New Concepts in Diabetes and Its Treatment - part 6 pot

Nomenclature used for diabetic retinopathyRetinopathy Inside the retina In front of the retina background retinopathy neovascularizations Not vision-threatening Simple Early Changes Not

Diabetic complications in the retina, diabetic retinopathy, is a somewhat

different matter This complication is presently one of the leading causes ofblindness in the western world From a phylogenic point of view, the retina

is an advanced part of the brain, and damage to its neuronal tissue is thereforeirreversible and leads to permanent reduction of the visual function Thisimplies that preventive measures are the cornerstone in the clinical manage-ment of diabetic retinopathy However, the preventive efforts should be effective

at many levels ranging from elimination of risk factors, initiation of screeningprogrammes, optimization of treatment intervention, and by educating diabeticpatients in self-care and good life habits Once vision-threatening changes havedeveloped the patient should be promptly referred to a specialist for clinicalevaluation and initiation of relevant treatment to stop or limit the visualdamage

This chapter will present an overview of current knowledge related to theclinical management of diabetic retinopathy The chapter will be introducedwith a brief account of the clinical and epidemiologic characteristics of thedisease, followed by a description of the practical management of prevention,screening, diagnostics, and treatment of diabetic retinopathy

Table 1 Nomenclature used for diabetic retinopathy

Retinopathy Inside the retina In front of the retina

(background retinopathy) (neovascularizations) Not vision-threatening Simple

Early Changes Not Accompanied by Visual Reduction

The most usual name for this retinopathy stage is nonproliferative diabetic retinopathy, but older terms are also used, such as simple retinopathy, or background retinopathy which alludes to the fact that the changes remain inside

the ocular background

Nonproliferative diabetic retinopathy is caused by changes in the retinal crocirculation leading to compromised barrier function of the retinal capillaries

mi-The changes first appear temporally from the fovea consisting of capillary roaneurysms and small intraretinal haemorrhages (fig 1) The increased capillary permeability leads to the development of whitish hard exudates consisting of lipo- protein from the bloodstream (fig 2) Additionally, cotton-wool spots may de-

mic-velop These are localized unsharply delimited whitish areas in the superficialparts of the retina representing intracellular material that has accumulated in thenerve fibres because of disturbances in their axoplasmic flow (fig 3) The retinalchanges characterizing nonproliferative diabetic retinopathy are reversible, andoften noticeable dynamic changes are seen at repeated examinations, so that thesame number of lesions are present, however located in different places

Late Changes Accompanied by Visual Reduction

Nonproliferative diabetic retinopathy can develop into one or both oftwo different types of retinopathy accompanied by visual reduction, namely

proliferative diabetic retinopathy and diabetic maculopathy.

Fig 1 Minimal nonproliferative diabetic retinopathy in a right eye A few red dots

representing haemorrhages and/or microaneurysms are seen temporally in the macular area which is the dark area surrounding the dark spot in the centre of the image (arrows).

Fig 2 Slight nonproliferative diabetic retinopathy in a left eye Several whitish hard

exudates have developed inside the macular area.

Proliferative Diabetic Retinopathy

Proliferative diabetic retinopathy develops secondary to occlusion of theretinal capillaries in the retinal periphery with a consequent stimulation of

vascular new growth Clinically, both a preproliferative and a true proliferative

stage can be differentiated

Fig 3 Moderate nonproliferative diabetic retinopathy in a right eye Larger

haemor-rhages and whitish lesions with flu ffy borders representing cotton-wool spots have developed.

Fig 4 Preproliferative diabetic retinopathy in a right eye Many large haemorrhages

are seen temporally in the macular area and there is calibre variation of the lower temporal branch vein (arrow) Hard exudates within one disk diameter of the fovea indicate the presence of clinically significant macular oedema.

