51, 52).
The UKPDS glycaemic study was an incidence study which examined
intensive monotherapy for safety profiles as well as differences in glycaemic
17
control. An earlier study(53) treated people with type 2 diabetes who had
failed on oral therapy and in whom insulin treatment was added to control
their glycaemia; the insulin therapy was either conventional or intensive.
The DCCT observational study(54) showed that the higher the initial
HbA1c, and the shorter the duration of diabetes at entry, the greater was
the benefit of intensive therapy and improved glycaemic control. The mean
HbA1c during the trial was the dominant predictor of retinopathy, a 10%
lower HbA1c (e.g. 7.2% versus 8%) was associated with a 44% lower risk. This
risk gradient applied over all the HbA1c values seen with no threshold value
for rapid deterioration. The change in risk is compounded by the duration
of exposure – total glycaemic exposure being most important.
In both DCCT and UKPDS studies, those treated intensively initially
had a worsening in the chance of developing and progression of retinopathy,
followed some three years later by a significant and increasingly significant
improvement in the chance of developing new or progression of existent
retinopathy.
In the DCCT study(51), 1441 patients were followed for a mean of 6.5
years. Intensive control achieved a mean HbA1c of 7.3%, with conventional
control a mean of 9.1%. This intensive control resulted in risk reduction of
76% (95% confidence intervals 62 – 85%) or and 54% (39 – 66%) in worsening
of retinopathy by 54% (39 to 66%); the development of new vessels was
retarded by 47% (14 to 67%)(51, 54). On completion of the study, the
intensive and controlled groups continued to be observed. Within one year
the HbA1c values in each group were similar and the difference was
insignificant at 3 years (8.1 versus 8.2%, P = 0.09) but over the continuing 7
years of the observational study the patients in the intensive control group
continued to have less risk of developing retinopathy when compared with
the control group(55).
The advantages of improved glycaemic control applied to all ages
studied and both genders. In particular a small subset of adolescents showed
the same findings(56). In the Kumamoto study(53), 55 type 2 patients
without retinopathy and 55 with retinopathy were assigned to either
conventional (CIT) or intensive therapy (MIT). Progression of retinopathy in
the secondary prevention group was 19.2% for MIT and 44% for CIT; in the
primary prevention it was 7.7% for MIT and 32% for CIT. The authors
concluded that progression was unlikely if HbA1c was below 6.5%.
In the UKPDS, Type 2 patients demonstrated an increased risk of the
chances of developing retinopathy for 3 – 5 years followed by a gradually
increasing risk reduction of developing retinopathy(52). The observational
data were analysed by a proportional hazards model which concluded that
duration of diabetes and HbA1c values were best thought of as 2
components of glycaemic exposure(57).
There were 3867 newly diagnosed patients randomised to
conventional or more intense therapy. The mean HbA1c values achieved
18
over the following 10 years was 7% (6.2-8.2) in the more intense, and 7.9%
(6.9-8.8) in the conventional. Intensive glycaemic control conferred a 34%
risk reduction in development of retinopathy. There were no differences
between the glycaemic treatment modalities for risk of developing
retinopathy except for chlorpropamide which appeared deleterious. The risk
of needing photocoagulation, and cataract extraction were significantly
reduced.
Initial post-study monitoring observational data (as yet
unpublished) show a similar pattern to the DCCT with continuing
improvement in the more intensively treated group.
EVIDENCE LEVEL 1
3.3.3 Recommendations
Any reduction of HbA1c is beneficial in reducing the development of
new and progression of existing retinopathy.
-
The following recommendations are made:
patients should be aware of their HbA1c, what it means, and how to
lower it.
patients should be encouraged to lower their HbA1c, and be given the
necessary treatment and support to allow this.
if retinopathy is present HbA1c should be maintained at a level below
7% but caution should be exercised if high risk retinopathy is present.
patients should be aware of the potential temporary worsening of
retinopathy should diabetes control improve dramatically, but long
term benefits should be emphasised
Establishment of local links between ophthalmologists and physicians
should be encouraged, in order to facilitate early referral for
management of risk factors in progressive cases.
RECOMMENDATION LEVEL A
3.4. HYPERTENSION
3.4.1 Introduction
In Type 1 diabetes, hypertension is associated with developing
abnormal renal function, including the early stages of abnormal urinary
protein excretion. Hypertension is exceedingly common in Type 2 diabetes,
with a prevalence of 80 – 85% in cohort studies.
3.4.2 Definitions
The definition of hypertension depends in part on the methods used
to measure blood pressure.
The current British Hypertension Society guidelines define
Hypertension in Diabetes Mellitus as systolic blood pressure greater
than/equal to 140 mm Hg, and/or diastolic blood pressure greater
than/equal to 90 mm Hg. Treatment targets should be systolic level <130
19
mm Hg and diastolic < 80 mm Hg. Lower levels may be required for younger
patients with Type 1 diabetes and micrvascular complications.
3.4.2.1 Methods used to measure blood pressure.
In the UKPDS an electronic sphygmomanometer was used, the patient
sat in a quiet room, on their own, and after 5 minutes rest, had a series of 4
readings separated by 2 minutes. The first reading was discarded, and the
mean taken of the others. Similar methods were used in all other studies to
prevent chance casual high readings.
3.4.2.2 Systolic or Diastolic blood pressure
To determine whether intensive diastolic blood pressure control
offers additional benefit over moderate control, the Appropriate Blood
Pressure Control in Diabetes (ABCD) Trial(58) randomised patients to either
intensive or moderate blood pressure control. Hypertensive subjects,
defined as having a baseline diastolic blood pressure of 90 mmHg, were
randomised to intensive blood pressure control (diastolic blood pressure goal
of 75 mmHg) versus moderate blood pressure control (diastolic blood
pressure goal of 80–89 mmHg). A total of 470 patients were randomised to
either nisoldipine or enalapril and followed for a mean of 5.3 years. The
mean blood pressure achieved was 132/78 mmHg in the intensive group and
138/86 mmHg in the moderate control group. Changes in retinopathy were a
secondary outcome. Although intensive therapy demonstrated a lower
incidence of deaths (5.5 vs. 10.7%, P = 0.037) (Fig.2), there was no
difference between the intensive and moderate groups with regard to the
progression of diabetic retinopathy and neuropathy. . At present, there is no
definitive evidence suggesting increased benefits accruing from the
treatment of systolic versus diastolic BP levels.
3.4.3 Relationship between hypertension and diabetic retinopathy
Hypertension has been found to be very important in determining the
chances of developing retinopathy in observational studies.
In Type 1
patients, antihypertensive treatment with ACE inhibitors resulted in a 23%
reduction in the progression of retinopathy (13). In Type 2 diabetes, in the
UKPDS study, tight control of blood pressure (144/82 mm Hg) versus ‘less’
tight control (152/87) resulted in 34% and 47% reduction in significant
deterioration of retinopathy and visual acuity, respectively(59). This
observational relationship can be applied throughout the entire blood
pressure range with no apparent worsening of retinopathy with low blood
pressure.
The beneficial effects of anti-hypertensive medication are
immediate, as are the deleterious effects of further increases in blood
pressure or of stopping treatment, therefore regular measurement of blood
pressure levels is needed, especially in the presence of established
retinopathy.
20
3.4.4 Type of antihypertensive therapy.
The EURODIAB Controlled Trial of Lisinopril in Insulin Dependent
Diabetes (EUCLID) study group(60) investigated the effect of lisinopril on
retinopathy in type 1 diabetes compared with placebo. Eligible patients
were not hypertensive, and were normoalbuminuric (85%) or
microalbuminuric. Patients assigned to lisinopril had significantly lower
HbA1c at baseline. Treatment reduced the development of retinopathy, but
the effect may have been due to its pressure-lowering effect(60). The ABCD
study was unable to demonstrate any significant differences between ACE
inhibitors and dihydropyridine calcium channel blockers(58).
Studies are currently in progress to examine the effects of blocking
the Renin Angiotensin system in reducing the development/progression of
retinopathy over and above the protection afforded by blood pressure
control. Until then, reduction of blood pressure per se with any appropriate
group of antihypertensive is of paramount importance. It may, however, be
appropriate to utilise ACE inhibitors or angiotensin receptor antagonists as a
part of the antihypertensive regimen, as many of the patients with
retinopathy will have concomitant renal disease, where these agents do
appear to posses a specific renoprotective effect, over and above blood
pressure control. The beneficial effects of control of hypertension are
immediate on starting treatment. However, the effects wear off as soon as
control is lost as shown after cessation of the UKPDS: when blood pressure
returned to control levels in the intensive treated group of patients at the
end of the study, the chances of developing retinopathy were identical.
3.4.5 Recommendations
-
The following recommendations are made:
correct blood pressure measurement methodology should be used,
and not casual clinic measurements.
any reduction in blood pressure, especially systolic blood pressure is
beneficial.
patients should be aware of their blood pressure, what it means, and
how to lower it.
patients should be aware of the potential harm if they stop their
therapy and their blood pressure increases.
patients should be encouraged to lower their blood pressure, and be
given the necessary treatment and support to allow this.
there should be regular measurement of blood pressure, to ensure
continuing control.
if retinopathy is present systolic blood pressure should be below
130mm Hg.
an ACE inhibitor or angiotensin receptor antagonist antihypertensive
drug may be considered since it provides additional benefit, over and
above its blood pressure lowering effect.
21
RECOMMENDATION LEVEL A
3.5.AGE
3.5.1 Relationship of age to vision impairment in diabetic patients
Older patients with diabetes have a greater risk of visual
impairment(36).
3.6. PREGNANCY
3.6.1 Relationship of pregnancy to worsening diabetic retinopathy
Most pregnant patients with background retinopathy will not
experience a worsening of their retinopathy during pregnancy. A small and
unpredictable group of patients will progress rapidly to PDR; in addition,
they remain at risk for a year post partum(61). It is difficult to separate the
various likely factors for this since predictive factors include poor prepregnancy control of diabetes, rapid improvement of glycaemic control
intensively during the early stages of pregnancy, and the development of
pregnancy complications such as pregnancy-related hypertension, preeclampsia and fluid retention.
There is limited evidence that counselling to improve control before
conception is beneficial, in terms of deterioration of retinopathy during
pregnancy.
3.6.2. Recommendations
-
The following recommendations are made:
patients should have access to pre-pregnancy counselling, especially
for improvement in glycaemic control.
eyes should be screened before conception, in each trimester and
between 3-9 months post-natally.
RECOMMENDATION LEVEL A
3.7. RENAL DISEASE
3.7.1. Introduction
There is an association between retinopathy and all levels of
abnormal renal function, independent of duration of diabetes and level of
glycaemic control, in both types 1 and 2 diabetes, especially in some ethnic
groups. The commonest means of evaluating renal function is the
measurement of urinary albumin excretion rates. In both Types 1 and 2
diabetes, renal disease evolves through a stage of normoalbuminuria,
progressing to abnormal levels with microalbuminuria and finally to
22
persistent albuminuria (established nephropathy). Traditional measurements
of renal function, such as urea and creatinine, may well remain normal until
well into the established nephropathy stage (persistent proteinuria). All
stages of abnormal renal function with abnormal urinary albumin excretion
are associated with increased incidence of retinopathy. Deteriorating renal
function is also invariably associated with hypertension, including patients
with early nephropathy, as manifest by microalbuminuria, with further
deleterious effects on the development and progression of retinopathy.
3.7.2. Definition
End stage renal failure is defined as a creatinine of greater than 500
µmol/l or requiring dialysis or transplantation.
3.7.3. Relationship between renal failure and worsening of diabetic
retinopathy.
Patients with renal failure develop worsening of their retinopathy
particularly affecting the macula (macular oedema), but are also at risk of
PDR(62). This may relate to mode of therapy with haemodialysis being a
stronger associated risk factor. Conversely treatment of the renal disease
may be associated with an improvement in the retinopathy and a more
beneficial response to treatment, as seen for instance after renal
transplantation, particularly if combined with pancreas transplantation.
Patients with developing nephropathy as determined by the presence
of microalbuminuria invariably have a rise in blood pressure, which may be
the cause of the increased risk of retinopathy.
3.7.4. Recommendations
The following recommendations are made:
-
patients with retinopathy in the presence of established renal
dysfunction require more regular supervision of retinopathy.
aggressive blood pressure control is essential for reduction of the rate
of progression of both retinopathy and nephropathy.
RECOMMENDATION LEVEL A
3.8.
HYPERLIPIDAEMIA
3.8.1 Relationship between hyperlipidemia and diabetic retinopathy
In the WESDR and Hoorn(23, 63) studies there was a correlation
between high cholesterol blood levels and risk of retinopathy in the diabetic
population. This was not found in the UKPDS and as yet no randomised
control trial has shown a benefit of lowering elevated cholesterol levels in
23
terms of risk reduction of development and progression of retinopathy or
blindness.
EVIDENCE LEVEL 1
3.9
SMOKING
3.9.1. Relationship between smoking and diabetic retinopathy
The relationship between cigarette smoking and microvascular
complications of diabetes is complex. However, it appears that cigarette
smoking is not a risk factor for the development or progression of
retinopathy in observational studies(64). It is not clear if this is a direct
causative relationship or a survivor artefact. Discontinuation of smoking is
recommended for reducing the development other complications of
diabetes, especially cardiovascular disease
EVIDENCE LEVEL 1
3.10 ACE INHIBITION
3.10.1 Relationship between ACE inhibition and diabetic retinopathy
Several studies which are not placebo controlled have shown benefit
of ACE Inhibition to diabetic retinopathy over and above blood pressure
lowering(65), for instance the MICROHOPE study. In the UKPDS, there was
no difference between those assigned to captopril compared with those
assigned to atenolol(59). The effective mechanism for the benefits of
blockade of the renin angiotensin system may be reduced intracapillary
pressures, which may also apply to beta blockade. ACE inhibitor or
angiotensin 2 receptor antagonist inhibition is beneficial in delaying
progression of nephropathy and it is likely that ACE inhibition, betablockade and angiotensin 2 inhibition all have an effect at reducing the risk
of developing retinopathy.
EVIDENCE LEVEL 2
3.11. ASPIRIN AND THROMBOLYTIC THERAPY
3.11.1 Relationship of aspirin and thrombolytic therapy to diabetic
retinopathy
Aspirin therapy does not reduce the risk of developing retinopathy,
but also does not increase the incidence of retinal haemorrhages(66).
Reperfusion therapy for acute myocardial ischaemia, with thrombolytic
therapy, does not increase the risk of retinal haemorrhages.