Preproliferative diabetic retinopathy is characterized by many cotton-woolspots, larger blot haemorrhages temporally in the macular area, and a variety

of vascular abnormalities These abnormalities are intraretinal microvascular normalities (IRMA vessels) often representing arteriovenous shunt vessels, and

ab-beading and loop formation on the larger venules (fig 4) These abnormalities

Fig 5 Proliferative diabetic retinopathy in a left eye A large neovascularization has

developed from the optic disk and has given rise to a preretinal haemorrhage that extends arcuately along the lower temporal branch vein.

develop secondary to changes in the retinal haemodynamics that result fromocclusion of the capillary bed in the retinal midperiphery and periphery At thisstage the retinopathy will often become proliferative within a few months.Proliferative diabetic retinopathy is characterized by outgrowth of newvessels from the larger venules in the retina and on the optic nerve head (fig 5).This neovascular process is assumed to be caused by growth stimulation fromcytokines released from the ischaemic areas in the retinal periphery where thecapillary bed is occluded However, the newly formed blood vessels do notgrow out to replace the occluded retinal vessels Rather, they grow aberrantlyinto the vitreous body Preretinal neovascularizations can lead to visual reduc-

tion because of spontaneous haemorrhages into the vitreous body The cause

of this vascular rupture is unknown, but may be caused by attachments ofthe new vessels to the posterior hyaloid membrane that break secondary tomovements of the vitreous body Finally, neovascularizations may contain

connective tissue that shrinks and causes tractional retinal detachment (fig 6).

In some cases the vasostimulatory cytokines released in the retinal ery diffuse to the anterior eye chamber to cause neovascularization in the iris(rubeosis iridis) (fig 7) and in the anterior chamber angle The resultingblocking of the aqueous drainage from the eye will lead to neovascular glau-coma The high intraocular pressure may endanger the intraocular blood flowand consequently the visual function, and if the rise in intraocular pressure

periph-is rapid, severe acute pain may develop

Fig 6 Severe proliferative diabetic retinopathy in a left eye The new vessels contain

whitish fibrous tissue that covers most of the view of the fundus Shrinkage of this fibrous tissue may lead to tractional retinal detachment.

Fig 7 Iris rubeosis New vessels in the iris (arrows) have made the pupil immobile.

The small pupil together with the white cataractous lens seen behind the pupil opening makes inspection as well as treatment of the fundus background impossible.

Diabetic Maculopathy

Diabetic maculopathy is nonproliferative diabetic retinopathy complicated

by retinal oedema When the oedema area becomes large enough or is too

close to the fovea, it becomes vision-threatening (fig 4) and is termed clinically significant macular oedema (table 2) The oedema may be exudative or ischae-

Table 2 Clinically significant macular oedema is defined as presence of one or both of

the criteria shown

1 Oedema and/or exudates within one-half disk diameter from the fovea

2 Oedema and/or exudates with a size of one disk diameter or more, part of which is located within a zone of one disk diameter from the fovea

mic The exudative form is most frequent, and it may be both focal or diffuse.Exudative diabetic maculopathy is accompanied by hyperpermeability of themacular vessels When the oedema, the exudates, and the haemorrhages extendtowards the fovea, central vision may become threatened, partly by blockinglight access to the retinal photoreceptors, and partly because of a direct de-structive effect on the neuronal components of the retina Ischaemic oedema

develops secondary to occlusion of macular capillaries similarly to capillary occlusion in the retinal periphery, with a subsequent fallout of neuronal func-

tion in the affected area If the areas close to the fovea are included, visualacuity may drop Frequently, mixed types of maculopathy occur with exudativeand ischaemic retinal oedema located in different parts of the macular area

Epidemiology

Almost all persons having diabetes mellitus will eventually develop proliferative diabetic retinopathy In countries with good diabetes care, reti-nopathy does not develop until after 10 years of diabetes duration, whereasretinopathy may be present at the time of diagnosis in type 2 diabetes Nonpro-liferative diabetic retinopathy can later be complicated by one or both of thetwo late complications, proliferative diabetic retinopathy and diabetic macu-lopathy In type 1 diabetes the most frequent vision-threatening complication isproliferative diabetic retinopathy, whereas in type 2 diabetes the most frequentvision threat is diabetic maculopathy

non-Prevention

Preventing the development of diabetic retinopathy is one of the basicpillars in the management of diabetic eye complications, since the damagethat occurs to the retina is irreversible

The two most significant factors now known to limit the risk of developing

diabetic retinopathy are tight regulation of the blood glucose and of the blood pressure For many years it was suspected that exposition to hyperglycaemia

accelerated the development of diabetic retinopathy, but it was not established

Table 3 Characteristics of diabetic

Can be prevented Can be detected Can be treated Screening is cost-e fficient

until a few years ago in the Diabetes Control and Complications Trial (DCCT)study that the risk of developing retinopathy is considerably lowered by tightglycaemic control Recently, several studies have been published unanimouslyshowing that the risk of developing retinopathy in type 1 as well as in type 2diabetes can be considerably lowered by antihypertensive treatment Further-

more, it has been shown that treatment with especially ACE inhibitors can

reduce the risk for developing retinopathy with an effect that adds to theantihypertensive effect However, these studies have not been conducted farenough to show that this intervention also has an effect on the visual prognosis

Pregnancy is a definite risk factor for the development of diabetic

retinopa-thy A tight regulation of the blood glucose during pregnancy alone can slowand often halt the development of retinopathy completely, suggesting that therisk of developing retinopathy is to a large extent caused by disturbances in thediabetic metabolism in pregnancy Since the risk for developing diabetic retino-pathy during pregnancy increases with increasing duration of diabetes, diabeticwomen should be counselled to have children as early as possible in life

A multitude of studies have been conducted to identify new preventivemeasures for diabetic retinopathy These studies have for example shown that

aspirin and aldose reductase inhibitors have no beneficial effect on diabeticretinopathy More recent studies have shown that pharmaceutical intervention

on second messengers such as protein kinase C might be a future treatmentmodality for diabetic retinopathy, and these hypotheses are presently underinvestigation in clinical trials

Screening

Background

Even when optimal preventive measures are undertaken, some patientswill unavoidably develop vision-threatening retinopathy Since these changesmay not be recognized by the patient before they have advanced to a stagewhere vision damage is irreversible, early detection is important Diabeticretinopathy fulfills a number of criteria that makes it appropriate to screenfor this complication among the diabetic population (table 3)

Screening for diabetic retinopathy is performed by inspecting the ocularbackground through the optics of the eye, supplemented by measurement ofthe visual acuity

Examination of the Ocular Background

Inspection of the ocular background can be done by ophthalmoscopy that enables a qualitative assessment of retinopathy Alternatively, photography of

the ocular background allows a semiquantitative analysis by comparison withstandard photographs, or a quantitative computerized analysis of the retinalchanges

Examination of the ocular background by ophthalmoscopy has beenknown for almost 150 years, and this technique is therefore one of the oldestknown examination methods in ophthalmology During ophthalmoscopy theretina is illuminated continuously, and inspection is either done directly orindirectly through a lens positioned with its focal point in the pupil plane ofthe examined eye The relevance of doing ophthalmoscopy in diabetic patientswas realized during the fifties where it became usual for diabetic patients

to survive long enough to develop retinal complications The advantage ofophthalmoscopy is that only simple equipment is needed for the examination.The disadvantages of this method is that the severity of the retinal lesionscannot be documented in detail, that the retinal changes are difficult to quan-tify, and that the quality and conclusion of the examination depend on theexperience and attitude of the examiner In spite of these weaknesses, ophthal-moscopy has until now been the most important examination technique forearly detection of diabetic retinopathy, and globally it is still the most widelyused method

During the last decades, increasing focus has been directed at a differenttechnique to screen for diabetic retinopathy by examination of the ocular back-ground with fundus photography This method has a number of advantages.Firstly, the retinal changes are documented so that it is possible to re-evaluate theretinopathy, and the grader can consult other specialists at a later time Secondly,retinal photography enables a standardized and centralized semiquantitativeevaluation of the severity of the changes, and thirdly, photography enables anevaluation of even minimal changes in retinopathy Fourthly, ophthalmologistsneed not have primary patient contact Thus, with technicians doing the photog-raphy and opthalmologists performing the evaluation of the photographs, moreexaminations can be carried out with the same specialist resources Finally, ithas been shown that for other than retinal specialists the sensitivity in detectingvision-threatening retinal changes is higher when the retinopathy is evaluatedfrom retinal photographs than by ophthalmoscopy