EVIDENCE LEVEL 1
24
3.11.2. Recommendation
The following recommendation is made:
-
retinopathy should not be a contraindication for aspirin therapy or
thrombolytic therapy for myocardial infarction.
RECOMMENDATION LEVEL A
3.12 ANTIOXIDANTS.
3.12.1. Relationship of antioxidant therapy to diabetic retinopathy
Antioxidants are currently under evaluation for several age related
and other diseases such as macular degeneration and cataract. The role of
antioxidants in developing retinopathy, and changing existing retinopathy to
more aggressive disease has been investigated with observational studies.
There is no evidence of effectiveness(67).
EVIDENCE LEVEL 2
3.13
ALCOHOL
3.13.1 Relationship of alcohol to worsening of diabetic retinopathy.
There is no consensus about the effects of alcohol consumption and
the development or progression of diabetic retinopathy. One observational
study reports worsening in some groups(68); whilst another found
improvement(69).
3.14 COUNSELLING FOR DIABETIC RETINOPATHY
3.14.1 Introduction
The management of the diabetic patient with retinopathy requires
teamwork and close liaison between physicians, ophthalmologists, specialist
diabetes nurses, general practitioners, practice nurses and paramedical
staff including chiropodists, dieticians, screeners and many other personnel
including psychologists. The patient and the health care team need to be
kept informed. Only in this way will the risk factors be managed adequately.
3.14.2 Evidence for value of Counselling
The UKPDS Quality of Life study(70) showed that no particular
treatment produced an adverse psychological event, but that complications
did. Treatment for complications such as photocoagulation was an example
of this effect, producing long term anxiety. Another observational
population based study of Type 1 and 2, showed a significant and enduring
elevation of anxiety and depression, above that normally presented in
25
community samples in people with diabetes who were newly registered
blind or visually handicapped(71).
Screening for psychological distress and managing psychological
morbidity is therefore important. All health and social care professionals
working with retinopathy need to be vigilant to the presence of
psychological morbidity. This is currently not standard practice but if
sufficient and timely could prevent psychological and physical deterioration,
social exclusion and dependency. Such screening may be a desirable annual
adjunct to attendance at an eye clinic and would require training of
professionals both in identification and management of distress(72).
The latter study also showed that certain demographic features,
coping styles and thinking style were predictive of poorer psychological
outcome (lower age, poorer physical health status, perception of increased
symptoms, denial, self-blame and lack of acceptance). It may be
appropriate to focus assessment in these areas to develop early intervention
strategies, particularly since avoidant coping strategies may interfere with
the rehabilitative process.
EVIDENCE LEVEL 1
3.14.3
Recommendations
3.14.3.1
Risk Factor Reduction
Due to the chronic nature of and insidious development of diabetic
complications many patients fail to appreciate the seriousness of the
condition and the life-shortening effects of the disease, in particular, the
clear evidence of the importance of establishing good glycaemic control to
delay significantly the complications. This is especially true for retinopathy.
The potential explanation of newly diagnosed retinopathy will depend on
the pre-existent level of education.
It is equally the remit of all medical personnel caring for one or more
aspects of the diabetic state that they explain not only the value of good
control of diabetes but that diet, exercise, avoidance of cigarette smoking
and attention to weight will all have beneficial effects on the prevention of
complications generally. Even in cases of advanced DR with maculopathy, it
is not too late to institute a change of life-style which will benefit the endorgan disease.
Educational aids and advice on how to improve glycaemic and blood
pressure control are now widely available, and in particular can be accessed
from the Diabetes UK web site(73). For those who prefer other languages
than English, the Australian web site is useful.
3.15.3.2. The Young Diabetic
26
A small sub-group of young, patients with type 1 diabetes appears to
be susceptible to a particularly aggressive rapidly advancing form of PDR. In
some cases, even extensive laser therapy fails to control the proliferative
disease and extensive vitreo-retinal surgery is performed with limited
functional success.
It is unclear whether poor compliance and/or poor attention to their
diabetes is the main factor in the progression of the disease or whether
other factors such as hormone dysfunction particularly growth hormone/IGF1, have a part in this serious condition. These patients require special
attention and monitoring and the value of frequent, positive counselling
cannot be overstated. Alteration of their therapeutic regimen, including
insulin therapy, may improve adherence, and consequently glycaemic
control.
3.15.3.3. Driving and Visual Fields
It is now recognised that panretinal photocoagulation (see Section 6,8
and 9) may have damaging effects on visual field function, in addition to the
effects of retinopathy itself. In the UK, the Driving and Vehicle Licensing
Authority (DVLA) has set minimal standards of visual field function which are
required for permission to hold a Driver's License.
All patients who require retinal photocoagulation should be asked to
provide informed written consent to therapy as for any surgical procedure.
It is the ophthalmologist's duty to explain clearly the reasons for laser
therapy, the type of therapy to be undertaken and the likely effects on the
patient's vision.
In the UK, it is the patient's responsibility to inform the DVLA that
he/she has had laser therapy for diabetic retinopathy. If this is not possible,
then the patient's next of kin or GP should inform the DVLA of the patient's
visual status. As a last resort the ophthalmologist is duty-bound to inform
the Medical Adviser of the DVLA. Advice regarding driving restrictions on
patients with diabetic retinopathy may best be provided in the form of an
information leaflet.
3.15.3.4 Pregnancy
Patients with diabetes who are considering pregnancy should
preferably attend a pre-pregnancy clinic, with their husband / partner if
possible, where the risks of pregnancy for the eyes can be carefully
explained within the context of each patient's particular state of health. In
particular, the potential deleterious effects of tightening control on
retinopathy can be explained and the need for frequent monitoring of the
retinopathy throughout the pregnancy. In addition, the safety of fluorescein
angiography and or laser therapy if required during the pregnancy, can be
emphasised.
27
The minimum recommendations suggested by Diabetes UK are that
fundus examination should be performed at pre-pregnancy, at the diagnosis
of pregnancy, at the end of each trimester and 9 – 12 months post-natally.
More frequent examinations are recommended if active disease is detected.
Patients who have become pregnant sometime after scatter PRP laser
therapy for proliferative diabetic retinopathy are considered not at
significant risk of developing reactivation of proliferative disease but should
be monitored and counselled during their pregnancy.
3.15.3.5. Social Services for the Visually Handicapped
In spite of appropriate treatment a small group of patients will fail to
respond and progress inexorably to severe visual impairment and blindness.
It is important that such patients are advised fully concerning the support
services which are available to them through the Social Services and in
particular what benefits are available to them to enable them to lead as
normal a life as possible. In particular with appropriate visual aids they
should be encouraged to maximise the residual vision which they possess.
The ophthalmologist’s role is to ensure that such patients are referred to
the appropriate professionals and services for their individual needs.
Early registration with the Social Services will minimise the
handicapping effects of visual impairment through the use of appropriate
low visual aids for use at home and at work, including CCTV's (closed circuit
television). Young people in particular benefit from mobility and
rehabilitation support services of this nature.
There should also be close liaison with the diabetes specialist nurse and
often district nurse to ensure that treatment can be given easily without
needing extra effort: dosette boxes for tablets, and different injection
devices and insulin regimen can be helpful.
RECOMMENDATION LEVEL A
28
SECTION 4 CLINICAL FEATURES OF DIABETIC RETINOPATHY
4.1 NON-PROLIFERATIVE
PROLIFERATIVE)
DIABETIC RETINOPATHY (NPDR)(BACKGROUND
AND PRE-
NPDR includes all forms of retinopathy which precede the
development of new vessels. The AAO classification describes three grades
(mild , moderate, severe) while the NSC-UK system describes two grades:
background (Level R1) and pre-proliferative (Level R2) (see Section 1.2 and
Appendix). Background retinopathy may consist of microaneurysms only
(Fig. 3), progressing to microaneurysms and small haemorrhages ("dots”),
and then to larger haemorrhages (blots") (Fig.4) which can be of various
degrees (Fig.5). Flame shaped haemorrhages are also seen in combined
hypertensive/diabetic retinopathy (Fig 6).
Exudates (background retinopathy, Level 1), more common in Type II
diabetes, are waxy yellow deposits with discrete edges, extending
sometimes to the equatorial fundus often in clusters or forming circinate
patterns whose centre may be a leaking microaneurysm (Fig 7). “Cotton
wool spots” (CWS) (preproliferative retinopathy, Level 2), are fluffy white
lesions representing ischaemia-associated lesions of the nerve fibre layer hence are only found in the posterior retina where the nerve fibre layer is of
appreciable thickness (Fig.8). They may appear suddenly during periods of
changing glucose regulation and in association with hypertension.
Venous dilatation may occur as an early sign (see Fig.5) but becomes
more pronounced as more of the capillary bed is closed. A general
dilatation of the veins is observable even when the retinopathy is mild and
is to be distinguished from venous beading, which is a sign of
preproliferative retinopathy (Level 2) (Fig.9). Beading is indicative of
extensive non-perfusion (due to capillary closure) of the retina and
manifests fusiform bulges in the wall of the vein (Fig 9). Fluorescein
angiography will invariably show closure of the capillary bed on either side
of the vessel (Fig. 10). A further important FFA sign of pre-proliferative
disease is 360 degree of mid-peripheral non-perfusion which demarcates the
ischaemic interface and guides future treatment protocols for
photocoagulation (see Section 9)(74).
Other signs of severe / preproliferative retinopathy are dilated
capillaries which can mimic new vessels but are better described as
intraretinal microvascular abnormalities (IRMA) (see Fig. 6). They frequently
occur adjacent to CWS’s, and may be associated with other signs such as
“omega” venous loops (Fig. 11,12), venous reduplication and white lines
which represent occluded arterioles (Fig 13). According to the Early
Treatment for Diabetic Retinopathy Study (ETDRS) report, severe / preproliferative retinopathy is definitely present if the signs conform to the
following rule: ie the presence of venous beading and/or IRMA and /or large
blot haemorrhages in 1-3 quadrants of the fundus(1).
29
A classification of NPDR as mild, moderate and severe has been
proposed as an International Diabetic Retinopathy Severity Scale (see
American Academy of Ophthalmology Web
http://www.aao.org/aao/education/library/) (3, 75,
site:
available
at:
76) and provides
classification criteria used in several large studies including the DCCT(77)
and the UKPDS(59, 78, 79). However, NPDR severity grading using the
additional classification of mild, moderate, severe and very severe has been
used for major studies such as the ETDRS and is based on standard
photographs of fundus lesions set by the Airlie House Grading system (1, 80).
Precise classifications for the purposes of clinical trials and other
studies based on the Airlie House grading system have used the following
criteria to define each of the grades of NPDR:
•
•
•
•
mild:
at least one microaneurysm
moderate: severe retinal haemorrhages in at least one quadrant, or
CWS, venous beading or IRMA definitely present
severe:
severe retinal haemorrhages in four quadrants; or
venous beading in 2 quadrants; or extensive IRMA in one quadrant
very severe: any two of the features of severe NPDR.
This has later been simplified to three grades(1) as follows:
Mild NPDR: at least one microaneurysm, but not as severe as moderate
NPDR.
Moderate NPDR: extensive intraretinal haemorrhages and/or
microaneurysms, and/or cotton wool spots, venous beading or intraretinal
microvascular abnormalities definitely present but not as severe as severe
NPDR.
Severe NPDR: cotton-wool spots, venous beading and IRMA all present in at
least two quadrants; or two of them present in at least two quadrants with
intraretinal haemorrhages and microaneurysms present in all quadrants; or
IRMA present in each quadrant, being severe in at least one of them, but no
PDR.
However, such classifications are difficult to use in clinical practice
on a routine basis since certain features such as venous beading are common
to both moderate and severe retinopathy. It is preferable, therefore, to
consider NPDR as either mild or "low risk" (ie not requiring regular close
observation by an ophthalmologist) and severe or "high risk" (ie requiring
regular close observation as a prelude to scatter panretinal
photocoagulation (PRP)).
This simple approach has been described
previously(2) approximating to Level R1 (background) and Level R2 (preproliferative) using the NSC-UK system and may be of more value in practice
(See Section 1, Table 1.1 and Appendix).
30
Therefore, for the purposes of defining those patients at risk of
developing new vessels, the features of "low risk" (mild/moderate) NPDR
(background DR) are :
•
mildly dilated veins,
•
microaneurysms,
•
dot haemorrhages,
•
exudates,
•
occasional CWS’s.
and the features of "high risk", pre-proliferative (severe) NPDR are
•
IRMA,
•
venous beading and “omega” loops,
•
clusters of large "blot" or "blotch" haemorrhages,
•
multiple CWS’s.
(Note, maculopathy is covered in section 2.4.)
EVIDENCE LEVEL 1
RECOMMENDATION LEVEL A
4.2. PROLIFERATIVE DIABETIC RETINOPATHY (PDR)
Proliferative retinopathy (PDR) usually appears late in the disease.
However, PDR may occur with little warning in young adolescent or postadolescent individuals and have a particularly aggressive course usually
because of poorly controlled diabetes and often failure to attend for
ophthalmological review. The retinopathy in these individuals may be
“florid” see Section 9.5.3).
New vessels mostly arise from the venous side of the circulation and
are recognisable by their abnormal location and their unusual pattern (Figs.
14, 15). Unlike normal vessels which have a branching pattern that divides
dichotomously, new vessels form loops or rete (arcades). While normal
vessels appear to supply or drain an area of retina, it may be difficult to
identify such a role for new vessels. For example, a rete of vessels may
arise from the main trunk of a vein and criss-cross the vessel randomly or a
venule may arise from the disc and after forming a tortuous loop wind back
towards the disc (Figs. 16,17,18). Early new vessels usually lie flat on the
surface of the retina, but as the vitreous detaches, they are drawn forward.
Patients with new vessels individuals require extensive counselling
(see Section 3). It is important to emphasise that new vessels by themselves
rarely produce symptoms; their sequelae are the cause of visual loss.
New vessels are classified by (a) location and (b) severity (see Section
1.2.2).
(a) Location. New vessels arise from the retina (NVE) (Figs 14,17) or the disc
(NVD) (Figs.18-20). Most new vessels arise from veins in a central, circular
31
area about 31/2 disc diameters from the disc margin in any of 4 quadrants.
New vessels may also arise peripherally and be missed on examination. In
such patients there may also be evidence of rubeosis (iris new vessels, see
below). Where there is sectoral ischaemia, new vessels characteristically
arise at the junction of the perfused and non-perfused area as demonstrated
on fluorescein angiograms (Figs. 21,22). In eyes with widespread ischaemia,
NVD are common. Disc NVD may be flat or forward depending on the
position of the posterior vitreous face.
(b) Severity. New vessels per se do not cause visual loss. However, their
sequelae may. Accordingly in attempts to define risk of visual loss, major
treatment studies such as the DRS, the ETDRS and the DRVS(81-99)
combined the dual risk of developing new vessels and of developing visual
loss in a continuous grading system of retinopathy from preproliferative
(severe and very severe retinopathy) to proliferative (early PDR, high risk
PDR and severe PDR). Only the high risk PDR and severe PDR were
recommended for pan-retinal photocoagulation in all cases. Severe PDR
included cases of retinal fibrosis and tractional retinal detachment.
Involutionary PDR is also a late form of PDR which has responded to
treatment or regressed spontaneously (rare).
EVIDENCE LEVEL 1
Untreated NV (D or E) lead to vitreous haemorrhage (VH) and
blindness. VH may be subhyaloid before the vitreous is fully detached and
present as small boat-shaped “crescents” with a level superior border where
the PVD is present (Figs. 23-25).
In the late stage of the natural history of proliferative disease,
fibrous tissue (gliosis) gathers around the new vessels and contraction of this
tissue causes repeated bleeding and eventually, tractional retinal
detachment. Occasionally, fine epiretinal gliosis occurs with minimal
traction on the retina but this is uncommon.
4.3 MACULOPATHY
Visual loss in diabetic maculopathy is usually the result of macular
oedema but there is no direct correlation of the clinical appearance and
degree of visual loss. Macular oedema may be difficult to detect;
characteristically it appears as “retinal thickening” on binocular,
stereoscopic slit lamp examination. Retinal thickening at the macula can be
confirmed objectively by imaging techniques such as scanning laser
ophthalmoscopy (100) and optical coherence tomography (OCT)(101-106)
but most of these techniques have not as yet been validated in large
multicentre studies.
When maculopathy occurs within one disc diameter of the fovea, it is
termed clinically significant macular oedema (CSMO)(107) (See Section 7)
since under these conditions it is considered to be visually threatening. This
term was introduced to facilitate studies of laser therapy for macular
oedema. However, the term itself is somewhat confusing since each of the
32
different types of CSMO may have different outcomes and the evidence for
progression to sight loss is not clear since definitive natural history studies
have not been performed. Current clinical trials of new medical therapies
for macular disease may provide data on the natural history of macular
disease.
Fluorescein angiography also reveals vessels with abnormal
permeability causing leakage and pooling of dye in the late phase but this
does not consistently correlate with CSMO(107, 108). A classification of
maculopathy based on ophthalmological features is detailed below. However
it is important to note that the terms “focal” and “diffuse” are used to
convey a sense of the extent of macular involvement, and if the
ophthalmological findings are interpreted in conjunction with the corrected
visual acuity a more accurate impression of the severity of disease will be
obtained. For instance, diabetic maculopathy with reduced vision may
occur in the relative absence of CSMO and fluorescein dye leakage on
angiography. In this condition, ischaemia is the likely pathology.
Maculopathy may also be tractional ie where there is vitreo-retinal
adhesion and there is forward contraction of the vitreous gel from the
retinal surface. This can be visualised by optical coherence tomography
(OCT) and may constitute a component of mixed maculopathy (see below)
4.3.1 Clinical types of diabetic maculopathy
4.3.1.1. Focal maculopathy
The characteristic features of focal maculopathy are well
circumscribed, leaking areas associated with complete or incomplete rings
of hard exudates. These are often related to micro-aneurysms, particularly
in the centre of exudative rings (Figs 7,26,27). The exudative rings have a
predilection for the perifoveal area where the retina is thickest. The focal
areas of leakage are thickened by retinal oedema and fluorescein
angiography is usually not necessary to identify them.
4.3.1.2 Diffuse maculopathy
Diffuse maculopathy consists of generalised thickening of the central macula
caused by widespread leakage from dilated capillaries in this area. Severe
oedema is a feature and it is often associated with cystic changes. The
other features of diabetic retinopathy may not be present and in particular
there may be no exudates. In severe cases it may be impossible to identify
the fovea due to the diffuse retinal thickening. The fluorescein angiogram
may provide more definitive evidence of maculopathy than the
ophthalmoscopic picture (Figs. 28,29). . There is evidence also that retinal
pigment epithelial damage may contribute to the macular oedema probably
by failing to remove the tissue fluid accumulating in the retina from the
leaking capillaries(109).
4.3.1.3 Ischaemic maculopathy
33
Ischaemic maculopathy may be suspected, based on unexplained
visual loss in the presence of a relatively normal looking macula. Blot
haemorrhages in the paramacular region may be indicative of ischaemic
maculopathy.
There may be associated haemorrhages and exudates
elsewhere. The exact extent of the ischaemia can only be seen on
fluorescein angiography as shown by an increase in the foveal avascular
zone (FAZ) (Fig. 30-32). It is therefore important that patients with
maculopathy in which ischaemia is suspected are investigated with this
technique. There does not appear to be a direct correlation between the
visual acuity and the degree of ischaemia. Perifoveal microaneurysms in the
absence of retinal thickening may indicate ischaemic maculopathy. In
addition, sometimes there may be patches of ischaemia present within an
area of exudative maculopathy indicated by a cotton wool spot (Fig.33).
4.3.1.4 Tractional maculopathy
Previously it has been accepted that vitreoretinal maculopathies are
due to traction caused by vitreoretinal adhesions or by membrane formation
either as epiretinal membranous sheets or distinct transretinal bands.
Tractional retinoschisis may also occur and may be one form of severe
macular oedema. In the extreme form traction retinal detachment occurs
(110).
Since the introduction of optical coherence tomography (OCT)
imaging, it has become clear that a tractional element may apply to many
diabetic maculopathies which appear predominantly intraretinal (101, 103,
106), and that the distinction between the two classes of maculopathy may
be blurred. Difficulties relate to the interpretation of OCT images.
Currently, several reports have established in-house methodologies for
evaluation of the normal macula. Clear evidence of macular thickening has
been demonstrated but the sensitivity and specificity of the technology has
been validated in only a few centres and different centres adopt different
criteria for examination (105, 111). However, it appears to be possible to
differentiate between tractional and non-tractional macular pathology(101,
104, 105, 111).
4.3.1.3
Mixed maculopathy
Many cases do not fit exactly into the groups described above.
Frequently, there is combined pathology particularly of diffuse oedema and
ischaemia. Variable degrees of traction may also be involved. Nevertheless,
classifying the maculopathy according to its predominant features is useful
from a therapeutic and prognostic point of view.
34
SECTION 5
SCREENING FOR DIABETIC RETINOPATHY
5.1 INTRODUCTION
Several guideline groups have published in recent years on various
aspects of diabetic retinopathy, including NICE(112), SIGN(113) and HTBS
(5, 114). This section of the revised RCOphth guidelines covers background
issues in screening and makes specific recommendations of relevance to
ophthalmologists.
5.2 DEVELOPMENT OF SCREENING IN THE UK
The development of screening in Europe was first encouraged by the
St. Vincent Declaration which in 1992 set a target for reduction of new
blindness by one third in the following 5 years (115). The British Diabetic
Association (now Diabetes UK) supported the establishment of mobile
photographic screening in a number of UK centres which has been shown to
be effective with high sensitivities and specificities(116, 117). At the same
time a number of optometry based programmes were reporting various
levels of success. This led to calls for the introduction of screening in the
UK(118, 119) which was taken up by the National Screening Committee
(NSC) of the Department of Health with a proposed National Risk Reduction
Programme(120). In late 2002 the National Service Framework for Diabetes
was published which includes the specific requirement for the introduction
of a national programme for screening for diabetic retinopathy in England
and Wales(121). At the same time the Health Technologies Board of
Scotland (HTBS) published its recommendations with detailed guidance on
implementation(114) followed by the adopted grading scheme(5). At the
time of publication an implementation process was underway in all four UK
nations with the aim of 80% coverage by 2006 and 100% coverage by the end
of 2007. A consensus grading protocol has been developed(4) and details are
available on the NSC website(122).
5.3 EVIDENCE FOR THE EFFECTIVENESS OF SCREENING
The evidence of effectiveness of screening is based on evidence of
treatment efficacy presented later in Sections 7.3.1 and 9.3, especially
after early detection, and of cost- effectiveness. Screening for diabetic
retinopathy has been shown to be cost-effective in health economic
terms(123-125). A Department of Health (DoH) commissioned three-centre
study of cost-effectiveness in diabetic eye screening reported relatively high
costs per true positive case detected(126, 127). This was improved in later
studies using screening techniques with higher sensitivity and
specificity(117). A health economics study of the effectiveness of changing
from opportunistic to systematic screening reported a small incremental
cost for a large increase in cases of sight threatening diabetic retinopathy
(STDR) detected(128). Diabetic retinopathy therefore represents an
35
excellent paradigm for screening as laid out in the principles for screening
of human disease described by Wilson and Junger in 1968(129).
5.4 ORGANISATION OF SCREENING SERVICES
The introduction of National Screening Standards by 2006 will alter
significantly the delivery of screening in the UK. The key feature of these
standards is the need for rigorous quality control at all stages and for all
personnel. Internal and external quality control are requirements for
screening services and will be monitored through regional quality assurance
centres with submission of outcome data as a minimum data set to a central
data quality network.
A key requirement for the introduction of systematic screening in the
UK is the need for disease registers in all Primary Care Trusts. This will be
essential to achieve full coverage of the target population.
5.5 SCREENING METHODOLOGY
Various screening methods have been employed in the past depending
on local expertise and staff availability(117, 130). Because of the need for
quality control the NSC has determined that the method of screening for
England and Wales will be digital photography through dilated pupils.
Scotland has adopted a non-mydriatic protocol with the option of pupil
dilatation if images are poor.
Two options exist for the delivery of NSC/HTBS standard screening:
(1) ambulant primary care based screening by teams of retinal screening
technicians
and
(2) optometry based with photography in optometry practices.
In each case grading will be performed using trained and quality controlled
graders either in central grading units or in optometry based grading
practices. During the transition to photographic screening slit lamp
biomicrosopy will continue to be used by optometry screening systems.
Opportunistic screening should continue in diabetic clinics and
elsewhere for case detection of patients who fail to attend or are missed
from systematic screening.
It is recognised that photography cannot detect all cases of oedema
particularly if not associated with exudates but these cases are relatively
rare and should be detectable if the patient has symptoms of reduced
vision. With rapid advancements in technology new approaches to screening
may prove effective including computerised methods for detection and
assessment of retinopathy(5, 131-133).
36
5.6 GRADING AND REFERRAL
A national consensus grading protocol has recently been agreed for
England and Wales(4) with the following key principles :
to detect any retinopathy
to detect the presence of sight threatening diabetic retinopathy
(STDR)
to allow precise quality assurance at all steps
to minimise false positive referral to the hospital eye service
The grading protocol is described briefly below and fully in the
Appendix. Four discrete ophthalmoscopic entities are identified.
---------------------------------------------------------------------------------------------Table 5.1 Disease grading protocol in National Guidelines on Screening for
Diabetic Retinopathy – minimum data set
Retinopathy (R)
Maculopathy (M)
Photocoagulation (P)
Level 0
Level 1
Level 2
Level 3
Level 0
Level 1
Level 0
Level 1
None
Background
Pre-proliferative
Proliferative
None
Present
None
Present
Unclassifiable (U)
---------------------------------------------------------------------------------------------The management of each type of case after screening is as described in the
following Table:
---------------------------------------------------------------------------------------------Table 5.2 Management of cases after completion of grading in the National
Guidelines on Screening for Diabetic Retinopathy for England and Wales
Retinopathy (R)
R0
R1
R2
R3
M1
P1
Annual screening
Annual screening
Refer to HES
Fast-track referral to HES
Maculopathy (M)
Refer HES
Photocoagulation (P)
New screenee → refer HES
Quiescent post treatment
→ annual screening
Other lesions (OL)
Refer to HES or inform primary physician
Ungradable /unobtainable (U) Poor view but gradable on biomicroscopy
→ refer HES
Unscreenable
→ discharge, inform GP
(option to recall for further photos if purely technical failure)
---------------------------------------------------------------------------------------------Legend HES = Hospital Eye Service
37
A similar protocol has been developed for Scotland with the addition
of one level each of retinopathy and maculopathy (5, 114). The two grading
protocols map to each other for future data comparison. They also broadly
correlate with the International Classification System recently proposed but
are aimed at screening technologists and other non-specialist users(3) (see
Appendix and Section 1, above). They can be expanded and cross-mapped
with existing and future research grading protocols.
5.7 POPULATION TO BE SCREENED
All patients aged over 12 years should be screened. Screening should
be increased in frequency during pregnancy(134, 135). Particular targeting
of post cataract diabetic patients and “at risk” ethnic groups might be
considered.
5.8 FREQUENCY OF SCREENING
Both the NSC and HTBS have determined that screening should be
performed annually for all patient groups. Evidence is emerging that less
frequent screening may be appropriate for patients with no retinopathy (43,
79). Similarly more frequent targeted screening may be appropriate for
patients with intermediate levels of retinopathy and maculopathy(43, 114).
5.9 QUALITY STANDARDS
A series of quality standards has been developed as part of the process of
implementing screening in England and Wales with similar standards
developed for Scotland and Northern Ireland. The full list is available in the
UK NSC Workbook, “Essential Elements in Developing a Diabetic Retinopathy
Screening Programme”(122). The table below lists the standards which have
greatest impact on the HES.
Table 5.3: National quality standards for diabetic retinopathy screening relevant to
hospital eye service.
Standard Objective/Criterion
1
4
10
To reduce new blindness due to diabetic
retinopathy
Reduction within 5 years
To maximise the number of invited persons
accepting the screening test.
Initial screen
Repeat screen
To ensure timely consultation for all screen
positive patients.
Time between notification of +ve test and
consultation:
PPDR (R2)
PDR (R3)
Minimum
standard
10%
Achievable
standard
40%
70%
80%
90%
95%
70% <13 wks
70% <13 wks
95% <13 wks
95% <13 wks
38
11
12
13
maculopathy (M1)
To ensure timely treatment of those listed by
ophthalmologist.
Time between listing and first laser in a course:
PDR (R3)
maculopathy (M1)
To minimise overall delay between screening event
and first laser in a course.
PDR (R3)
maculopathy (M1)
To follow up screen positive patients.