With the current development within computerized image analysis it can

be expected that within a few years it will be possible to replace semiquantitativegrading of fundus photographs with a fully computerized quantification ofthe fundus photographic changes Many initiatives have been taken to startthis process, and the results achieved hitherto appear promising

Stereoscopic examination of the ocular background is done by examining

the same part of the retina from different angles with the examiner’s two eyes,thus giving an impression of the depth relation of the retinal structures Thiscan be done directly by binocular inspection of the ocular background, orindirectly by studying stereo photographs of the ocular background Thevalidity of this technique depends on the examiner’s stereo vision which showsgreat interindividual variation The significance of this type of examinationlies in its potential for detecting retinal oedema Until now there has been

no documentation of the value of stereoscopic examination of the ocularbackground for screening for diabetic retinopathy

Measurement of Visual Acuity

In most countries there is general agreement that measurement of the

visual acuity should be part of the routine screening examination for diabetic

retinopathy The visual acuity may be valuable as a supplement to the tion of the ocular background, especially if it has to be decided whether thepatient should be referred for further evaluation by an ophthalmologist Thus,

inspec-in exudative diabetic maculopathy, hard exudates and retinspec-inal oedema may belocated in the border zone of being clinically significant A reduced or decliningvisual acuity in these cases will speak in favour of referral for further evaluation.Similarly, in ischaemic maculopathy with no hard exudates and questionablemacular oedema, the visual acuity may be a valuable help in determiningwhether incipient retinal damage needs referral for further evaluation

Organization

In order to ensure that screening efforts are efficient it is necessary that:(1) the health system is organized to permit the establishment of efficientscreeningprogrammes; (2) sufficient resources are made available in the short term (theywill always pay back in the long term); (3) qualified personnel is available to carryout the screening examinations and evaluations, and (4) patients are taught aboutthe advantages of screening, and are given motivation to participate

Iceland is a positive example of a country where all these factors havebeen optimal This country has succeeded in setting up a screening programmewhere, in principle, all the country’s diabetic patients are known and followed

In most countries, however, screening efforts do not live up to expectations,for the most part due to social or geographic differences Generally, screening

is of a high quality near centres with high expertise and impact in the nity, and similarly of a poorer quality in peripheral areas.

commu-An optimization of screening efforts meets with various barriers in ent countries In some countries it is the structure of the health system thathinders free access to retinopathy screening for the whole diabetic population,whereas in other countries problems inherent in health system structure orgeography can be solved within the existing framework The exploitation ofnew technology may play a central role for removal of these barriers Forexample, it is conceivable that the ongoing developments within teleophthal-mology will enable the setting up of decentral screening clinics for diabeticretinopathy from which fundus photographs taken by technicians can be trans-mitted electronically to a central place for evaluation Such an organizationwould be a huge step towards more efficient care in areas where the bottleneck

differ-is shortage of qualified specialdiffer-ists, and would solve problems with tion of patients over long distances

transporta-Screening Interval

Patients with type 1 diabetes mellitus should be examined at least once a yearwhen diabetes duration is long enough for the development of vision-threateningchanges to be conceivable This critical diabetes duration is only a few years insome societies with poor diabetes care, e.g in some of the former east blockcountries, but up to 10 years in societies where diabetes care is optimal.Patients with type 2 diabetes mellitus should be screened at the time ofdiagnosis, and then every other year if no or minimal retinopathy is found atthe initial examination In both diabetes types the screening interval should

be shorter when there is progression of retinopathy or changes appear thatpossibly in the near future will require treatment

Economy

Several health economic analyses have shown that screening for diabeticretinopathy is very cost-efficient Thus, from a socio-economic point of view,the ability to rescue a few cases from blindness each year is sufficent to balancethe total cost of screening efforts in an area with several thousand diabeticpatients, not to mention the personal and social consequences for the individualdiabetic patient who can preserve visual health

Diagnostics

If a screening examination leads to suspicion of proliferative diabeticretinopathy or maculopathy that potentially threatens central vision, the pa-

tient should be referred for further evaluation with an ophthalmologist havingfacilities for fluorescein angiography and photocoagulation treatment.