Combined cancellation and DNA rate for
ophthalmology clinic
for PDR within 1 month
for maculopathy within 6 months
70% <2 wks
95% <2 wks
90% <2 wks
70% <10 wks
95% <2 wks
95% <10 wks
70% <4 wks
70% <13 wks
95% <4 wks
95% <15 wks
<10%
<10%
<5%
<5%
5.10 ROLE OF THE OPHTHALMOLOGIST IN SCREENING
The role of the ophthalmologist in the delivery of screening and
management of patients with diabetes is pivotal. The responsibilities of the
ophthalmologist are :
-
to form a team with one or more diabetologists to lead the delivery
of the screening programme. A specific linked ophthalmologist is
required for each individual programme.
to involve local management structures at PCT and SHA level
to act as higher level grader as appropriate to local methodology
to act as quality assurance reference standard after suitable training
to ensure the training and accreditation of local screening staff
to agree and monitor local quality assurance
to ensure access to prompt treatment within agreed quality standards
(10 to 12)
to organise the collection and prompt transfer of data on vision and
disease outcome within the minimum data set to central data
collection networks. This will most likely be best achieved through
the establishment of dedicated clinics for the management and
follow-up of cases detected through screening.
39
SECTION 6 LASERS
Photocoagulation for diabetic retinopathy is now performed almost
exclusively with the use of ophthalmic lasers. There are various types of
lasers currently in use and others under development.
6.1 METHOD OF LASER APPLICATION
Laser energy may be applied to the retina either through the dilated
pupil using a contact lens or the indirect ophthalmoscope, or externally
through the sclera. Transpupillary laser is normally applied using the slitlamp bio-microscope and a contact lens. The modern wide-angled contact
lenses are superior to the 3 mirror contact lens although the mirrors on the
3 mirror may enable laser to be applied more peripherally to the retina.
Contact lenses such as the VOLK or MAINSTER or RODENSTOCK lenses give a
good view of the macula, the equatorial and pre- and post- equatorial
regions. These lenses give an inverted image but provide easy access to the
retina even in the presence of media opacity such as mild to moderate
cataract.
Lasers can also be applied using a non contact indirect method such
as the 90 dioptre or 66 dioptre or superfield lenses again using a biomicroscopy technique with the slit-lamp. They may also be used with special
adaptation of an indirect ophthalmoscope and this enables good access to
peripheral retina and is the method of choice when applying laser during a
general anaesthetic. It is very important to remember that the spot size
may vary with the different types of lenses that are used and the operator
should be familiar with the lens he or she normally uses. A sample of
different spot sizes achieved with different lenses is shown in the table
Table 6.1 at the end of this document
Trans-scleral laser therapy may also be used and a special
attachment for the DIODE laser is available for this application. The laser
intensity is monitored through an indirect ophthalmoscope and lens.
6.2 LASERS
Optical radiations produced by gas or solid lasers are unique in that
they are emitted at effectively one wavelength. DYE lasers are produced
with inorganic dyes and have varying wavelengths (Fig. 34). Gas lasers
(ARGON and KRYPTON) produce optical radiations in the visible spectrum
while the newer DIODE lasers produce energy in the infrared band. The
infrared lasers can be either continuous or multipulsed (MICROPULSE).
Lasers act by inducing thermal damage after absorption of energy by tissue
pigments. The three main pigments are luteal pigment, haemoglobin and
melanin and the appropriate laser wavelength can be used to be selectively
absorbed in one or more of these three pigments. The main target cell
however is the pigment epithelium and this is site where much of the tissue
damage is induced.
40
6.2.1 The ARGON Laser
The ARGON laser is the commonest and main source of laser energy
for treating diabetic retinopathy. The ARGON laser produces two major
peaks of energy in the 488 and 514 wavelengths (Figure 22). The 488
wavelength has been shown by reflection off the contact lens to cause
operator blue colour vision damage and this wavelength is now filtered out
of the system(136-139). The 514 wavelength has a potential for causing
similar damage but this has as yet not been proven; to prevent reflection of
this waveband there is a barrier filter and the aiming beam is replaced with
a HeNe (helium neon) laser which is coaxial with the treating laser beam.
This green laser energy is absorbed both by haemoglobin and by pigment
epithelium. It is therefore possible with this wavelength to directly close
microaneurysms or close new blood vessels and if applied over a retinal
vessel, may cause spasm or closure of the vessel. However in clinical
practice, although it is possible to close vessels, the main application of the
laser is to the underlying pigment epithelium where it produces a visible
burn. A burn if gently applied causes a blanching of the outer neural retina;
a more intense laser burn will produce marked whitening of the entire
retinal thickness with a surrounding pigment ring developing later. The
energy applied to the pigment epithelium raises the temperature by
approximately 10 degrees C with a temperature gradient from the centre of
the burn to the adjacent retina resulting in enlargement of the visible area
of RPE cell loss, damage to the neural retina and progressive choriocapillaris
atrophy. It is therefore important that the laser energy should be set to
induce a minimal reaction at the time of application.
Although the second peak from the ARGON laser is in the 488 this
wavelength has now fallen into disuse. The disadvantages of this wavelength
was that it is absorbed by the luteal pigment in the nerve fibre layer in the
macular area risking damage to the perimacular nerve fibre layer. The 514
nm wavelength is minimally absorbed by the luteal pigment and therefore is
safer for treatment of retina close to the macula(140-142).
6.2.2. The KRYPTON laser
KRYPTON laser peaks at 647 nm and 568 nm and thus emits in the red
and yellow wavebands. The red waveband was initially thought to be useful
in treating parafoveal lesions because it is not absorbed by luteal pigment.
However, this colour is no longer used because of the super-sensitivity of
the pigment epithelium to changes in power. A small increase in power
changed a white RPE reaction either to a haemorrhage or to disruption of
the pigment epithelium. A slight tilting of the lens leading to a change in
the spot size had the same effect. The yellow peak of the KRYPTON laser is
similar to the yellow of the DYE laser.
41
6.2.3. The DYE laser
The Dye laser (570nm – 630nm) was developed in order to give a
variable wavelength laser in the green, yellow and red wavebands. In the
green waveband it had no advantage over the ARGON laser and the red
waveband is similar to the KRYPTON and has the same complications.
However the yellow wavelength (577 nm) has gained some popularity
because it is absorbed by haemoglobin and therefore direct closure of
microaneurysms and blood vessels can be achieved. In addition, much less
power is required compared to the ARGON laser to achieve a satisfactory
burn and therefore in those patients with a low pain threshold or very thin
retinas, this wavelength can be very helpful(143, 144). Some operators feel
that they are most comfortable treating with this wavelength. The yellow
wavelength can be obtained either with the KRYPTON laser or with the DYE
laser.
6.2.4. The DIODE Laser
The DIODE laser at 810 nm in the infrared or invisible spectrum is
delivered via a portable machine. The lack of a bright flash provides
increased patient comfort. Also because of the minimal bleaching of the
retina, rapid recovery from the laser treatment occurs. However with the
DIODE laser the end point is more difficult to assess being a greyish lesion at
the level of the pigment epithelium rather than more obvious white lesion
produced by other wavelengths. If the laser surgeon is unaware of this
difference, there may be a tendency to raise the power of the DIODE laser
to produce a white lesion similar to that produced with the ARGON laser
and that this more intense lesion may cause pain and excessive damage to
the retina(145, 146). Around 9% of the energy from the diode laser is
absorbed by the pigment epithelium, the remaining energy penetrating into
the choroid to be absorbed by choroidal melanocytes compared to the 50%
energy uptake by the RPE from the ARGON laser(147, 148)
The DIODE laser has been adapted to fire in a rapid sequence
micropulse mode (THE MICROPULSE LASER). In this mode there are short
applications of laser of approximately 100 micro-seconds in length with an
interval in the region of 1900 micro-seconds. Thus 100 micro-bursts of the
laser can be put into an envelope of 0.2 of a second.
The method of
application of this laser is to increase the power of the laser to achieve a
whitening of the retina and then to reduce the energy levels by around 50%
to continue treatment. The effect of this laser is to raise the temperature
within the pigment epithelium by only thus minimising collateral damage to
both neuroretina and choroid. In addition, unlike the DIODE laser in which
pain may occur, with the MICROPULSE there is no associated pain. Initial
non-randomised clinical studies in particular for diabetic maculopathy are
encouraging(149, 150) and there is currently a large multi-centre study in
progress comparing this laser with the ARGON laser.
42
6.2.5 The Frequency-doubled YAG laser
Recent application of the frequency doubled YAG laser has shown that it is
as effective in treatment of diabetic macular oedema as other laser types
and that it is gaining some popularity(151, 152).
6.2.6 Lasers in Development
The YLF laser (Yitrium Lithium Fluoride) is in the infrared
wavelength. It is a picosecond multipulse laser which selectively destroys
melanosomes within the pigment epithelial cells, leading to dysfunction but
not death of the RPE cells. Thus, the YLF laser appears to induce even less
collateral damage than the MICROPULSE laser. This laser is currently under
clinical trial for treatment of diabetic maculopathy.
6..3. LASER APPLICATION : GENERAL PROTOCOLS
Laser treatment can be carried out either as a single application or in
repeated sessions. Both eyes can be treated in the same session both for the
macula and for the peripheral retina. Caution should be taken when
treating in the macular area when there are associated exudates lying
immediately adjacent to the fovea as sometimes when the oedema has been
treated, the exudates increase and these can encroach into the fovea and
permanently affect foveal function. Under these circumstances, the
treatment should be fractionated. The aim of treatment of panretinal
photocoagulation (PRP) is to destroy the areas where there is capillary nonperfusion / retinal ischaemia. In some eyes this may mean an initial
treatment of over 2000 burns of 500 microns size, or more if the burn size is
smaller. If there is an inadequate response without full regression of new
vessels, then re-treatment can be carried out. This re-treatment can be
performed within one month to three months of the initial treatment. If
there has been insufficient laser prior to vitrectomy, then further laser can
be applied during the vitrectomy via the indirect ophthalmoscope or the
endolaser (see section on vitrectomy).
RECOMMENDATION LEVEL A
6.4. SIDE EFFECTS OF LASERS
6.4.1 Pain
Delivery of laser energy to the ocular fundus may in some cases be
associated with pain. Diode lasers may be more painful than conventional
lasers. The cause of the pain is unclear but may be due to direct thermal
damage to branches of the posterior ciliary nerves. Pain may be prevented
with the use of simple analgesia but on occasion may require entonox,
peribulbar anaesthesia, or less frequently general anaesthesia, to achieve a
satisfactory full PRP particularly in patients with florid proliferative
retinopathy in whom a delay in therapy may be risky. Pain may also be felt
by patients who have had previous laser treatment if the new laser burns
43
encroach on the previously treated areas. It is therefore important when
applying repeat laser therapy to try to avoid the previously treated areas.
6.4.2. Vitreous haemorrhage
Laser therapy in patients with forward new vessels may be sufficient
to cause marked regression of vessels which separate from the posterior
hyaloid face and produce vitreous and subhyaloid haemorrhage. In most
cases this is a rare event but patients require information concerning this
risk prior to initiation of therapy.
6.4.3. Effect on visual function
There is now good evidence that the risk of causing reduction in
visual field is around 40-50% after full PRP. This has implications for fitness
to drive and should form part of the information provided to patients prior
to treatment(153-156). There may also be other more subtle effects of PRP
on visual function such as some degree of loss of contrast sensitivity and a
reduction in the ERG(157). Finally, it must be remembered that visual
function may also be lost through inadvertent laser application to the foveal
and parafoveal regions, or through the development of secondary
neovascular membranes after focal treatment of microaneurysms.
EVIDENCE LEVEL 1
Other persistent side effects that may occur following laser
treatment are some loss of visual acuity, a possible reduction in
accommodative power, some dimness of vision like looking through a
neutral density filter, some patients may complain of nyctalopia(158). Loss
of colour vision in the blue spectrum may occur following extensive
peripheral laser treatment and photophobia may also occur after laser
therapy. This photophobia is due to halation and although it may be helped
by dark glasses, it is possibly helped more by shading the eyes.
6.4.4 Secondary choroidal neovascularisation
If laser application is applied very close to the macula and is of a high
energy, then there is a risk of loss of central vision due to disruption of the
pigment epithelium and Bruch’s membrane, giving rise to foci of
chorioretinal neovascularistation, such as occurs spontaneously in exudative
age-related macular degeneration (the disciform response). This may occur
rapidly following laser treatment and may result in loss of central vision.
There is an increased risk of choroidal neovascularisation when moving from
a peripheral region to a more central region without appropriately reducing
the power of the laser or taking account of possible effects of lens tilt.
6.4.5. Macular Burn
It is very important to prevent the development of a foveal burn by
constantly referring back to the macula to be sure that the laser does not
44
stray into the macular area. In addition, recognition is growing of the risk of
extension of laser burn size with time into the foveal zone.
6.4.6. Macular oedema
Scatter peripheral pan-retinal photocoagulation has been reported to
be followed by development or worsening of macular oedema which
fortunately is transient but it is important to warn the patient that there
may be some loss of vision following the laser treatment. It is important to
treat the maculopathy either at the same time or prior to peripheral scatter
retinal photocoagulation (PRP)(159-162).
6.4.7 Other side effects
Rare complications such as corneal burns, raised intraocular pressure
or angle closure (associated with shallowing of the anterior chamber,
choroidal effusion and accompanying myopia)(163) and preretinal or
subretinal fibrosis have been reported. Full panretinal laser
photocoagulation is commonly followed by pallor of the optic disc as a result
of loss of some of the nerve fibre layer, particularly with relatively heavy
burns. Such patients have poor pupillary reactions and dilate poorly with
short-acting mydriatics. This can compromise examination of the fundus and
increase difficulty with intraocular surgery, if required post laser. There is
also the recognised potential risk of traction retinal detachment with PRP.
45
SECTION 7
MANAGEMENT OF DIABETIC MACULOPATHY
The use of lasers to treat diabetic retinopathy is an invasive and
destructive procedure and it is essential to obtain informed consent for each
new treatment course as for any surgical procedure.
7.1 INTRODUCTION
Diabetic maculopathy (DM) causes gradual and largely irreversible
loss of central vision. Many patients with DM are elderly; thus assessment
and treatment may be complicated by co-existing ocular pathology, such as
cataract, glaucoma or poor mydriasis response. Medico-social problems may
also militate against optimal management .
Diabetic maculopathy is caused by oedema from leaking capillaries
and/or ischaemia due to capillary loss. Diabetic changes in the choroidal
vasculature may also worsen the ischaemia and contribute to the oedema by
reducing retinal pigment epithelial function. Visual loss is largely due to
disruption of the fovea and perifoveal neuro-retina by oedema. The
ETDRS(107) and the British Multi-centre Photocoagulation Study(164) showed
that macular photocoagulation was effective in slowing the cumulative rate
of central visual loss due to macular oedema. The aim of treatment is to
prevent further visual loss; since visual acuity rarely improves following
treatment, best results are achieved by applying treatment before central
vision deteriorates.
Loss of central vision due to macular ischaemia or generalised
oedema cannot be prevented by photocoagulation. Many cases of diabetic
maculopathy involve co-existing macular oedema and ischaemia. In such
cases the prognosis depends on the extent of the oedema and the severity
of the ischaemia
7.2 DEFINITION
Diabetic maculopathy is classified as focal, diffuse, ischaemic,
tractional or mixed (see Section 1). For the purposes of treatment, laser
therapy is recommended where there is evidence of clinically significant
macular oedema (CSMO) despite the recognised difficulties with the
definition of CSMO (see Section 4). CSMO has been defined by the ETDRS
group as retinal thickening involving the centre of the macula in one of
three ways(165):
1.
thickening of the retina at or within 500 microns of the centre of the
macula
2.
hard exudates at or within 500 microns of the centre of the macula,
if associated thickening of the adjacent retina (not residual hard exudates
remaining after disappearance of retinal thickening)
46
3.
a zone or zones of retinal thickening one disc area or larger, any part
of which is within one disc diameter of the centre of the macula
Retinal thickening is determined clinically by slit lamp biomicroscopy
/ indirect ophthalmoscopy or by evaluation of stereoscopic fundus
photographs of the macular area. Fluorescein angiography is useful to
evaluate leakage, while newer technology such as optical coherence
tomography (OCT) may assist in objectively determining increases in retinal
thickness (See Section 4).
7.3 EVIDENCE SUPPORTING TREATMENT RECOMMENDATIONS
7.3.1 Photocoagulation
Two RCTs have reported beneficial effects of focal argon laser to
microaneurysms in the treatment of maculopathy. Blankenship and
colleagues reported lower frequency of visual loss after 2 years in patients
with symmetrical macular oedema and preproliferative retinopathy(166).
The ETDRS found a significant reduction in moderate visual loss at 3 years in
patients with macular oedema plus mild to moderate retinopathy compared
to observation(165). Subgroup analysis found that treatment was
significantly more effective in eyes with clinically significant macular
oedema (CSMO), particularly in people in whom the centre of the macula
was involved or imminently threatened(92, 167). In a third RCT, Olk found
significant improvement in VA at 1 and 2 years in patients with diffuse
maculopathy with or without CSMO treated with grid laser to zones of
retinal thickening(168). Overall, photocoagulation reduced the risk of
moderate visual loss (defined as a doubling of the visual angle, equivalent to
loss of about two Snellen lines) by 50-70%(165, 168). However, it is clear
that photocoagulation therapy does not per se lead to an improvement in
vision and, while it reduces the risk of visual loss in a majority of patients
particularly those with PDR, a significant proportion do not benefit from
photocoagulation especially for macular disease. Despite this, there are
currently no alternative validated therapies (see Section 7 below).
According to the ETDRS(165) which is the largest reported study
involving a control untreated group, treatment of diabetic maculopathy is
indicated when there is clinically significant macular oedema (CSMO)
involving the centre of the macula ie where retinal thickening has
encroached to within <500 nm of the fovea. Although patients with normal
central vision and CSMO were included in the study, clear benefit was
achieved when pre-treatment visual acuity was < 6/9 and was most
beneficial when vision was between 6/12 and 6/24. Controversy exists as to
whether laser therapy is beneficial when CSMO co-exists with normal vision
ie 6/6 or better. It is important to note that benefit in the ETDRS was taken
as a delay in progression of visual loss ie that even when photocoagulation
treatment was applied there was still an increasing, albeit at a slower rate,
incidence of visual loss. While the ETDRS data indicated a trend towards
benefit ie a 10% to 5% reduction in incidence of visual loss of 2 lines of
47
Snellin acuity equivalent in patients with CSMO and normal visual acuity,
there was no statistical analysis to indicate that this was significant.
Although the ETDRS study represents the main body of evidence
demonstrating the value of laser therapy in the management of macular
oedema, several points should be noted:
1. the study was designed to compare no therapy with any type of
photocoagulation therapy, panretinal and/or focal, in the treatment of
diabetic retinopathy, including maculopathy; subgroup analysis of different
types of retinopathy was performed as the overall data was accumulated
2. focal photocoagulation referred to focal treatment in the macular
area and included both direct laser therapy for focal lesions at the macula
and grid therapy for diffuse macular oedema
3. treatable lesions ie leaking microaneurysms or diffuse macular
leakage, were identified by fluorescein angiography
Fluorescein angiographic evidence of retinal oedema in the absence
of clinically obvious retinal thickening (Clinically Significant Macular
Oedema, CSMO in the ETDRS(165) is not normally regarded as an indication
for treatment.
EVIDENCE LEVEL 2
7.3.2 Treatment of Systemic Risk Factors
Data from the UKPDS (Type II diabetes)(42, 52, 57, 59, 78, 79, 169-173) and
the DCCT (Type I diabetes)(174-182) indicate that the progression of nonproliferative diabetic retinopathy including maculopathy is significantly
delayed by attention to general measures such as diabetes and blood
pressure control, dietary (especially lipid) intake, and the taking of regular
exercise if possible, combined with regular clinical observation (see Section
3).
EVIDENCE LEVEL 1
7.3.3 Intravitreal Steroids
Intraocular
injections
of
crystalline
steroid
preparations
(Triamcinolone) has been advocated for treatment of refractory CSME which
has not responded to laser therapy(102, 183-187). Most studies are single
case reports or open label interventional case series. No randomised control
study of intravitreal steroids has yet been reported. The evidence to date is
that retinal thickening as evaluated by optical coherence tomography as
well as by clinical techniques can be reduced and there is some
improvement in vision in some cases. A prospective study comparing a group
of 20 patients treated by intravitreal steroid injection with a group of 16
patients treated with laser therapy indicated an beneficial effect on vision
in the steroid treated group with no improvement in the laser treated
group(184). Difficulties with control of intraocular pressure and
48
development of cataract have been experienced. In addition, the effect of
treatment is transient and repeat injections are required.
EVIDENCE LEVEL 2
7.3.4 Medical Treatment of Diabetic Maculopathy
Considerable research is currently in place to determine the value of
several pharmacologic approaches to the treatment of macular oedema. The
EUCLID study of lisinopril indicated that there was 50% reduction in
progression of retinopathy following use of the drug(60, 188) but the UKPDS
data indicated that this effect was due predominantly to control of the
hypertension(59, 169) and not primarily to effects of these drugs on the
renin-angiotensin system(173, 189). Accordingly a larger trial is underway to
determine whether there is an effect for delay in retinopathy progression in
normotensive patients.
A further approach has been to determine whether inhibitors of
protein kinae C may be beneficial for treatment of diabetic maculopathy on
the basis of the anti-growth factor effects of the inhibitor. Initial results
from a randomised controlled multicentre trial are inconclusive(190) and
further trials are in progress.
EVIDENCE LEVEL 1
7.3.5 Vitrectomy for treatment of tractional maculopathy (diffuse nonresponsive macular oedema)
Severe diffuse macular oedema which is non-responsive to grid laser
photocoagulation or repeated grid laser photocoagulation, may benefit from
vitrectomy with removal of the attached posterior hyaloid face. Cases likely
to benefit have an appearance which may be very subtle, but presents as
posterior hyaloid face thickening, surface wrinkling and a detectable sheen,
or abnormal reflex from the inner limiting lamina (46).
Evidence for the value of vitrectomy in tractional diabetic macular oedema
comes mostly from interventional case series in cases of severe CSMO
refractory to laser therapy(101, 103, 104, 106, 191-194). There has been
one non-randomised control trial in which a small series of seven cases with
previously untreated bilateral symmetrical tractional macular oedema were
assigned to vitrectomy in one eye and laser to the second eye(193). The
results showed some resolution of CSMO by OCT in both groups but with
visual improvement only in the vitrectomised group. Approximately 50% of
patients may experience modest improvement of vision, up to 2 lines or
more.
EVIDENCE LEVEL 2
49
7.4 RECOMMENDATIONS FOR TREATMENT
7.4.1 Photocaogulation
The cumulative evidence to date indicates that photocoagulation
therapy remains the mainstay of therapy for sight-threatening diabetic
macular oedema. Based on the evidence of the ETDRS(107, 108, 167, 195200) and previous less extensive studies the following recommendations for
the laser treatment of diabetic macular oedema, as identified as retinal
thickening by clinical stereoscopic viewing on biomicroscopy or by
stereoscopic fundus photographs, are proposed:
Laser therapy for maculopathy is recommended
(1) where the centre of the macula is involved) in which vision is 6./9
or less.
Laser treatment may be considered
(2) only after counselling with regard to potential side effects and
risks of treatment for patients in patients where vision in 6/6 or better
Laser therapy should involve scatter treatment in the area of leaking
lesions 500 microns or more distant from the centre of the macula. Where
there are no discrete identified lesions ie where leakage is diffuse, a grid of
laser therapy should be applied. Areas of leakage may be identified by
fluorescein angiography
RECOMMENDATION LEVEL A
7.4.2 Medical Treatment
Currently there are no recommendable pharmacological agents for
treatment of diabetic retinopathy. In all patients but especially in those
patients with maculopathy and vision of 6/6 or better, attention to possible
systemic risk factors should be made (see Section 4).
RECOMMENDATION LEVEL A
7.4.3 Intravitreal steroid therapy
No firm recommendations regarding the use of intravitreal steroids
for diffuse non-responsive macular oedema can be made at this time but it
should be noted that benefit is usually transient.
RECOMMENDATION LEVEL B
7.4.4 Vitrectomy for diabetic macular oedema
50
Vitrectomy may be considered in selected cases of tractional severe
macular oedema not responsive to other therapies (see Section 10).
RECOMMENDATION LEVEL B
7.5 TREATMENT PROTOCOLS FOR DIABETIC MACULOPATHY
The aims of treatment are (a) to delay the progression of visual loss
and (b) to promote resolution of maculopathy. These two aims overlap but
are not necessarily equivalent.
7.5.1 Photocoagulation
The current standard of care for sight threatening diabetic
maculopathy is focal laser photocoagulation, a term used to differentiate
this form of treatment from pan-retinal photocoagulation. Focal treatment
may be directly to leaking microaneurysms or administered as a grid to the
macular area. Treatment is normally delivered via a slit-lamp / contact lens
system involving topical corneal anaesthesia and placement of a hand-held
contact lens.
Photocoagulation therapy for diabetic retinopathy is currently
performed using custom-designed ophthalmic lasers (see Section 6). Safe
treatment depends on accurate identification of the fovea and avoidance of
excessively intense burns. The fovea can be difficult to identify if there is
considerable oedema. Excessively intense burns can be avoided by starting
treatment with very low powered burns, and gradually increasing the
intensity until a satisfactory moderate blanching of the retina is achieved.
Energy uptake varies, depending on the degree of the retinal oedema, so it
is important to reduce power when treating less oedematous areas.
Satisfactory results can be achieved with a number of different light
wavelengths (see elsewhere in these guidelines). The most frequently used
wavelengths are 514nm (the “Green” component of the Argon Blue/Green
laser) and 810nm (from the infra-red diode laser). The Argon blue/green
laser should not be used for treatment of microaneurysms that are very
close to the central area. This is because the blue light from this laser (487
nm) is absorbed by xanthophyll pigment overlying the parafoveal area. This
can cause nerve fibre layer damage and parafoveal scotomata (see Section
6). In general, the blue laser waveband is not recommended due to its
possible deleterious effects on the user (see Section 6).
7.5.1.1 Treatment of focal leaking areas at the macula (focal
maculopathy)
This type of maculopathy responds most readily to photocoagulation.
Areas of focal leakage, usually at the centre of circinate exudative rings,
(identifiable by fluorescein angiography), are treated using a 50-100 micron
beam of 0.1 sec duration at sufficient power level to obtain moderate
51
blanching of the retina. Repeated "hits" can be applied to large
microaneurysms (>40mm) When the microaneurysm is close to the fovea, a
short (0.05sec) superficial burn just sufficient to blanch it may be used.
However the treatment of microaneurysms within 300 icrons of the centre
of the fovea should be undertaken with caution because of the significant
risk of closure of the perifoveal arcade or of direct foveolar coagulation.
An alternative to direct treatment of focal leakage is to apply a
gentle grid to the entire circinate ring, including the margin, in a fashion
similar to that used for diffuse maculopathy.
RECOMMENDATION LEVEL A
7.5.1.2 Treatment of diffuse maculopathy
Diffuse maculopathy is a more difficult form of diabetic retinopathy
to treat. However, scatter laser photocoagulation has been accepted as the
mainstay of therapy in the ETDRS(165). The technique consists of applying
100-200 micron burns delivered at a power level sufficient to obtain a
minimum blanching reaction at the pigment epithelium in a scatter pattern
over the central macula avoiding the fovea itself. Spacing of lesions by
intervals of one burn diameter is recommended. Gentle treatment within
the papillomacular bundle is safe to within one disc diameter of the optic
disc and the centre of the macula provided microaneurysmsare not directly
treated and re-treatment of the same spot is not performed.
RECOMMENDATION LEVEL A
7.5.1.3 Treatment of Mixed maculopathy
Focal and diffuse areas of oedema should be identified and treated as
described above.
RECOMMENDATION LEVEL A
7.5.1.4 Treatment of Ischaemic maculopathy
Although the ETDRS included patients with perifoveal capillary
closure in the design of the study and have recommended treatment of
ischaemic maculopathy, there is no evidence that laser therapy is of value
in isolated forms of this condition. However, if the degree of ischaemia is
sufficiently large that it forms part of proliferative retinopathy, then this of
itself may warrant therapy.
RECOMMENDATION LEVEL C
7.5.2 Recommendations regarding vitrectomy for tractional macular
oedema
52
The evidence in favour of this therapy is restricted to cases of
tractional macular oedema not responsive to other means and in which
there is evidence of a clear tractional component to the maculopathy with
significant elevation of the retina. Preference is for objective clinical
evidence via OCT or high resolution ultrasound in case selection and
subsequent monitoring of results. The surgical goal should be the removal of
all thickened posterior hyaloid and cortical gel material via a three port
pars plan vitrectomy (see below).