In diabetic maculopathy it is necessary to do fluorescein angiography to

distinguish between exudative maculopathy, that can be treated by lation, and ischaemic maculopathy that is not treatable Fluorescein angiogra-

photocoagu-phy is performed by intravenous injection of the tracer compound fluoresceinwhich is transported and distributed in the bloodstream to reach the eye in

a few seconds Under normal circumstances, fluorescein cannot pass the retina barrier and therefore remains inside the bloodstream However, in exu-dative diabetic maculopathy the blood-retina barrier is broken down and areaswhere fluorescein leaks out of the bloodstream into the retinal tissue and thevitreous can be recognized In ischaemic maculopathy, however, areas withfocal occlusion of retinal capillaries are seen in the macular area When theocular background is inspected by ophthalmoscopy or by evaluation of fundusphotographs, the type of maculopathy can often be diagnosed Thus, exudativemaculopathy is almost always associated with hard exudates, while the ocularbackground in ischaemic maculopathy almost always appears slightly yellowishcombined with many intraretinal haemorrhages and no exudates However,since mixed types with both exudative and ischaemic maculopathy may occur,angiography is an important tool to differentiate and locate leakage and capil-lary occlusion

blood-Exudative diabetic maculopathy should be treated with retinal agulation when there is clinically significant macular oedema (table 2), orwhen exudates or oedema are otherwise suspected to threaten central vision.Clinically significant macular oedema has previously been difficult to describequantitatively since no technique was available to quantify retinal thickness.However, in recent years this has changed, and several new methods makingthis possible have now been developed One of the most promising of thesemethods is optical coherence tomography that detects the phase shift of lightreflected from different surfaces in the retina and transforms this signal to acolour code that expresses the reflectivity and depth of different retinal levels.The method has a depth resolution of approximately 10lm and gives a preciseindication of whether there is retinal oedema, and the method can be used toquantify the effect of therapeutic intervention

photoco-When the diagnosis of proliferative diabetic retinopathy is certain, nomore diagnostic evaluation is required and retinal photocoagulation can beinitiated immediately In less clear cases, differential diagnostic alternatives

should be carefully considered, the most frequent being shunt vessels or other

intraretinal microvascular abnormalities On the basis of the criteria shown intable 4, the presence or not of neovascularizations requiring photocoagulationtreatment can almost always be established clinically

Table 4 Characteristics of new vessels in proliferative diabetic retinopathy requiring

photo-coagulation treatment and intraretinal microvascular abnormalities not requiring treatment New vessels requiring photocoagulation Intraretinal microvascular abnormalities not

May cross their feeder vessel Do not cross their feeder vessel

Always emerge from larger venules Connect venules and arterioles

Are recursive back to venule of origin Are not recursive

Displays extensive branching Branching pattern normal

In proliferative diabetic retinopathy complicated with vitreous rhage it may be difficult to get a view of the ocular background In these casesultrasound B-scan examination is useful to establish whether the vitreousopacities are associated with retinal detachment, in which case operation willgive no benefit for vision

haemor-Treatment

Retinal Photocoagulation

Retinal photocoagulation is the only known treatment modality with a

docu-mented effect on diabetic retinopathy The treatment itself, however, may incurimpairment of vision and should therefore only be performed by ophthalmolo-gists with special interest and training within this field The mechanism of action

of retinal photocoagulation is unknown, but the effect can be achieved with anylight source that destroys the outer retinal layers after absorption in the retinalpigment epithelium Retinal photocoagulation is usually performed using theblue line of an argon laser which is mounted on a slit lamp so that treatment can

be applied through a contact glass The contact glass enables the viewing of theocular background by eliminating the corneal refraction, enables treatment ofthe retinal periphery through built-in angled mirrors, and dampens voluntary

or reflectory eye movements The treatment is done by applying burns with adistance of one burn in between but avoiding retinal vessels, and the energy ofthe burns is adjusted to produce a distinct retinal whitening

Proliferative Diabetic Retinopathy

In proliferative diabetic retinopathy, treatment should be panretinal,

mean-ing that the whole retina peripherally from the temporal arcades should be