RECOMMENDATION LEVEL C
7.5.3 Diffuse maculopathy in the presence of neovascularistion.
Occasionally maculopathy co-exists with disc or retinal
neovascularisation. Whether to treat the new vessels with PRP or to treat
the maculopathy first depends on the age of the patient and the relative
severity of the retinopathy. In young patients with active new vessels it is
generally recommended to treat the new vessels first with PRP since new
vessels in these patients can advance rapidly with devastating
consequences. In older patients, with NIDDM it is better to treat the
maculopathy first or at least at the same time since PRP itself in these
patients can hasten the progression of the maculopathy. Fractionating PRP
into sessions of 700-800 burns separated by 2-3 weeks reduces the risk of
this progression.
RECOMMENDATION LEVEL C
7.6. FOLLOW-UP AFTER TREATMENT FOR DIABETIC MACULOPATHY
Patients with diabetic maculopathy should be reviewed 3-4 months
after treatment. If oedema persists, or if the visual acuity worsens, repeat
fluorescein angiography may be helpful in identifying areas of residual focal
leakage which should then be retreated. Treatment of leaking areas
associated with exudates may cause regression of the exudates over many
months.
Since focal maculopathy can recur, patients with treated
maculopathy should be followed for a sufficient time to ensure that the
condition is inactive.
Patients with cataracts and treated diabetic
retinopathy should have the maculopathy reassessed before cataract surgery
since surgery can induce recurrence or advance of existing macular oedema.
Any persistent areas of oedema should be retreated either before or soon
after surgery.
53
SECTION 8
MANAGEMENT OF NEW VESSELS ELSEWHERE (NVE)
8.1 INTRODUCTION
NVE may occur on any vessel but usually are restricted to the major
arcades of the posterior pole. Their presence can be verified by fluorescein
angiography if there is doubt as to whether they are truly present and
active. Panretinal photocaogaulation of the peripheral retina is the current
standard of care based on several large treatment trials (see below). NVE
may vary in their severity depending on age, glucose control, and other
associated vascular disease and in minimal or early stages there is not the
same urgency to treat as with NVD according to the ETDRS data (81-85, 8792, 94-97, 157, 201-206).
8.2 DEFINITION
NVE are defined as any abnormal collection of leaking vessels
occurring on the retina outwith an area circumscribed by the distance of
one disc diameter from the rim of the optic disc. They usually occur in the
post-equatorial retina with a predilection for the vascular arcades.
However, NVE in the nasal retina also occur, often as an initial focus, and
may be easily missed. Untreated NVE in particular are associated with
tractional retinal detachment, hence the importance of their early
detection and treatment.
Rubeosis iridis also represents a form of neovascularisation occurring
on the iris and may present in severe forms of diabetic ocular ischaemia. A
short note on rubeosis is included at the end of this Section.
8.3 EVIDENCE FOR CURRENT STANDARD OF TREATMENT OF NVE
The evidence for treatment of NVE is derived from the ETDRS and DRS
studies(81, 85, 92, 206).
EVIDENCE LEVEL 1
8.4 RECOMMENDATIONS FOR TREATMENT OF NVE
PRP should be given with fully informed consent (see above under
counselling, Sections 3 and 6) and can be tailored to the nature of the NVE
in order to minimise effects on the visual field.
54
Based on the available evidence these guidelines recommend the
following:
--------------------------------------------------------------------------------------------Condition
observe
PRP
Vitrectomy
---------------------------------------------------------------------------------------------Flat (early) NVE
sometimes usually
no
Flat (mature / florid) NVE
no
Flat "stable" (treated) NVE yes
yes
+/- "fill-in"
sometimes
no
Forward NVE
no
yes
sometimes
Forward NVE with VH
no
yes
sometimes
Forward NVE with traction RD
no
yes
yes
--------------------------------------------------------------------------------------------RECOMMENDATION LEVEL A
8.5 TREATMENT PROTOCOLS
Treatment of NVE (and NVD, see Section 9) is by pan-retinal laser
photocoagulation (PRP). Treatment is normally delivered via a slit-lamp /
contact lens system involving topical corneal anaesthesia and placement of
a hand-held contact lens as for laser therapy of macular oedema. To
minimise discomfort in some patients peribulbar or retro-bulbar anaesthesia
may be offered under appropriate expert control (see RCOphth Guidelines
on Anaesthesia in Ophthalmology). For patients unable to comply with a slitlamp delivery system, PRP may be delivered via a head-mounted binocular
indirect ophthalmoscope system. Using this system it may be possible to
deliver bilateral PRP in a single session.
Areas of retinal ischaemia as determined by fluorescein angiography
should be preferentially treated and a more peripheral application of the
laser burns helps to preserve more of the visual field.
8.5.1 Early NVE.
Early NVE responds to a basic scatter PRP, defined as treatment of all
four quadrants, by regression within days to weeks (Figs.35,36). A basic PRP
comprises 1500-2000, 200-500 micron laser burns applied pre- and postequatorially outside the vascular arcades. Lesions should normally be
applied leaving lesion-wide (ie 200-500 micron) intervals throughout the
fundus to preserve visual field. Some practitioners prefer routinely to use a
smaller spot size such as 200 m but a correspondingly larger number of
burns is required to achieve an effect. In addition, spot size will vary with
the lens used (see Section 6). Sufficient energy should be applied to achieve
"blanching" (ie a greyish white lesion) of the retina without producing
55
visible necrosis. The amount of energy required will vary for each patient
and also at different retinal locations in the same eye depending on factors
such as retinal thickness, oedema and degree of melanisation of the retinal
pigment epithelium (the main energy absorbing tissue in this procedure)
(see Section 6 on Lasers).
8.5.2 Progressive NVE.
NVE may present as relatively advanced abnormal vascular structures
(Fig. 11) which require a full PRP with particular attention being paid to the
area of ischaemic retina in the proximity of the NVE but avoiding direct
application to the new vessels (Fig.37).
8.5.3 Florid NVE.
NVE may develop rapidly and in more than one site (Fig. 14). This
condition requires aggressive management as for florid NVD (see below),
attention being paid to the regions of ischaemic retina.
8.5.4 Non-responding NVE.
On occasion, NVE may not fully respond to PRP and persist as foci of
leaking vessels. Attempts should be made to close down such vessels with
the application of further laser, particularly around the site of the NVE, in a
series a short focal applications. The active vessels should be monitored
every 2-3 weeks.
8.5.5 NVE with gliosis.
NVE particularly on the vascular arcades may form firm vitreo-retinal
adhesions which may promote the development of gliosis (Fig 38). Such
lesions may act as the focus for traction on the retina, with retinal
detachment, which, if treated too aggressively with laser therapy, may
develop retinal holes and lead to rapidly extending, rhegmatogenous retinal
detachment. Application of the laser some distance from the site of the
gliotic NVE may help to induce regression of the new vessels. If the
condition progresses however, for instance with vitreous haemorrhage or
retinal detachment, vitrectomy may be required (see below).
8.5.6 NVE with vitreous haemorrhage.
NVE are frequently the cause of vitreous haemorrhage but the site of
bleeding may be masked by the blood (Figs. 24,25). NVE may be tracked to
the point or tip of a subhyaloid haemorrhage. NVE with vitreous
haemorrhage should be treated as for NVD with vitreous haemorrhage (see
next Section).
56
8.6 NEW VESSELS ON THE IRIS (RUBEOSIS IRIDIS)
8.6.1 Introduction
Rubeosis iridis (Fig. 39) is a manifestation of severe retinal ischaemia
and heralds the onset of rubeotic glaucoma. In the presence of clear
media, further immediate photocoagulation should be applied since
regression can be induced although this is perhaps better documented
following central retinal vein occlusions(207). However rubeosis is often
associated with advanced PDR rendering it impossible to apply further laser
due to vitreous haemorrhage. In these circumstances prompt vitreous
surgery is required to enable peroperative photocoagulation to be carried
out (see Section 10 below). The results of the Early Vitrectomy Study show
the benefits of surgery in eyes with severe neovascularisation and vitreous
haemorrhage; thus, the presence of rubeosis indicates that surgery cannot
be further delayed(208). Ultrasound examination is mandatory to exclude a
retinal detachment, since co-existing rubeosis implies a poorer prognosis for
surgery (see above). Utrasound biomicroscopy also may be of value to
examine the peripheral retina and vitreous base / pars plana.
EVIDENCE LEVEL 1
8.6.2 Therapy / Management
Glaucoma due to rubeosis responds poorly to standard
trabeculectomy procedures(209). When trabeculectomy is combined with
mitomycin-C however, the results are more encouraging(210), and compares
favourably with other anti-proliferative agents such as 5-Fluorouracil(211)
as well as other surgical procedures such as Molteno tubes and
Cyclocryotherapy. When it is possible to apply further photocoagulation,
trabeculectomy with mitomycin may be delayed to allow as much regression
of the rubeosis as possible prior to surgery(209). However, many
ophthalmologists believe that urgent aggressive management of rubeotic
glaucoma, involving vitrectomy and extensive PRP are required to control
the process, particularly if there is a minimal response to non-surgical
approaches. In extreme cases cycloablation( destruction of the aqueous
producing cells of the ciliary body may be necessary either by cylco-diode or
cryotherapy. In eyes which are already blinded by rubeotic glaucoma, the
aim is to achieve a pain-free condition. Under these circumstances, topical
steroids together with atropine is the appropriate palliative treatment.
EVIDENCE LEVEL 3
RECOMMENDATION LEVEL B
57
SECTION 9
MANAGEMENT OF NEW VESSELS ON THE DISC (NVD)
9.1 INTRODUCTION
NVD usually indicate a measure of global retinal ischaemia which can
be confirmed on fluorescein angiographic assessment of the peripheral
fundus. Consequently, panretinal photocaogaulation of the peripheral retina
is the current standard of care based on several large treatment trials as for
NVE(76, 81, 83-85, 87-89, 91, 93, 95-97, 144, 157, 198, 202, 206, 212-215).
NVD may however vary in their severity depending on age, glucose control,
and other associated vascular disease(42, 52, 57, 59, 60, 75, 76, 79, 86, 89,
91, 108, 120, 169, 171, 188, 203, 216-233).
9.2 DEFINITION
NVD are defined as any abnormal collection of leaking vessels
occurring on the optic disc or within one disc diameter of the optic disc.
They may be distinguished from collateral vessels by the presence of dye
leakage on fluorescein angiography.
9.3 EVIDENCE FOR CURRENT STANDARD OF TREATMENT
The initial evidence for the effectiveness of panretinal
photocoagulation (PRP) was based on a number of uncontrolled or small
clinical trials(163, 213, 214). The first definitive evidence for PRP in PDRNVD was provided by the DRS / ETDRS in the USA and by the British
Multicentre Study Group in Europe (see references cited in Section 9.1
above). The risk of severe visual loss in patients with high risk
characteristics is reduced by 50% at 2 and 5 years by this therapy and by up
to 70% in moderate risk patients(81). However, a reduction of the risk of
severe visual loss in patients with early NVD or with severe or very severe
ischaemic background retinopathy was not observed in these studies.
Despite this, many ophthalmologists institute PRP at an earlier stage than
recommended by the DRS or ETDRS
Scatter peripheral retinal photocoagulation (PRP) has been shown to
be effective in six RCTs(84, 93, 164, 202, 214). Two British RCTs from the
1970s recruited patients with proliferative diabetic retinopathy and found
that peripheral photocoagulation versus no treatment significantly reduced
the risk of blindness after 2 or 3 years(164, 202). The Diabetic Retinopathy
Study(84) found that early versus deferred argon treatment decreased the
risk of severe visual loss at 5 years in patients with either preproliferative or
proliferative retinopathy. A subgroup analysis(204) of the Early Treatment
Diabetic Retinopathy Study (ETDRS)(93) found that the benefit was
significant in people with type 2 diabetes and with severe preproliferative
or early proliferative retinopathy without high risk characteristics. The
British Multicentre Study(164) and the ETDRS(85) recruited patients with
preproliferative disease most of whom had maculopathy; both found that
58
PRP significantly reduced the risk of visual deterioration at 5 years
compared to no treatment.
EVIDENCE LEVEL 1
9.4 RECOMMENDATIONS FOR TREATMENT
PRP should be given with fully informed consent (see above under
counselling, Section 3) and can be tailored to the nature of the NVD in order
to minimise effects on the visual field.
Based on the available evidence these guidelines recommend the
following:
---------------------------------------------------------------------------------------------Condition
observe
PRP Vitrectomy
---------------------------------------------------------------------------------------------Very severe (ischaemic) BDR
yes
no
no
Flat (early) NVD
no
yes
Flat (mature / florid) NVD
no
yes
Flat "stable" (treated) NVD
yes
+/- "fill-in"
no
sometimes
no
Forward NVD
no
yes
sometimes
Forward NVD with VH
no
yes
sometimes
Forward NVD with traction RD
no
yes
yes
---------------------------------------------------------------------------------------------RECOMMENDATION LEVEL A
9.5 TREATMENT PROTOCOLS
Treatment of NVD (and NVE, see Section 8) is by pan-retinal laser
photocoagulation (PRP). Treatment is delivered uniformly to the retina with
particular attention to obvious areas of retinal ischaemia, frequently
detectable in the temporal paramacular area. Treatment is usually
restricted to retinal areas outside the vascular arcades unless the NVD is
particularly active.
9.5.1 Early NVD.
Newly-developing flat "early" new vessels usually respond well to a
basic PRP comprising 1500-2000, 200-500 micron laser burns applied preand post- equatorially outside the vascular arcades as described above for
NVE (Figs.40,41).
59
9.5.2 Established NVD.
"Established" new vessels are those which have developed into mature
branching and/or arcade formations, but are still "flat" ie they lie on the
retinal surface, and have not led to haemorrhage. Established NVD may
require a full PRP (>2000 laser burns) applied over more than one session.
The precise number of burns will depend on the response to treatment
which should be monitored at 2-3 weekly intervals.
9.5.3 Florid NVD.
NVD in young adolescents may progress rapidly to extensive sheets of
vessels occupying a wide region of the peripapillary retina (Fig 18). (Such
vessels require urgent, aggressive management which should comprise a full
PRP applied in a single session if possible. In appropriate circumstances this
may require PRP delivery through a head-mounted binocular indirect
ophthalmoscope system under general anaesthetic. Laser lesions should be
sufficiently strong in florid retinopathy which may be difficult to achieve in
the presence of vitreous opacities and retinal ischemia and is also difficult
in lightly pigmented fundi. Further laser should be applied at weekly
intervals until regression of vessels is achieved. If the neovascularisation
cannot be controlled, vitrectomy with endolaser may be required (see
Section 10).
9.5.4 Stable (quiescent, treated) NVD.
NVD respond to PRP either by regressing completely (especially in
older subjects and if treated early) or by "maturing" into non-leaking smaller
vascular formations which do not progress. These can be described as
"stable" NVD which require observation and monitoring, if necessary with
fluorescein angiography, but probably do not require further
photocoagulation. These patients can be followed in an accredited,
systematic screening programme.
9.5.5 Non-responding NVD.
In a proportion of patients, NVD fail to regress and/or mature into an
inactive stable state. Inadequate laser therapy is a frequent cause, often
due to poor patient compliance with the PRP procedure. This may be
improved by performing the laser with local or general anaesthetic (see
Section 6 above). In the latter case, the laser may be applied via the
binocular indirect ophthalmoscope with good effect and a larger burn size
(see above).
Even if fully treated as described above, certain patients still fail to
respond. Re-treating treated areas of the retina may then be performed,
usually however at the expense of the visual field. This will affect the
patient's fitness to drive and appropriate counselling is essential. Recourse
to vitrectomy may be necessary if the neovascularisation cannot be
controlled (see below).
60
9.5.6 Forward NVD
Patients may present with untreated "forward" NVD or the NVD may
project into the vitreous cavity during the course of treatment as a result of
posterior vitreous detachment (PVD). In the absence of vitreous
haemorrhage forward NVD should be treated urgently with a full PRP with
the proviso that an overly aggressive PRP may induce too rapid a regression
of the forward vessels and cause vitreous bleeding. In such circumstances
vitrectomy and intra-operative endolaser therapy is likely to be the
treatment of choice (see below).
9.5.7 NVD with vitreous haemorrhage.
Treatment of NVD in the presence of small collections of subhyaloid
or intra-gel blood should be aimed at performing a basic PRP (2000 laser
burns, 500 micron) followed by careful application of further brief laser
applications (200-300 laser burns per session) until regression of the NVD is
achieved. However, this may not be successful and vitrectomy with
endolaser may be required.
RECOMMENDATION LEVEL A/B
61
SECTION 10
VITRECTOMY IN DIABETIC EYE DISEASE
10.1 SURGICAL OBJECTIVES
Vitrectomy is a specialised procedure which is the domain of
appropriately trained vitro-retinal surgeons. Vitrectomy surgery is used to
achieve specific goals, which may limit or halt the progress of advanced
diabetic eye disease. These are:
•
to remove vitreous opacity (commonly vitreous haemorrhage,
also intra-ocular fibrin, or cells) and/or fibrovascular proliferation (severe
extensive proliferative retinopathy; anterior hyaloidal fibrovascular
proliferation)
•
to allow completion of panretinal laser photocoagulation (with
the endolaser, introduced into the vitreous cavity or with the indirect laser
ophthalmoscope), or direct ciliary body laser photocoagulation
•
to relieve retinal traction, tractional displacement or ectopia,
traction detachment by removal or dissection of epiretinal membranes, in
cases of non-rhegmatogenous retinal detachment
•
to achieve retinal reattachment by closure of breaks and
placement
of
internal
tamponade
(in
cases
of
combined
traction/rhegmatogenous detachments).
•
to remove the posterior hyaloid face in some cases of diffuse
macular oedema with posterior hyaloid face thickening
10.2 VITREOUS / SUBHYALOID HAEMORRHAGE
10.2.1 Definition
Vitreous haemorrhage is defined as bleeding into the vitreous cavity
from ruptured normal or new retinal vessels, usually caused by forward
detachment of the vitreous gel and leading to loss of vision from vitreous
opacification. Vitreous haemorrhage may be intragel (ie into the vitreous
substance) or retrogel (subhyaloid) when it occurs into the space between
the detached vitreous gel and the retinal surfacce
10.2.2 Simple vitreous haemorrhage.
Simple vitreous haemorrhage occurs in the absence of other
intravitreal pathology. It is a relative indication for vitreous surgery. DRS
studies(234, 235) have shown that several factors should be considered: the
patient’s age, the rapidity of progress and degree of severity of diabetic eye
disease, the patient’s appreciation of risks, and benefits, of surgery, and
the patient’s ability to co-operate with surgery, and in particular with postoperative positioning, and supplemental laser photocoagulation where
indicated. Various types of simple vitreous haemorrhage occur as discussed
below:
10.2 3. Severe non-clearing vitreous haemorrhage.
62
Vitreous haemorrhage often clears within a matter of days to weeks,
and it is usually possible to achieve delivery of initial or supplemental
panretinal laser photocoagulation without vitrectomy (see Section 6 on
lasers). If laser photocoagulation is not possible, or vitreous haemorrhage
persists for more than one month then vitrectomy should be considered
since maculopathy and/or proliferative disease may progress unchecked,
thus compromising the final visual result .
Patients with Type II diabetes are less likely to have severe
progressive proliferative retinopathy and while they also gain benefit from
early surgery, as opposed to deferred surgery (surgery deferred for more
than 6 months) the benefit is less. These patients should nonetheless have
surgery within 3 to 6 months from onset of persistent non-clearing vitreous
haemorrhage.
Regular (2-4) weekly ultrasonic examinations are required to ensure
early detection of retinal detachment, and clinical biomicroscopy to detect
iris or iridocorneal angle neovascularisation, or haemolytic/ghost cell
glaucoma. Patients with any of these complications should be considered
for early vitrectomy(234-236).
RECOMMENDATION LEVEL A
Surgical Goals and Procedure
For this indication the surgical goal is to remove the vitreous opacity
through a 3-port pars plana vitrectomy procedure. The posterior hyaloid
face should be removed (this is a structural support for fibrovascular
proliferation and its removal usually prevents subsequent re-proliferation),
and initial or supplemental panretinal laser photocoagulation should be
performed to help prevent re-bleeding, re-proliferation, anterior hyaloidal
fibrovascular proliferation, entry site complications (fibrovascular ingrowth)
and rubeosis.
10.2.4 Non-clearing Post-vitrectomy Haemorrhage
Post-operative inrtavitreal blood is common in the early postvitrectomy period (~ 2-4 weeks) but usually clears spontaneously within a
short time. Usually it takes the form of a diffuse vitreous haze generated by
widespread fibrin deposition. Clearance is associated with spontaneous
fibrinolysis which is often delayed in patients with diabetes. In all cases
where the retina cannot be adequately visualised, it is essential to confirm
the absence of underlying retinal detachment with ultrasonography. If
cavity haemorrhage does not clear within the first few post-operative
weeks, revision surgery should be considered.
RECOMMENDATION LEVEL A
Surgical Goals and Procedures
63
The surgical goal is to remove the haemorrhage, and treat the cause.
Revision normally requires a 3-port pars plana vitrectomy to allow an
adequate internal search for the source of bleeding. In particular,
examination of the previous entry sites is important to search for possible
bleeding sources, and top up PRP is indicated if previous phototherapy is
found to be inadequate.
10.2.5 Dense Pre-macular Haemorrhage
Subhyaloid premacular haemorrhages may be seen with or without
associated intra-gel vitreous haemorrhage (Fig.42) usually in immediate
vicinity of neovascular complexes. Limitation of blood to this site indicates
incomplete vitreous detachment, providing a ready surface for continued
forward proliferation of the new vessels and risk of tractional (tabletop)
retinal detachment. Consequently, early vitrectomy should be considered to
clear premacular haemorrhage. While temporising, PRP to visible, untreated
areas of retina should be performed(237). Some surgeons also promote the
use of YAG laser vitreolysis based on a number of small case series(238-244)
(Figs. 43,44). Intravitreal tissue plasminogen activator has also been used to
clear premacular haemorrhages(245).
Indications for vitrectomy in this type of haemorrhage include severe
visual loss (for example in only eyes), failure of regression or resumption of
haemorrhage after supplemental laser photocoagulation and the presence of
significant subhyaloid pre-macular haemorrhage in eyes with good preexisting panretinal laser photocoagulation.
RECOMMENDATION LEVEL B
Surgical Goals and Procedures
A 3-port pars plana vitrectomy is performed taking care to remove
the posterior hyaloid face, particularly from the posterior pole and the
temporal arcades. Haemorrhage is removed, residual membrane dissected
and supplemental panretinal endolaser photocoagulation is placed if
needed. Long standing cases are more likely to require significant
membrane dissection with its attendant risk of iatrogenic retinal break
formation.
10.3 HAEMOLYTIC GHOST-CELL GLAUCOMA
Elevated intra-ocular pressures may be caused by partially lysed red
cells (red cell ghosts or “erythroclasts”) particularly in those eyes with a
disrupted anterior hyaloid face after previous vitrectomy for vitreous
haemorrhage(245), or in aphakic eyes with vitreous haemorrhage.
"Erythroclasts" pass from the vitreous cavity into the anterior chamber and
obstruct the trabecular meshwork. After a vitrectomy for diabetic vitreous
haemorrhage, ghost cell glaucoma should be suspected in patients with
elevated intraocular pressure in the early post-operative period(246). It is
important to differentiate this condition from steroid induced glaucoma,
since many of these patients may also be using topical steroid drops. The
64
physical signs of fine pigmented (cells) and flare in the anterior chamber
indicate ghost cell glaucoma and may be subtle. Ghost cell glaucoma ia
particularly common if vitrectomy is performed for removal of dense
vitreous haemorrhage (ochre membrane). If the intra-ocular pressure
remains elevated despite medical therapy after one to 3 weeks, surgery
should be considered.
RECOMMENDATION LEVEL B
Surgical Goals and Procedures
Revision pars plana vitrectomy with removal of all vitreous cavity and
anterior chamber haemorrhage is the preferred surgical procedure.
Glaucoma filtering surgery is usually not required.
10.4 RETINAL DETACHMENT
10.4.1 Tractional Macular Ectopia and Detachment
Traction retinal detachment (TRD) arises from tension caused by
contraction of the fibrovascular proliferations.(Fig 28.) The hazards of
surgery are high in this condition, and thus vitrectomy in TRD is generally
limited to those eyes with one of: a) involvement of the macula in the TRD;
(b) evidence of a progressive, extensive extra-macular traction retinal
detachment; (c) combined traction rhegmatogenous retinal detachment
which threatens to involve the macular area (see below). Traction retinal
detachment involving the macula is major indication for vitrectomy surgery
if present for less than six months. Surgery in cases with macular
involvement for more than 6 months is usually associated with little or no
functional improvement and is not recommended(236, 247, 248).
RECOMMENDATION LEVEL B
Surgical Goals and Procedures
In addition to removal of media opacity, specific goals include release
of tractional components by removal of cortical vitreous and the posterior
hyaloid vitreous face, dissection and removal of fibrovascular membranes,
closure of persistently bleeding vessels and treatment of any iatrogenic
retinal breaks. Cases with pure tractional elevation will experience
spontaneous post-operative retinal reattachment and macular remodelling
as a result of successful surgery. Anatomic success has been reported in
between 64% to 80% or patients (with a 6 month follow-up) with visual
function improvement in 26% to 65%(49, 52).
10.4. 2 Combined Traction - Rhegmatogenous Retinal Detachment
Most extra-macular traction retinal detachments are only relative
indications for surgery since they may remain stable for indefinite periods.
In some patients the force of the fibrovascular traction is sufficient to
create a retinal tear, often in relation to previous laser photocoagulation
scars. These tears are frequently difficult to identify pre-operatively.
65
Clinically, a rhegmatogenous retinal detachment caused by
fibrovascular proliferation presents with a convex configuration rather than
the concave contour of a tractional, non-rhegmatogenous detached retina.
In addition, white (hydration) lines in the inner retina, are more
characteristic of a rhegmatogenous component. Surgery is indicated if there
is sudden visual loss, evidence of progressive peripheral combined
traction/rhegmatogenous retinal detachment, or evidence of progressive iris
rubeosis.
RECOMMENDATION LEVEL B
Surgical Goals and Procedures
Pars plana vitrectomy techniques are used to gain access to the
retinal surface, to dissect fibrovascular membranes and thickened hyaloid
face structures and thereby to relieve traction on and around retinal breaks.
Vitrectomy also allows the performance of an internal search to help the
actually identification of the retinal breaks. Subretinal fluid is removed and
the retina reattached, followed by delivery of per-operative laser both
locally to the break(s) and peripherally as supplemental or initial panretinal
photocoagulation. Internal tamponade (gas, or silicone oil) will be
necessary, and scleral buckles may be placed in some cases to support
peripheral pathology, particularly if there has been extensive anterior
hyaloid/pars plana proliferation. Care, however, should be taken to leave
these patients phakic if at all possible. Accurate post-operative positioning
is of critical importance.
10.5 SEVERE WIDESPREAD FIBROVASCULAR PROLIFERATION
Some patients (typically young adult type 1 diabetics with a history of
diabetes since childhood) are seen with a pattern of active fibrovascular
proliferation that progresses despite extensive panretinal laser
photocoagulation. These eyes have a high risk of severe visual loss and
blindness. The Diabetic Retinopathy Vitrectomy Study Group(208) compared
standard laser and vitrectomy indications (with vitrectomy for vitreous
haemorrhage, or traction macular detachment) in a randomised fashion with
early vitrectomy surgery, in a total of 370 eyes. The number of patients
experiencing preservation of good visual function (20/40 or better) was
almost twice as high in the early vitrectomy group (44%) compared to the
conventional management group (28%) after 4 years of follow-up. However,
the proportion of eyes with severe visual loss or blindness was similar in
both groups and this stage was reached earlier in the early vitrectomy
group. Clinical characteristics which warrant referral for early vitrectomy,
even in the absence of extensive laser photocoagulation, include
widespread fibrovascular proliferation (three disc diameters or more of
fibrovascular tissue).
It is to be emphasised that these patients frequently have extensive
proliferation as their sole indication and do not necessarily have vitreous
haemorrhage or macular tractional displacement. While these patients
66
should receive panretinal laser photocoagulation, the presence of high risk
characteristics should indicate vitreoretinal referral at an early stage.
RECOMMENDATION LEVEL B
Surgical Goals and Procedures
A 3-port pars plana vitrectomy is performed, with great care being
taken to remove all detectable posterior hyaloid face which is typically
adherent to the retina.
10.6 IRIS / ANGLE NEOVASCULARISATION WITH VITREOUS OPACITY
Anterior segment neovascularisation which is mild and nonprogressive may be safely monitored. Progressive iris or angle
neovascularisation requires panretinal laser photocoagulation, and if
vitreous haemorrhage prevents adequate and effective panretinal laser
photocoagulation, vitrectomy with endolaser photocoagulation is indicated.
Patients with established neovascular glaucoma may undergo
combined surgery, comprising pars plana vitrectomy, with extensive
endolaser photocoagulation and in some cases with additional direct ciliary
body photocoagulation. This surgery is combined with silicone oil exchange
in some eyes or with glaucoma filtration surgery in others.
RECOMMENDATION LEVEL C
10.7 ANTERIOR HYALOIDAL
FIBROVASCULAR PROLIFERATION
FIBROVASCULAR
PROLIFERATION
/
RETROLENTAL
Fibrovascular proliferation on the anterior hyaloidal surface or its
remnant is typically seen after vitrectomy in severely ischaemic eyes of
patients with type 1 diabetes mellitus. This fibrous tissue, which causes
contraction of adjacent tissue and may cause peripheral traction retinal
detachment, posterior iris displacement and lens displacement or recurrent
vitreous haemorrhage, is highly vascular and difficult to treat. In some
patients this process may be localised to the area of the entry site and is
associated with typical sentinel vessels on the adjacent episclera and
sclera(249). Anterior hyaloidal fibrovascular proliferation may also occur
after cataract extraction in patients with active proliferative disease(250).
RECOMMENDATION LEVEL B
Surgical Goals and Procedure
The surgical goal is to remove all fibrovascular tissue. This requires
basal vitrectomy, lensectomy, membrane dissection and extensive,
confluent laser photocoagulation to the peripheral retina and pars plana,
often combined with scleral buckling surgery and silicone oil exchange.
10.8 VITRECTOMY FOR DIABETIC MACULAR OEDEMA
67
Vitrectomy for removal of hard exudates has been proposed, but
apart from an initial report(251) there have been no further studies for this
indication alone.
Vitrectomy with posterior hyaloid face removal, with or without inner
limiting lamina removal(252) has been advocated for non-ischaemic diffuse
diabetic macular oedema which is not responsive to at least one macular
grid laser treatment, and who have an attached posterior hyaloid.
Vitrectomy surgery has been documented to be associated with improved
visual acuity in other types of macular oedema, including pseudophakic
macular oedema(253),and retinitis pigmentosa(254). In vitrectomy for
diabetic macular oedema, case selection has varied, with initial studies
attempting only to include cases with a taut posterior hyaloid, while later
studies have not used this criterion.
Surgery is associated with a reduction in foveal thickness, as
measured with optical coherence tomography, in many studies(101, 104,
193, 255-257). One study reports that the mean perifoveal capillary blood
flow velocity was significantly increased after vitrectomy for macular
oedema (2.19 mm per second to 2.68 mm per second postoperatively, P
=.02), and that this was associated with complete regression of oedema in
the 9 eyes studied(258). Many studies report visual benefit(194, 259) and
approximately 40 to 50% of cases experience an improvement in acuity of 2
lines or more (LogMAR)(104, 193, 259-261). A recent study reports
encouraging results with the final visual acuity improved by 2 or more lines
in 32 of 65 eyes (45%), while remained unchanged in 49%, and worse in
6%(104). These apparently encouraging results were from a retrospective
study with no control cases. There is a small fellow eye study(193) using
cases with bilateral macular oedema, one eye operated. A controlled study
of 15 operated eyes and 16 controls found an improvement in acuity in the
treatment group, although the numbers were small and differences not
statistically significant(260).
Most studies have significant design flaws. Most have been
retrospective, or lacking in controls, and there are no randomised controlled
studies reported to date. Statistical significance at the level of 0.02 or
better is reported in most studies, but the small numbers mean that the
confidence intervals are large. Since significant numbers of eyes are
undergoing this surgery, with one group reporting follow up data on 485
eyes of 325 patients(262), the need for a prospective randomized controlled
trial is apparent.
EVIDENCE LEVEL 2
RECOMMENDATION LEVEL B
68
SECTION 11
CATARACT
11.1 INTRODUCTION
Cataract is common in diabetic patients, with prevalence rates of 8%
of younger patients, and 25% of older-onset diabetic patients, over a 10 year
study period(263). Acute metabolic cataract remains rare(264) . Indications
for cataract surgery in diabetic eyes are similar to those in non-diabetic
eyes. In addition, surgery may be indicated to allow accurate assessment of
retinal disease, or to allow delivery of laser photocoagulation(265).
11.2 AIMS OF CARTARACT SURGERY IN PATIENTS WITH DIABETIC RETINOPATHY.
While the primary aim of cataract surgery is to restore vision, the
recent trend towards lens extraction for early cataract raises issues for
patients with diabetes, since it is recognized that there is a risk of
progression of retinopathy after surgery (see below). In such situations, it is
advisable to treat any retinopathy prior to surgery if possible. However, in
the presence of cataract which precludes an adequate view of the fundus, a
primary aim of surgery may be to permit fundus visualization. In such
circumstances, it may be advisable to perform PRP with indirect laser at the
time of surgery.
11.2 CATARACT SURGERY IN PATIENTS WITH DIABETES
The major determinant of visual acuity outcome and complication
rate are the level of maculopathy and the degree of underlying retinopathy,
plus the overall care of the diabetes. It is therefore essential that these
aspects are dealt prior to addressing other variables.
In general, cataract surgery and intraocular lens implant materials
are well tolerated in patients with diabetes(266) and there are no obvious
differences in post-surgical inflammation in eyes receiving hydrophobic
acrylic lenses, or heparin surface-modified rigid polymethylmethacrylate
lens implants(267). However, hydrophilic acrylic intraocular lens implants
from some manufacturers have been associated with opacification in
diabetic eyes(268, 269). Caution should be exercised if a hydrophilic
intraocular lens implant is to be used in diabetic eyes.
Diabetic eyes, particularly those which have been treated with PRP,
may have poor pupil function and so may not dilate well at cataract surgery
(20). Microscope-associated retinal phototoxicity is usually associated with
prolonged operating times (usually in excess of 100 minutes), but has been
described in short cases (operating times less than 30 minutes) in diabetic
eyes(270). Care should be taken to ensure that diabetic cataract surgery is
not prolonged, and that posterior pole illumination is minimised (pupil
occlusion).
There is evidence that the size of the capsulorrhexis opening in
cataract surgery may shrink in diabetic eyes, as opposed to non-diabetic
69
eyes(271-273). These changes were not apparent in the early post-operative
period, but were present by 3 months follow-up. Silicone intraocular lens
implants are also associated with significant anterior capsule fibrosis and
shrinkage(274-277), sometimes leading to capsulophimosis or lens
decentration, and are thus contra-indicated in diabetic eyes.
Diabetic eyes have a significantly higher rate of posterior capsule
opacity requiring YAG laser capsulotomy(271, 278), although this does not
correlate with degree of retinopathy.
Massive proliferation of lens
epithelial remnants has been reported in rare diabetic eyes after YAG laser
capsulotomy(279).
Diabetic eyes undergoing combined cataract and glaucoma filtering
surgery have a similar course to non-diabetic eyes(280).
EVIDENCE LEVEL 2
RECOMMENDATION LEVEL B
11.3 CATARACT SURGERY AND VITRECTOMY IN PATIENTS WITH DIABETES
Cataract may develop in as many as 75% of patients after diabetic
vitrectomy (273). Consideration may therefore be given to performing
combined lensectomy / vitrectomy routinely in diabetic patients requiring
vitrectomy surgery since such patients respond well to combined vitrectomy
and cataract surgery(281-284).
Although combined cataract and vitrectomy surgery achieves good
results, diabetic eyes undergoing this surgery are more likely than nondiabetic eyes to develop uveitis of varying degrees with posterior iris
symechiae(285).
EVIDENCE LEVEL 2
RECOMMENDATION LEVEL C
11.4 Cataract surgery, new vessels, rubeosis and risk of worsening
retinopathy
Cataract surgery may precipitate aggressive iris neovascularisation,
and if not recognised or treated swiftly and aggressively, may result in
irreversible blindness(286). It is important that eyes with ischaemic
retinopathy are identified and are treated with pan-retinal laser
photocoagulation in the preoperative or per-operative period, as it may not
be possible to deliver adequate laser treatment postoperatively(287).
Cataract surgery can be safely undertaken in diabetic eyes with iris
neovascularisation, with an acceptable complication rate (hyphaema,
70
fibrin), provided care is taken to treat the retinopathy in the preoperative
or per-operative period(288).
EVIDENCE LEVEL 3
RECOMMENDATION LEVEL C
11.5 Visual outcomes of cataract surgery
The presence and degree of maculopathy is the main predictor of
final visual acuity after cataract surgery, while severity of retinopathy is
also a significant factor(289, 290). Maculopathy present at the time of
cataract surgery is unlikely to resolve spontaneously, while macular oedema
developing after cataract surgery in non-diabetic patients is likely to
resolve. Eyes with advanced diabetic retinopathy are much less likely to
experience resolution of any post-cataract surgery macular oedema(291).
The risk of macular
retinopathy(293) and may occur
retinopathy(294, 295). Specific
known or pre-existing macular
aqueous growth factors such as
levels(295, 296).
oedema(292) rises with severity of
in as many as 30% of patients with severe
risk factors include severe retinopathy,
oedema, hypertension(295), and elevated
VEGF [vascular endothelial growth factor]
EVIDENCE LEVEL 2
11.6 Cataract surgery and progression of diabetic retinopathy
The question of whether cataract surgery causes more rapid
progression of diabetic retinopathy has been raised in many studies(293,
297-304). There is evidence that progression is associated with longer
operating times(302, 305). For patients with mild to moderate retinopathy,
cataract surgery is a safe procedure with no significant risk of progression to
sight-threatening complications(306). However, since early fluorescein
leakage at the macula is common after cataract surgery, the differentiation
of post-operative pseudophakic leakage and incipient diabetic maculopathy
may be difficult. Careful monitoring is therefore required (see 11.5 above).
EVIDENCE LEVEL 2
71
List of Working Party Members
J.V.Forrester (Chair), F.Burden, A.H.M.Hamilton, M.Lavin, S.P.Harding,
S.H.D.Wong, J.F.Talbot, J.Vora, R.Williams, Heidi Packer (College
secretary).
72
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100
APPENDIX
Grading Protocols for Diabetic Retinopathy
1. ETDRS Grading based on original Airlie House Classification
The ETDRS grading protocol is based on fundus photographs of
seven overlapping fields of view of the fundus which grade various
aspects of retinopathy against a set of standard photographs. Field 1 is
centred on the macula and field 2 is centred on the optic disc. Fields 3-8
two above, two below and on enasal to the discsuroound fields 1 and 2.
The seven fields of view are centred around the disc and macula.
Features graded in fileds 2-8 include haemorrhages and/or
microaneurysms, hard exudates, cotton wool spots, venous calibre
abnormalities, venous sheathing, perivenous exudates, arteriolar
abnormalities, intraretinal microvascular abnormalities, arteriovenous
nicking, NVE, fibrous proliferation, retinal elevation, preretinal
haemorrhages, and vitreous haemorrhage. Features graded in field 1
only include NV, features graded in field 2 only include posterior
vitreous detachment, macular oedema. Grading is based on a general
protocol for each feature as follows:
Grade
Grade
Grade
Grade
Grade
0
1a
1b
2a
2b
questionable presence
definite presence but less than a specified size
greater than a specified size but less than standard photo
greater area than standard photo
In this way, grades of retinopathy are determined by the cumulative
severity of each of the features and an overall grading score applied as
per the Table below.
Table. ETDRS grading system for severity of retinopathy
101
10
None
20
Microaneurysms only
35
Mild NPDR
43
Moderate NPDR
47
Moderately severe NPDR
53A-D
Severe NPDR
53E
Very severe NPDR
61 Mild PDR
65 Moderate PDR
71,75 High risk PDR
81,85 Advanced PDR
2. Current Proposed Grading in use by the NSC and NSF (UK)(4)
___________________________________________________
Disease grading protocol in National Guidelines on Screening for Diabetic
Retinopathy (minimum dataset)
___________________________________________________________
Retinopathy (R)
Level 0
None
Level 1
Background Microaneurysm(s)
Retinal haemorrhage(s) ± any exudate
Level 2
Preproliferative
Venous beading
Venous loop or reduplication
Intraretinal microvascular abnormality (IRMA)
Multiple deep, round or blot haemorrhages
(CWS careful search for above features)
Level 3
Proliferative New vessels on disc (NVD)
New vessels elsewhere (NVE)
Preretinal or vitreous haemorrhage
Preretinal fibrosis±tractional retinal detachment
Maculopathy (M)
Exudate within 1 disc diameter (DD) of the centre of the fovea
Circinate or group of exudates within the macula
Retinal thickening within 1 DD of the centre of the fovea (if stereo
available)
102
Any microaneurysm or haemorrhage within 1 DD of the centre of the fovea
only if associated with a best VA of (if no stereo) 6/12
Photocoagulation (P)
Focal grid to macula
Peripheral scatter
Unclassifiable (U)
___________________________________________________________
3. Proposed International Classification endorsed by the
American Academy of Ophthalmology(3)
Table . International Clinical Diabetic Retinopathy (DR) Disease Severity
Scale
Proposed
Severity Level
Disease Findings
Observable
Ophthalmoscopy
No apparent DR
No abnormalities
Mild nonproliferative DR
Microaneurysms only
With
Dilated
Moderate nonproliferative More than "mild" but less than "severe"
DR
Severe nonproliferative DR Any
of
the
following:
20 or more intraretinal hemorrhages in 4
quadrants
Definite venous beading in 2 or more quadrants
Prominent IRMA in 1 or more quadrants and no
neovascularization
Proliferative DR
1
or
more
of
the
following:
Definite
neovascularization
Preretinal or vitreous hemorrhage
IRMA = intraretinal microvascular abnormalities
103
Contact lens
Optical
magnification
factor
Therapy spot
size settings
for common
lenses
Laser spot size settings
50
100
200
300
500
800
1200
2000
2200
3200
5000
Calculated
spot at
retina
(emmetropic
eye)
Goldmann 3
mirror
Goldmann
Fundus
Yannuzzi
Fundus
Mainster
standard
Mainster Wide
Field
1.08
54
108
216
324
540
864
1296
2160
2376
3456
5400
1.10
55
110
220
330
550
880
1320
2200
2420
3520
5500
1.08
54
108
216
324
540
864
1296
2160
2376
3456
5400
1.04
52
104
208
312
520
832
1248
2080
2288
3328
5200
1.47
73.5
147
294
441
735
1176
1764
2940
3234
4704
7350
Mainster PRP
Volk Area
centralis
Volk
TransEquator
1.96
98
196
392
588
980
1568
2352
3920
4312
6272
9800
1.06
53
106
212
318
530
848
1272
2120
2332
3392
5300
1.44
72
144
288
432
720
1152
1728
2880
3168
4608
7200
SuperQuad 160
2.00
100
200
400
600
1000
1600
2400
4000
4400
6400
10000
Table 6.1
104